Download Indications and usage Soliris is a complement

Indications and usage
Soliris is a complement inhibitor indicated for:
• The treatment of patients with paroxysmal nocturnal hemoglobinuria (PNH) to reduce hemolysis
• The treatment of patients with atypical hemolytic uremic syndrome (aHUS) to inhibit
complement-mediated thrombotic microangiopathy
The effectiveness of Soliris in aHUS is based on the effects on thrombotic microangiopathy (TMA) and
renal function. Prospective clinical trials in additional patients are ongoing to confirm the benefit of
Soliris in patients with aHUS.
Limitation of Use
Soliris is not indicated for the treatment of patients with Shiga toxin E. coli related hemolytic uremic
syndrome (STEC-HUS).
Adverse reactions
The most frequently reported adverse reactions in the PNH randomized trial (*10% overall and greater
than placebo) are: headache, nasopharyngitis, back pain, and nausea.
The most frequently reported adverse reactions in aHUS single arm prospective trials (*15% combined
per patient incidence) are: hypertension, upper respiratory tract infection, diarrhea,
headache, anemia, vomiting, nausea, urinary tract infection, and leukopenia.
Visit www.soliris.net/hcp or call 1.888.SOLIRIS (1.888.765.4747)
to learn more about the benefits of Soliris.
IMPORTANT SAFETY INFORMATION
WARNING: SERIOUS MENINGOCOCCAL INFECTIONS
See full prescribing information for complete boxed warning
Life-threatening and fatal meningococcal infections have occurred in patients treated
with Soliris. Meningococcal infection may become rapidly life-threatening or fatal if not
recognized and treated early.
• Comply with the most current Advisory Committee on Immunization Practices (ACIP)
recommendations for meningococcal vaccination in patients with complement deficiencies
• Immunize patients with a meningococcal vaccine at least 2 weeks prior to administering
the first dose of Soliris, unless the risks of delaying Soliris therapy outweigh the risks
of developing a meningococcal infection. (See Serious Meningococcal Infections for
additional guidance on the management of the risk of meningococcal infection.)
• Monitor patients for early signs of meningococcal infections, and evaluate immediately if
infection is suspected
Soliris is available only through a restricted program under a Risk Evaluation and Mitigation
Strategy (REMS). Under the Soliris REMS prescribers must enroll in the program.
Enrollment in the Soliris REMS program and additional information are available by
telephone: 1-888-SOLIRIS (1-888-765-4747).
Please see brief summary on following pages.
®
( e c u l i z u m a b )
®
( e c u l i z u m a b )
Concentrated solution for intravenous infusion
Brief summary—please see full prescribing information
IMPORTANT SAFETY INFORMATION
WARNING: SERIOUS MENINGOCOCCAL INFECTIONS
See full prescribing information for complete boxed warning
Life-threatening and fatal meningococcal infections have occurred
in patients treated with Soliris. Meningococcal infection may become
rapidly life-threatening or fatal if not recognized and treated early.
t$PNQMZXJUIUIFNPTUDVSSFOU"EWJTPSZ$PNNJUUFFPO*NNVOJ[BUJPO
1SBDUJDFT"$*1
SFDPNNFOEBUJPOTGPSNFOJOHPDPDDBMWBDDJOBUJPOJO
patients with complement deficiencies.
t*NNVOJ[FQBUJFOUTXJUIBNFOJOHPDPDDBMWBDDJOFBUMFBTUXFFLTQSJPS
UPBENJOJTUFSJOHUIFmSTUEPTFPG4PMJSJTVOMFTTUIFSJTLTPGEFMBZJOH
4PMJSJTUIFSBQZPVUXFJHIUIFSJTLTPGEFWFMPQJOHBNFOJOHPDPDDBM
infection. (See Serious Meningococcal Infections for additional
HVJEBODFPOUIFNBOBHFNFOUPGUIFSJTLPGNFOJOHPDPDDBMJOGFDUJPO
t.POJUPSQBUJFOUTGPSFBSMZTJHOTPGNFOJOHPDPDDBMJOGFDUJPOTBOE
evaluate immediately if infection is suspected.
4PMJSJTJTBWBJMBCMFPOMZUISPVHIBSFTUSJDUFEQSPHSBNVOEFSB3JTL
&WBMVBUJPOBOE.JUJHBUJPO4USBUFHZ3&.4
6OEFSUIF4PMJSJT3&.4
prescribers must enroll in the program. Enrollment in the Soliris
REMS program and additional information are available by telephone:
40-*3*4
INDICATIONS AND USAGE
Paroxysmal Nocturnal Hemoglobinuria (PNH)
Soliris is indicated for the treatment of patients with paroxysmal nocturnal
IFNPHMPCJOVSJB1/)
UPSFEVDFIFNPMZTJT
Atypical Hemolytic Uremic Syndrome (aHUS)
Soliris is indicated for the treatment of patients with atypical hemolytic uremic
TZOESPNFB)64
UPJOIJCJUDPNQMFNFOUNFEJBUFEUISPNCPUJDNJDSPBOHJPQBUIZ
5IF FGGFDUJWFOFTT PG 4PMJSJT JO B)64 JT CBTFE PO UIF FGGFDUT PO UISPNCPUJD
NJDSPBOHJPQBUIZ5."
BOESFOBMGVODUJPO1SPTQFDUJWFDMJOJDBMUSJBMTJOBEEJUJPOBM
QBUJFOUTBSFPOHPJOHUPDPOmSNUIFCFOFmUPG4PMJSJTJOQBUJFOUTXJUIB)64
-JNJUBUJPOPG6TF: Soliris is not indicated for the treatment of patients with Shiga
toxin E. coliSFMBUFEIFNPMZUJDVSFNJDTZOESPNF45&$)64
CONTRAINDICATIONS
Soliris is contraindicated in:
t 1BUJFOUTXJUIVOSFTPMWFETFSJPVTNeisseria meningitidis infection
t 1BUJFOUT XIP BSF OPU DVSSFOUMZ WBDDJOBUFE BHBJOTU Neisseria meningitidis,
VOMFTTUIFSJTLTPGEFMBZJOH4PMJSJTUSFBUNFOUPVUXFJHIUIFSJTLTPGEFWFMPQJOHB
meningococcal infection [see Warnings and Precautions].
WARNINGS AND PRECAUTIONS
Serious Meningococcal Infections
The use of Soliris increases a patient’s susceptibility to serious meningococcal
JOGFDUJPOT TFQUJDFNJB BOEPS NFOJOHJUJT
-JGFUISFBUFOJOH BOE GBUBM
meningococcal infections have occurred in patients treated with Soliris.
"ENJOJTUFSBQPMZWBMFOUNFOJOHPDPDDBMWBDDJOFBDDPSEJOHUPUIFNPTUDVSSFOU
"EWJTPSZ$PNNJUUFFPO*NNVOJ[BUJPO1SBDUJDFT"$*1
SFDPNNFOEBUJPOTGPS
patients with complement deficiencies. Revaccinate patients in accordance
XJUI"$*1SFDPNNFOEBUJPOTDPOTJEFSJOHUIFEVSBUJPOPG4PMJSJTUIFSBQZ
7BDDJOBUFQBUJFOUTXJUIPVUBIJTUPSZPGNFOJOHPDPDDBMWBDDJOBUJPOBUMFBTU
XFFLT QSJPS UP SFDFJWJOH UIF mSTU EPTF PG 4PMJSJT *G VSHFOU 4PMJSJT UIFSBQZ JT
indicated in an unvaccinated patient, administer the meningococcal vaccine
BTTPPOBTQPTTJCMF*ODMJOJDBMTUVEJFTQBUJFOUTXJUIB)64XFSFUSFBUFE
XJUI4PMJSJTMFTTUIBOXFFLTBGUFSNFOJOHPDPDDBMWBDDJOBUJPOBOEPGUIFTF
QBUJFOUT SFDFJWFE BOUJCJPUJDT GPS QSPQIZMBYJT PG NFOJOHPDPDDBM JOGFDUJPO
VOUJMBUMFBTUXFFLTBGUFSNFOJOHPDPDDBMWBDDJOBUJPO5IFCFOFmUTBOESJTLT
of antibiotic prophylaxis for prevention of meningococcal infections in patients
receiving Soliris have not been established.
7BDDJOBUJPO SFEVDFT CVU EPFT OPU FMJNJOBUF UIF SJTL PG NFOJOHPDPDDBM
JOGFDUJPOT *O DMJOJDBM TUVEJFT PVU PG 1/) QBUJFOUT EFWFMPQFE TFSJPVT
meningococcal infections while receiving treatment with Soliris; both had
been vaccinated [see Adverse Reactions>*ODMJOJDBMTUVEJFTBNPOHOPO1/)
QBUJFOUTNFOJOHPDPDDBMNFOJOHJUJTPDDVSSFEJOPOFVOWBDDJOBUFEQBUJFOU*O
BEEJUJPOBQSFWJPVTMZWBDDJOBUFEQBUJFOUXJUIB)64EFWFMPQFENFOJOHPDPDDBM
sepsis during the post-study follow-up period [see Adverse Reactions].
$MPTFMZ NPOJUPS QBUJFOUT GPS FBSMZ TJHOT BOE TZNQUPNT PG NFOJOHPDPDDBM
infection and evaluate patients immediately if an infection is suspected.
Meningococcal infection may become rapidly life-threatening or fatal if
not recognized and treated early. Discontinue Soliris in patients who are
undergoing treatment for serious meningococcal infections.
QBSBNFUFST NBZ JEFOUJGZ B 5." DPNQMJDBUJPO PDDVSSFODF PG UXP PS SFQFBUFE
NFBTVSFNFOUPGBOZPOFPGUIFGPMMPXJOHBEFDSFBTFJOQMBUFMFUDPVOUCZPS
NPSFDPNQBSFEUPCBTFMJOFPSUIFQFBLQMBUFMFUDPVOUEVSJOH4PMJSJTUSFBUNFOUBO
JODSFBTFJOTFSVNDSFBUJOJOFCZPSNPSFDPNQBSFEUPCBTFMJOFPSOBEJSEVSJOH
4PMJSJTUSFBUNFOUPSBOJODSFBTFJOTFSVN-%)CZPSNPSFPWFSCBTFMJOFPSOBEJS
during Soliris treatment.
*G5."DPNQMJDBUJPOTPDDVSBGUFS4PMJSJTEJTDPOUJOVBUJPODPOTJEFSSFJOTUJUVUJPOPG
Soliris treatment, plasma therapy [plasmapheresis, plasma exchange, or fresh
GSP[FOQMBTNBJOGVTJPO1&1*
>PSBQQSPQSJBUFPSHBOTQFDJmDTVQQPSUJWFNFBTVSFT
TABLE 1 (CONT.): ADVERSE REACTIONS OCCURRING IN AT LEAST 15% OF
PATIENTS LESS THAN 18 YEARS OF AGE ENROLLED IN aHUS STUDY 3
MedDRA
Number (%) of Patients
ver. 11.0
< 2 yrs
2 to < 12 yrs 12 to<18 yrs
Total
(n=5)
(n=10)
(n=4)
(n=19)
Respiratory,
Thoracic and
Mediastinal
Disorders
$PVHI
Thrombosis Prevention and Management
The effect of withdrawal of anticoagulant therapy during Soliris treatment has not /BTBMDPOHFTUJPO
been established. Therefore, treatment with Soliris should not alter anticoagulant $BSEJBD%JTPSEFST
management.
5BDIZDBSEJB
a.
Laboratory Monitoring
includes the preferred terms upper respiratory tract infection and nasopharyngitis.
PNH: Serum LDH levels increase during hemolysis and may assist in monitoring
4PMJSJT FGGFDUT JODMVEJOH UIF SFTQPOTF UP EJTDPOUJOVBUJPO PG UIFSBQZ *O DMJOJDBM Immunogenicity
studies, six patients achieved a reduction in serum LDH levels only after a decrease in "TXJUIBMMQSPUFJOTUIFSFJTBQPUFOUJBMGPSJNNVOPHFOJDJUZ5IFJNNVOPHFOJDJUZPG
UIF4PMJSJTEPTJOHJOUFSWBMGSPNUPEBZT"MMPUIFSQBUJFOUTBDIJFWFEBSFEVDUJPO Soliris has been evaluated using two different immunoassays for the detection of
JOTFSVN-%)MFWFMTXJUIUIFEBZEPTJOHJOUFSWBM<TFFClinical Pharmacology and BOUJFDVMJ[VNBCBOUJCPEJFTBEJSFDUFO[ZNFMJOLFEJNNVOPTPSCFOUBTTBZ&-*4"
using the Fab fragment of eculizumab as target was used for the PNH indication;
Clinical Studies].
B)64 &BSMZ TJHOT PG UISPNCPUJD NJDSPBOHJPQBUIZ 5."
JODMVEF B EFDSFBTF JO BOE BO FMFDUSPDIFNJMVNJOFTDFODF &$-
CSJEHJOH BTTBZ VTJOH UIF FDVMJ[VNBC
platelet count, and increases in serum LDH and creatinine levels. Follow patients for XIPMFNPMFDVMBSBTUBSHFUXBTVTFEGPSUIFB)64JOEJDBUJPO-PXUJUFSTPGBOUJCPEJFT
TJHOTPG5."CZNPOJUPSJOHTFSJBMQMBUFMFUDPVOUTTFSVN-%)BOEDSFBUJOJOFEVSJOH UP4PMJSJTXFSFEFUFDUFEJO
PGBMM1/)QBUJFOUTUSFBUFEXJUI4PMJSJTCZ
UIF&-*4"BTTBZ*OQBUJFOUTXJUIB)64USFBUFEXJUI4PMJSJTBOUJCPEJFTUP4PMJSJT
Soliris therapy and following discontinuation of Soliris.
XFSFEFUFDUFEJO
CZUIF&$-BTTBZ"O&$-CBTFEOFVUSBMJ[JOH)")"
BTTBZ XJUI B MPX TFOTJUJWJUZ PG NDHN- XBT QFSGPSNFE UP EFUFDU OFVUSBMJ[JOH
Infusion Reactions
"TXJUIBMMQSPUFJOQSPEVDUTBENJOJTUSBUJPOPG4PMJSJTNBZSFTVMUJOJOGVTJPOSFBDUJPOT BOUJCPEJFT GPS UIF QBUJFOUT XJUI B)64 /P OFVUSBMJ[JOH BDUJWJUZ UP 4PMJSJT XBT
JODMVEJOH BOBQIZMBYJT PS PUIFS IZQFSTFOTJUJWJUZ SFBDUJPOT *O DMJOJDBM USJBMT OP EFUFDUFE JO QBUJFOUT XJUI B)64 USFBUFE XJUI 4PMJSJT /P BQQBSFOU DPSSFMBUJPO PG
patients experienced an infusion reaction which required discontinuation of Soliris. antibody development to clinical response was observed in both indications. The
*OUFSSVQU4PMJSJTJOGVTJPOBOEJOTUJUVUFBQQSPQSJBUFTVQQPSUJWFNFBTVSFTJGTJHOTPG immunogenicity data reflect the percentage of patients whose test results were
DPOTJEFSFEQPTJUJWFGPSBOUJCPEJFTUP4PMJSJTJOBO&-*4"CBTFEBTTBZBOEPSBO&$-
cardiovascular instability or respiratory compromise occur.
based assay are highly dependent on the sensitivity and specificity of the assay
ADVERSE REACTIONS
VTFE"EEJUJPOBMMZUIFPCTFSWFEJODJEFODFPGBOUJCPEZQPTJUJWJUZJOUIFBTTBZNBZCF
Clinical Trial Experience
influenced by several factors including sample handling, timing of sample collection,
Meningococcal infections are the most important adverse reactions experienced concomitant medications and underlying disease. For these reasons, comparison
CZ QBUJFOUT SFDFJWJOH 4PMJSJT *O 1/) DMJOJDBM TUVEJFT UXP QBUJFOUT FYQFSJFODFE of the incidence of antibodies to Soliris with the incidence of antibodies to other
meningococcal sepsis. Both patients had previously received a meningococcal products may be misleading.
WBDDJOF*ODMJOJDBMTUVEJFTBNPOHQBUJFOUTXJUIPVU1/)NFOJOHPDPDDBMNFOJOHJUJT
occurred in one unvaccinated patient. Meningococcal sepsis occurred in one Postmarketing Experience
QSFWJPVTMZWBDDJOBUFEQBUJFOUFOSPMMFEJOUIFSFUSPTQFDUJWFB)64TUVEZEVSJOHUIF $BTFTPGTFSJPVTPSGBUBMNFOJOHPDPDDBMJOGFDUJPOTIBWFCFFOSFQPSUFE
post-study follow-up period [see Warnings and Precautions].
USE IN SPECIFIC POPULATIONS
PNH 5IF EBUB EFTDSJCFE CFMPX SFnFDU FYQPTVSF UP 4PMJSJT JO BEVMU QBUJFOUT
XJUI1/)BHFPGXIPNXFSFGFNBMF"MMIBETJHOTPSTZNQUPNTPG Pregnancy
intravascular hemolysis. Soliris was studied in a placebo-controlled clinical study (in 1SFHOBODZ$BUFHPSZ$
XIJDIQBUJFOUTSFDFJWFE4PMJSJTBOEQMBDFCP
BTJOHMFBSNDMJOJDBMTUVEZBOE There are no adequate and well-controlled studies of Soliris in pregnant women.
BMPOHUFSNFYUFOTJPOTUVEZQBUJFOUTXFSFFYQPTFEGPSHSFBUFSUIBOPOFZFBS"MM 4PMJSJTBSFDPNCJOBOU*H(NPMFDVMFIVNBOJ[FEBOUJ$BOUJCPEZ
JTFYQFDUFEUP
DSPTTUIFQMBDFOUB"OJNBMTUVEJFTVTJOHBNPVTFBOBMPHVFPGUIF4PMJSJTNPMFDVMF
patients received the recommended Soliris dose regimen.
Because clinical trials are conducted under widely varying conditions, adverse NVSJOFBOUJ$BOUJCPEZ
TIPXFEJODSFBTFESBUFTPGEFWFMPQNFOUBMBCOPSNBMJUJFT
reaction rates observed in the clinical trials of a drug cannot be directly compared BOEBOJODSFBTFESBUFPGEFBEBOENPSJCVOEPGGTQSJOHBUEPTFTUJNFTUIFIVNBO
to rates in the clinical trials of another drug and may not reflect the rates observed dose. Soliris should be used during pregnancy only if the potential benefit justifies
UIFQPUFOUJBMSJTLUPUIFGFUVT
in practice.
The most frequently reported adverse reactions in the PNH randomized trial "OJNBM SFQSPEVDUJPO TUVEJFT XFSF DPOEVDUFE JO NJDF VTJOH EPTFT PG B NVSJOF
öPWFSBMMBOEHSFBUFSUIBOQMBDFCP
BSFIFBEBDIFOBTPQIBSZOHJUJTCBDLQBJO BOUJ$BOUJCPEZUIBUBQQSPYJNBUFEUJNFTMPXEPTF
BOEUJNFTIJHIEPTF
the recommended human Soliris dose, based on a body weight comparison. When
and nausea.
animal exposure to the antibody occurred in the time period from before mating until
*OUIFQMBDFCPDPOUSPMMFEDMJOJDBMTUVEZTFSJPVTBEWFSTFSFBDUJPOTPDDVSSFEBNPOH early gestation, no decrease in fertility or reproductive performance was observed.
QBUJFOUT SFDFJWJOH 4PMJSJT BOE QBUJFOUT SFDFJWJOH QMBDFCP 5IF When maternal exposure to the antibody occurred during organogenesis, two cases
serious reactions included infections and progression of PNH. No deaths occurred PG SFUJOBM EZTQMBTJB BOE POF DBTF PG VNCJMJDBM IFSOJB XFSF PCTFSWFE BNPOH in the study and no patients receiving Soliris experienced a thrombotic event; one offspring born to mothers exposed to the higher antibody dose; however, the exposure
thrombotic event occurred in a patient receiving placebo.
did not increase fetal loss or neonatal death. When maternal exposure to the antibody
"NPOHQBUJFOUTXJUI1/)USFBUFEXJUI4PMJSJTJOUIFTJOHMFBSNDMJOJDBMTUVEZ occurred in the time period from implantation through weaning, a higher number of
or the follow-up study, the adverse reactions were similar to those reported in the NBMFPGGTQSJOHCFDBNFNPSJCVOEPSEJFEDPOUSPMTMPXEPTFHSPVQIJHI
QMBDFCPDPOUSPMMFEDMJOJDBMTUVEZ4FSJPVTBEWFSTFSFBDUJPOTPDDVSSFEBNPOHPG EPTFHSPVQ
4VSWJWJOHPGGTQSJOHIBEOPSNBMEFWFMPQNFOUBOESFQSPEVDUJWFGVODUJPO
the patients in these studies. The most common serious adverse reactions were: viral
Nursing Mothers
JOGFDUJPO
IFBEBDIF
BOFNJB
BOEQZSFYJB
B)64 5IF TBGFUZ PG 4PMJSJT UIFSBQZ JO QBUJFOUT XJUI B)64 XBT FWBMVBUFE JO UXP *U JT OPU LOPXO XIFUIFS 4PMJSJT JT FYDSFUFE JOUP IVNBO NJML *H( JT FYDSFUFE JO
QSPTQFDUJWFTJOHMFBSNTUVEJFTB)644UVEJFTBOE
BOEPOFSFUSPTQFDUJWFTUVEZ IVNBONJMLTPJUJTFYQFDUFEUIBU4PMJSJTXJMMCFQSFTFOUJOIVNBONJML)PXFWFS
B)644UVEZ
5IFEBUBEFTDSJCFECFMPXXFSFEFSJWFEGSPNBEVMUBOEBEPMFTDFOU QVCMJTIFEEBUBTVHHFTUUIBUBOUJCPEJFTJOIVNBONJMLEPOPUFOUFSUIFOFPOBUBM
QBUJFOUTXJUIB)64FOSPMMFEJOB)644UVEZBOEB)644UVEZ"MMQBUJFOUTSFDFJWFE BOEJOGBOUDJSDVMBUJPOJOTVCTUBOUJBMBNPVOUT$BVUJPOTIPVMECFFYFSDJTFEXIFO
UIFSFDPNNFOEFEEPTBHFPG4PMJSJT.FEJBOFYQPTVSFXBTXFFLTSBOHFXFFLT
4PMJSJTJTBENJOJTUFSFEUPBOVSTJOHXPNBO5IFVOLOPXOSJTLTUPUIFJOGBOUGSPN
gastrointestinal or limited systemic exposure to Soliris should be weighed against
Because clinical trials are conducted under widely varying conditions, adverse UIFLOPXOCFOFmUTPGIVNBONJMLGFFEJOH
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 Pediatric Use
in practice.
The safety and effectiveness of Soliris for the treatment of PNH in pediatric patients
5IFNPTUGSFRVFOUMZSFQPSUFEBEWFSTFSFBDUJPOTJOB)64TJOHMFBSNQSPTQFDUJWFUSJBMT below the age of 18 years have not been established.
öDPNCJOFEQFSQBUJFOUJODJEFODF
BSFIZQFSUFOTJPOVQQFSSFTQJSBUPSZUSBDU Three clinical studies assessing the safety and effectiveness of Soliris for the
infection, diarrhea, headache, anemia, vomiting, nausea, urinary tract infection, USFBUNFOUPGB)64JODMVEFEBUPUBMPGQFEJBUSJDQBUJFOUTBHFTNPOUITUP
BOEMFVLPQFOJB
ZFBST
5IFTBGFUZBOEFGGFDUJWFOFTTPG4PMJSJTGPSUIFUSFBUNFOUPGB)64BQQFBS
*OB)644UVEJFTBOEDPNCJOFE
PGQBUJFOUTFYQFSJFODFEBTFSJPVT similar in pediatric and adult patients [see Dosage and Administration, Adverse
BEWFSTFFWFOU4"&
5IFNPTUDPNNPOMZSFQPSUFE4"&TXFSFIZQFSUFOTJPO
Reactions, and Clinical Studies].
BOEJOGFDUJPOT
0OFQBUJFOUEJTDPOUJOVFE4PMJSJTEVFUPBEWFSTFFWFOUTEFFNFE "ENJOJTUFSWBDDJOBUJPOTGPSUIFQSFWFOUJPOPGJOGFDUJPOEVFUPNeisseria meningitidis,
unrelated to Soliris.
Streptococcus pneumoniae and Haemophilus influenzaUZQFC)JC
BDDPSEJOHUP"$*1
"OBMZTJTPGSFUSPTQFDUJWFMZDPMMFDUFEBEWFSTFFWFOUEBUBGSPNQFEJBUSJDBOEBEVMU guidelines [see Warnings and Precautions].
QBUJFOUTFOSPMMFEJOB)644UVEZ/
SFWFBMFEBTBGFUZQSPmMFUIBUXBTTJNJMBS
UPUIBUXIJDIXBTPCTFSWFEJOUIFUXPQSPTQFDUJWFTUVEJFTB)644UVEZJODMVEFE Geriatric Use
pediatric patients less than 18 years of age. Overall, the safety of Soliris in pediatric 4JYUFFOQBUJFOUTZFBSTPGBHFPSPMEFSXJUI1/)BOEXJUIB)64
XFSFUSFBUFE
QBUJFOUTXJUIB)64FOSPMMFEJO4UVEZBQQFBSFETJNJMBSUPUIBUPCTFSWFEJOBEVMU XJUI4PMJSJT"MUIPVHIUIFSFXFSFOPBQQBSFOUBHFSFMBUFEEJGGFSFODFTPCTFSWFEJO
QBUJFOUT5IFNPTUDPNNPOö
BEWFSTFFWFOUTPDDVSSJOHJOQFEJBUSJDQBUJFOUT UIFTFTUVEJFTUIFOVNCFSPGQBUJFOUTBHFEBOEPWFSJTOPUTVGmDJFOUUPEFUFSNJOF
whether they respond differently from younger patients.
are presented in Table 1.
Soliris REMS
#FDBVTFPGUIFSJTLPGNFOJOHPDPDDBMJOGFDUJPOT4PMJSJTJTBWBJMBCMFPOMZUISPVHIB
SFTUSJDUFEQSPHSBNVOEFSB3JTL&WBMVBUJPOBOE.JUJHBUJPO4USBUFHZ3&.4
6OEFS
the Soliris REMS, prescribers must enroll in the program.
1SFTDSJCFST NVTU DPVOTFM QBUJFOUT BCPVU UIF SJTL PG NFOJOHPDPDDBM JOGFDUJPO
provide the patients with the REMS educational materials, and ensure patients are
vaccinated with a meningococcal vaccine.
Enrollment in the Soliris REMS program and additional information are available by
Table 1: Adverse Reactions Occurring in at Least 15% of Patients Less
UFMFQIPOF40-*3*4
than 18 Years of Age Enrolled in aHUS Study 3
Other Infections
Number (%) of Patients
4PMJSJT CMPDLT UFSNJOBM DPNQMFNFOU BDUJWBUJPO UIFSFGPSF QBUJFOUT NBZ IBWF MedDRA
< 2 yrs 2 to < 12 yrs 12 to<18 yrs
Total
increased susceptibility to infections, especially with encapsulated bacteria. ver. 11.0
(n=5)
(n=10)
(n=4)
(n=19)
$IJMESFOUSFBUFEXJUI4PMJSJTNBZCFBUJODSFBTFESJTLPGEFWFMPQJOHTFSJPVTJOGFDUJPOT
due to Streptococcus pneumoniae and Haemophilus influenzaUZQFC)JC
"ENJOJTUFS General Disorders
vaccinations for the prevention of Streptococcus pneumoniae and Haemophilus and Administration
influenzaUZQFC)JC
JOGFDUJPOTBDDPSEJOHUP"$*1HVJEFMJOFT6TFDBVUJPOXIFO
Site Conditions
administering Soliris to patients with any systemic infection.
1ZSFYJB
Monitoring After Soliris Discontinuation
Gastrointestinal
Treatment Discontinuation for PNH: Monitor patients after discontinuing Soliris for at
Disorders
MFBTUXFFLTUPEFUFDUIFNPMZTJT
5SFBUNFOU%JTDPOUJOVBUJPOGPSB)64"GUFSEJTDPOUJOVJOH4PMJSJTNPOJUPSQBUJFOUT %JBSSIFB
XJUI B)64 GPS TJHOT BOE TZNQUPNT PG UISPNCPUJD NJDSPBOHJPQBUIZ 5."
7PNJUJOH
DPNQMJDBUJPOTGPSBUMFBTUXFFLT*OB)64DMJOJDBMTUVEJFTQBUJFOUTJOUIF
Infections and
QSPTQFDUJWF TUVEJFT
EJTDPOUJOVFE 4PMJSJT USFBUNFOU 5." DPNQMJDBUJPOT PDDVSSFE
GPMMPXJOHBNJTTFEEPTFJOQBUJFOUTBOE4PMJSJTXBTSFJOJUJBUFEJOPGUIFTFQBUJFOUT Infestations
$MJOJDBMTJHOTBOETZNQUPNTPG5."JODMVEFDIBOHFTJONFOUBMTUBUVTTFJ[VSFT 6QQFSSFTQJSBUPSZ
BOHJOB EZTQOFB PS UISPNCPTJT *O BEEJUJPO UIF GPMMPXJOH DIBOHFT JO MBCPSBUPSZ tract infectiona
HOW SUPPLIED/STORAGE AND HANDLING
4PMJSJTFDVMJ[VNBC
JTTVQQMJFEBTNHTJOHMFVTFWJBMTDPOUBJOJOHN-PG
mg/mL sterile, preservative-free Soliris solution per vial.
Soliris vials must be stored in the original carton until time of use under refrigerated
DPOEJUJPOTBU$'
BOEQSPUFDUFEGSPNMJHIU%POPUVTFCFZPOEUIF
expiration date stamped on the carton. Refer to Dosage and Administration (2) for
information on the stability and storage of diluted solutions of Soliris.
DO NOT FREEZE. DO NOT SHAKE.
/%$4JOHMFVOJUNHDBSUPO$POUBJOTPOF
N-WJBMPG4PMJSJT
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.BOVGBDUVSFECZ"MFYJPO1IBSNBDFVUJDBMT*OD
,OPUUFS%SJWF$IFTIJSF$564"
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Save the Date
2012 ASH STATE-OF-THE-ART
SYMPOSIUM:
Recent Advances in Hematologic Malignancies
Including a Special Focus on Thrombosis
September 28-29, 2012
Chicago, IL
Sheraton Chicago
New in
2012!
Two Dates –
Two Locations
October 12-13, 2012
Los Angeles, CA
Renaissance Hollywood Hotel
Join the experts to learn about the newest treatment
options for hematologic malignancies and thrombotic
disorders.
Program Co-Chairs:
Nancy Bartlett, MD, Washington University
Thomas Ortel, MD, PhD, Duke University
www.hematology.org/SAS
®
Navigate the uncertainty of relapsed/refractory
MCL with confidence
Count on the clear indication and proven significant PFS benefit
of TORISEL1,2
Trust in evidence1
TORISEL® Abbreviated Prescribing Information – Mantle Cell Lymphoma (MCL)
Before prescribing Torisel please refer to the full Summary of Product Characteristics.
Presentation: Torisel 30 mg concentrate and diluent for solution for infusion. Each vial of Torisel concentrate contains
30 mg temsirolimus dissolved in a total volume of 1.2 ml.
Uses: Treatment of adult patients with relapsed and/or refractory mantle cell lymphoma (MCL).
Dosage: 175mg infused over a 30 to 60 minute period once weekly for 3 weeks followed by weekly doses of 75mg, infused over a 30 to
60 minute period. To be administered under the supervision of a physician experienced in the use of antineoplastic medicinal products.
Administer an anti-histamine intravenously approximately 30 minutes before the start of each dose of temsirolimus. Treatment should
continue until the patient is no longer clinically benefiting or unacceptable toxicity occurs. Suspected adverse reactions may require
temporary interruption and/or dose reduction. The starting dose of 175mg should be reduced to 75mg and then 50mg. The continuing
dose of 75mg may be reduced to 50mg and then 25mg as necessary. In elderly, renal impairment and mild hepatic impairment patients
Temsirolimus should be used with caution but there is no specific recommended starting dose adjustment.
Contra-indications: Hypersensitivity to temsirolimus, its metabolites, polysorbate 80 and any of the excipients. Use of temsirolimus in
patients with moderate or severe hepatic impairment is not recommended.
Warnings and Precautions: The incidence and severity of adverse events is dose dependent. Patients receiving the starting dose of
175mg weekly for the treatment of MCL must be followed closely to decide on dose reductions/delays. Not recommended for paediatric
patients. Elderly patients may be more likely to experience certain adverse reactions. Use with caution in severe renal impairment patients.
Live vaccinations should be avoided. Use carefully in patients with CNS tumours and/or those receiving anticoagulation therapy due to an
increased risk of intracerebral haemorrhage. Hypersensitivity/infusion reactions including some life-threatening and rare fatal reactions
have been associated with the administration of Torisel. In all patients with severe infusion reactions, Torisel infusion should be interrupted
and appropriate medical therapy administered. Use with caution in patients with known hypersensitivity to antihistamines or in those who
cannot receive antihistamines. Torisel may be associated with an increase in blood glucose levels in diabetic and non-diabetic patients.
This may result in the need for an increase in dose of, or initiation of, insulin and/or hypoglycaemic agent therapy. Use of Torisel is
associated with increases in serum triglycerides and cholesterol. Torisel has also been associated with abnormal wound healing, so care
should be taken in the peri-operative period. Patients may be immunosuppressed and should be carefully observed for the occurrence
of infections, including opportunistic infections. Among patients receiving 175mg/week, infections were substantially increased
compared to lower doses and compared to conventional chemotherapy. Patients on temsirolimus with baseline neutropaenia may be
at risk of developing febrile neutropaenia. Grade 3/4 thrombocytopaenia has been observed. Patients on temsirolimus who develop
thrombocytopaenia may be at an increased risk of bleeding events, including epistaxis. Cases of non-specific interstitial pneumonitis,
including fatal reports, have been reported in patients receiving weekly intravenous Torisel. Patients should undergo baseline radiographic
assessment prior to the initiation of Torisel therapy. Patients should be followed closely for occurrence of clinical respiratory symptoms.
The concomitant use of Torisel with ACE inhibitors may increase the risk of angioneurotic oedema-type reactions. Torisel contains 35%
volume ethanol and this should be considered in patients suffering from alcoholism and high-risk groups, such as patients with liver
disease or epilepsy. For patients with mantle cell lymphoma, it is recommended that co-administration of CYP3A4/5 inducers should be
avoided due to the higher dose of Temsirolimus. Concomitant treatment with agents that have strong CYP3A4 inhibition potential shold
be avoided. Concomitant treatment with moderate CYP3A4 inhibitors should only be administered with caution in patients receiving 25mg
and should be avoided in patients receiving Temsiorolimus at a higher dose.
Pregnancy and Lactation: Torisel must not be used during pregnancy. Breast-feeding should be discontinued during Torisel therapy.
Interactions: CYP3A inhibitors and inducers, amphiphilic agents and ACE inhibitors.
Undesirable Effects: There have been reports of Stevens–Johnson syndrome and rhabdomyolysis in patients who received Torisel.
Very common (≥1/10): Bacterial and viral infections, Pneumonia, Urinary tract infections, Pharyngitis, Upper respiratory tract
infection, Thrombocytopaenia, Anaemia, Neutropaenia, Leucopaenia, Lymphopaenia, Hypokalaemia, Anorexia, Hyperglycaemia,
Hypercholesterolaemia, Insomnia, Anxiety, Dysgeusia, Dyspnoea, Epistaxis, Cough, Abdominal pain, Vomiting, Stomatitis, Diarrhoea,
Nausea, Rash, Pruritus, Nail disorder, Dry Skin, Back pain, Arthralgia, Myalgia, Oedema, Pyrexia, Asthenia, Mucositis, Pain, Chills.
Common (≥1/100 to <1/10): Allergic/ hypersensitivity reactions, Dehydration, Hypophosphataemia, Hyperlipaemia, Hypocalcaemia,
Depression, Paresthaesia, Dizziness, Ageusia, Conjunctivitis, Eye haemorrhage, Thrombosis, Pneumonitis, Hypertension, Bowel
perforation, Gastrointestinal haemorrhage, Gingivitis, Gastritis, Dysphagia, Acne, Moniliasis, Fungal dermatitis, Ecchymosis, Chest pain,
Blood creatinine increased, increased aspartate aminotransferase, Increased alanine aminotransferase, Sepsis, Rhinitis, Folliculitis.
Legal category: POM.
Package Quantities: Pack contains 2 x glass vials, 1 vial x 1.2ml of concentrate and 1 vial x 2.2ml of diluent.
European Marketing Authorisation number(s): EU/1/07/424/001. For full prescribing information and details of other side effects,
see Summary of Product Characteristics.
Further information is available on request from Medical Information Department at Pfizer Limited, Walton Oaks, Dorking Road, Tadworth,
Surrey, KT20 7NS, UK or from your local Pfizer office.
Date of Prescribing Information: July 2011.
Adverse events should be reported to Pfizer UK Medical Information on +44 1304 616161 or your local Pfizer office.
nd
1. Pfizer. TORISEL (temsirolimus) Summary of Product Characteristics. 2 September 2011.
2. Hess G, Herbrecht R, Romaguera J et al. Phase III study to evaluate temsirolimus compared with investigator’s choice therapy for the treatment of relapsed or refractory mantle cell lymphoma. J Clin Oncol 2009;27:3822–9.
2012 CPT-Hem 02
Date of preparation: Jan 2012
Hematologists Everywhere
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܈̅Ê̅iÊcauses and treatment of blood disorders!
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UÊÊÊDiscounted registration for all ASH meetings]ʈ˜VÕ`ˆ˜}Ê̅iÊ>˜˜Õ>Ê“iï˜}]ÊÊ
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œ“«ˆ“i˜Ì>ÀÞÊÃÕLÃVÀˆ«Ìˆœ˜ÃÊ̜Ê̅iÊ«Ài“ˆiÀʅi“>̜œ}ÞʍœÕÀ˜>]ÊÊ
Blood,Ê>˜`Ê>Ü>À`‡Üˆ˜˜ˆ˜}ʘiÜÏiÌÌiÀ] The Hematologist: ASH
News and Reports
UÊÊÊ1«`>ÌiÃʜ˜Ê̅iʏ>ÌiÃÌÊdevelopments in the fieldÊ̅ÀœÕ}…Êi‡˜iÜÏiÌÌiÀÃÊ
UÊÊʈÃVœÕ˜ÌÃʜ˜Êi`ÕV>̈œ˜>Ê«Àœ`ÕVÌÃ]ÊÃÕV…Ê>ÃÊ̅iÊASH Self-Assessment
Program (ASH-SAP)
UÊÊÊ`ۜV>VÞÊ>˜`ÊÀi«ÀiÃi˜Ì>̈œ˜ÊLivœÀiÊ̅iÊ1°-°Ê
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UÊÊÊConsult a Colleague]Ê>˜Êœ˜ˆ˜iÊÃiÀۈViÊvœÀÊ-ʓi“LiÀÃÊ̅>Ìʅi«ÃÊv>VˆˆÌ>ÌiÊÊ
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NOW ENROLLING
MCL
Clinical Trial in Mantle Cell Lymphoma
Temsirolimus | INTORFORM NCT01180049
Comparison of two doses of Temsirolimus (Torisel) in patients with relapsed mantle cell lymphoma1
Study design: Phase 4, interventional, randomized,
open-label, parallel assignment, efficacy study1
Primary endpoint: Progression-free survival (PFS)1
Secondary endpoints1,2:
Patients with
relapsed/refractory
MCL who received
2–7 prior lines
Study status: of therapy1,2*†
n=100
R
A
N
D
O
M
I
Z
A
T
I
O
N
Temsirolimus
175 mg (weekly x 3),
followed by 75 mg weekly
n=50
1:1
Temsirolimus
75 mg weekly
n=50
Selected inclusion criteria1,2:
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Please note that Temsirolimus is not approved for MCL in a number of countries, including the United States. Temsirolimus
is approved for the treatment of relapsed and/or refractory mantle cell lymphoma (MCL) in the European Union3, Serbia4,
Israel5, Australia6, Taiwan7, Philippines8 and Hong Kong9.
For more information about this trial, please visit www.clinicaltrials.gov or call 1-877-369-9753 (in the United States and
Canada) or +1-646-277-4066 (outside the United States and Canada).
*
†
Prior lines of therapy could have included hematopoietic stem cell transplant such as induction with consolidation and maintenance2.
In addition to having received these therapies, patients must have MCL that is at least one of the following2: primary and refractory to at least 2 regimens,
refractory to at least 1 regimen after first relapse, refractory or untreated after 2nd or greater relapse, refractory to first line and relapsed after 2nd line.
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© 2011 Pfizer Inc.
All rights reserved.
2011 EBT-Hem 20
Date of preparation: Sept 2011
AMERICAN SOCIETY of HEMATOLOGY
Join us in Atlanta, GA, for the
®
54th ASH Annual Meeting
and Exposition
December 8-11, 2012
INDICATION and IMPORTANT SAFETY INFORMATION for IV BUSULFEX® (busulfan) Injection
IV BUSULFEX is indicated for use in combination with cyclophosphamide
as a conditioning regimen prior to allogeneic hematopoietic progenitor
cell transplantation for chronic myelogenous leukemia.
IMPORTANT SAFETY INFORMATION
WARNING: BUSULFEX® (busulfan) Injection is a potent cytotoxic drug
that causes profound myelosuppression at the recommended dosage.
It should be administered under the supervision of a qualified physician
who is experienced in allogeneic hematopoietic stem cell transplantation,
the use of cancer chemotherapeutic drugs, and the management of
patients with severe pancytopenia. Appropriate management of therapy
and complications is only possible when adequate diagnostic and
treatment facilities are readily available. SEE “WARNINGS” SECTION OF
FULL PRESCRIBING INFORMATION FOR INFORMATION REGARDING
BUSULFAN-INDUCED PANCYTOPENIA IN HUMANS.
CONTRAINDICATIONS: Patients with a history of hypersensitivity to
BUSULFEX or any of its components.
• Hematologic—Profound myelosuppression (i.e., severe granulocytopenia, thrombocytopenia, anemia, or a combination thereof) occurred
in all patients at the recommended dosage. Frequent complete blood
counts should be monitored during treatment and until recovery.
Antibiotic therapy and platelet and red blood support should be used
when medically indicated. Patients should be monitored for signs of
local or systemic infection or bleeding.
• Neurological—Anticonvulsant prophylactic therapy should be
administered prior to treatment. Caution should be exercised in
patients with a history of seizure disorder or head trauma or who are
receiving other potentially epileptogenic drugs.
• Hepatic—Hepatic veno-occlusive disease (HVOD) was diagnosed in
8% (5/61) patients and was fatal in 40% (2/5) cases.
• Pulmonary—Bronchopulmonary dysplasia with pulmonary fibrosis is
a rare but serious condition following chronic busulfan therapy.
• Carcinogenicity, Mutagenicity, Impairment of Fertility—Busulfan
is a mutagen and a clastogen, and a presumed human carcinogen.
• Pregnancy and Nursing Mothers—Women of childbearing potential
should avoid becoming pregnant as busulfan may cause fetal harm.
• Drug Interactions—Itraconazole decreases busulfan clearance by
up to 25%. Phenytoin increases the clearance of busulfan by 15% or
more. Use of acetaminophen prior to (<72 hours) or concurrent with
BUSULFEX may result in reduced busulfan clearance.
Common non-hematologic adverse events—(incidence ≥80%): were
nausea (92% mild or moderate, 7% severe), stomatitis (71% grade 1-2,
26% grade 3-4), and vomiting (95% mild or moderate), anorexia (64%
mild or moderate, 21% severe), diarrhea (75% mild or moderate, 5%
grade 3-4), insomnia (83% mild or moderate, 1% severe), and fever
(78% mild or moderate, 3% life-threatening).
Please see brief summary of FULL PRESCRIBING INFORMATION, including Boxed WARNING, on the following pages.
© 2011 Otsuka America Pharmaceutical, Inc.
October 2011
0611A-3377
BUSULFEX® (busulfan) Injection
Rx only
Brief Summary of Prescribing Information. For complete prescribing information consult complete
package insert.
Caution: Must be diluted prior to use.
WARNING: BUSULFEX® (busulfan) Injection is a potent cytotoxic drug that causes profound
myelosuppression at the recommended dosage. It should be administered under the supervision of a
qualified physician who is experienced in allogeneic hematopoietic stem cell transplantation, the use of
cancer chemotherapeutic drugs and the management of patients with severe pancytopenia.
Appropriate management of therapy and complications is only possible when adequate diagnostic and
treatment facilities are readily available. SEE “WARNINGS” SECTION FOR INFORMATION
REGARDING BUSULFAN-INDUCED PANCYTOPENIA IN HUMANS.
INDICATIONS AND USAGE
BUSULFEX® (busulfan) Injection is indicated for use in combination with cyclophosphamide as a conditioning
regimen prior to allogeneic hematopoietic progenitor cell transplantation for chronic myelogenous leukemia.
CONTRAINDICATIONS
BUSULFEX is contraindicated in patients with a history of hypersensitivity to any of its components.
WARNINGS
BUSULFEX should be administered under the supervision of a qualified physician experienced in
hematopoietic stem cell transplantation. Appropriate management of complications arising from its
administration is possible only when adequate diagnostic and treatment facilities are readily available.
The following warnings pertain to different physiologic effects of BUSULFEX in the setting of allogeneic
transplantation.
Hematologic: The most frequent serious consequence of treatment with BUSULFEX at the recommended
dose and schedule is profound myelosuppression, occurring in all patients. Severe granulocytopenia,
thrombocytopenia, anemia, or any combination thereof may develop. Frequent complete blood counts,
including white blood cell differentials, and quantitative platelet counts should be monitored during treatment
and until recovery is achieved. Absolute neutrophil counts dropped below 0.5x10 9/L at a median of 4 days
post-transplant in 100% of patients treated in the BUSULFEX clinical trial. The absolute neutrophil count
recovered at a median of 13 days following allogeneic transplantation when prophylactic G-CSF was used in
the majority of patients. Thrombocytopenia (<25,000/mm3 or requiring platelet transfusion) occurred at a
median of 5-6 days in 98% of patients. Anemia (hemoglobin <8.0 g/dL) occurred in 69% of patients.
Antibiotic therapy and platelet and red blood cell support should be used when medically indicated.
Neurological: Seizures have been reported in patients receiving high-dose oral busulfan at doses producing
plasma drug levels similar to those achieved following the recommended dosage of BUSULFEX. Despite
prophylactic therapy with phenytoin, one seizure (1/42 patients) was reported during an autologous
transplantation clinical trial of BUSULFEX. This episode occurred during the cyclophosphamide portion of the
conditioning regimen, 36 hours after the last BUSULFEX dose. Anti-convulsant prophylactic therapy should
be initiated prior to BUSULFEX treatment. Caution should be exercised when administering the
recommended dose of BUSULFEX to patients with a history of a seizure disorder or head trauma or who are
receiving other potentially epileptogenic drugs.
Hepatic: Current literature suggests that high busulfan area under the plasma concentration verses time
curve (AUC) values (>1,500 μM•min) may be associated with an increased risk of developing hepatic venoocclusive disease (HVOD). Patients who have received prior radiation therapy, greater than or equal to three
cycles of chemotherapy, or a prior progenitor cell transplant may be at an increased risk of developing HVOD
with the recommended BUSULFEX dose and regimen. Based on clinical examination and laboratory findings,
hepatic veno-occlusive disease was diagnosed in 8% (5/61) of patients treated with BUSULFEX in the setting
of allogeneic transplantation, was fatal in 2/5 cases (40%), and yielded an overall mortality from HVOD in the
entire study population of 2/61 (3%). Three of the five patients diagnosed with HVOD were retrospectively
found to meet the Jones’ criteria. The incidence of HVOD reported in the literature from the randomized,
controlled trials (see CLINICAL STUDIES, in Full Prescribing Information) was 7.7%-12%.
Cardiac: Cardiac tamponade has been reported in pediatric patients with thalassemia (8/400 or 2% in one
series) who received high doses of oral busulfan and cyclophosphamide as the preparatory regimen for
hematopoietic progenitor cell transplantation. Six of the eight children died and two were saved by rapid
pericardiocentesis. Abdominal pain and vomiting preceded the tamponade in most patients. No patients
treated in the BUSULFEX (busulfan) Injection clinical trials experienced cardiac tamponade.
Pulmonary: Bronchopulmonary dysplasia with pulmonary fibrosis is a rare but serious complication following
chronic busulfan therapy. The average onset of symptoms is 4 years after therapy (range 4 months to 10
years).
Carcinogenicity, Mutagenicity, Impairment of Fertility:
Busulfan is a mutagen and a clastogen. In in vitro tests it caused mutations in Salmonella typhimurium and
Drosophila melanogaster. Chromosomal aberrations induced by busulfan have been reported in vivo (rats,
mice, hamsters, and humans) and in vitro (rodent and human cells). The intravenous administration of
busulfan (48 mg/kg given as biweekly doses of 12 mg/kg, or 30% of the total BUSULFEX dose on a mg/m2
basis) has been shown to increase the incidence of thymic and ovarian tumors in mice. Four cases of acute
leukemia occurred among 19 patients who became pancytopenic in a 243 patient study incorporating
busulfan as adjuvant therapy following surgical resection of bronchogenic carcinoma. Clinical appearance of
leukemia was observed 5-8 years following oral busulfan treatment. Busulfan is a presumed human
carcinogen.
Ovarian suppression and amenorrhea commonly occur in premenopausal women undergoing chronic, lowdose busulfan therapy for chronic myelogenous leukemia. Busulfan depleted oocytes of female rats. Busulfan
induced sterility in male rats and hamsters. Sterility, azoospermia and testicular atrophy have been reported
in male patients.
The solvent DMA may also impair fertility. A DMA daily dose of 0.45 g/kg/d given to rats for nine days
(equivalent to 44% of the daily dose of DMA contained in the recommended dose of BUSULFEX on a mg/m2
basis) significantly decreased spermatogenesis in rats. A single sc dose of 2.2 g/kg (27% of the total DMA
dose contained in BUSULFEX on a mg/m2 basis) four days after insemination terminated pregnancy in 100%
of tested hamsters.
Pregnancy: Busulfan may cause fetal harm when administered to a pregnant woman. Busulfan produced
teratogenic changes in the offspring of mice, rats and rabbits when given during gestation. Malformations and
anomalies included significant alterations in the musculoskeletal system, body weight gain, and size. In
pregnant rats, busulfan produced sterility in both male and female offspring due to the absence of germinal
cells in the testes and ovaries. The solvent, DMA, may also cause fetal harm when administered to a
pregnant woman. In rats, DMA doses of 400 mg/kg/d (about 40% of the daily dose of DMA in the BUSULFEX
dose on a mg/m2 basis) given during organogenesis caused significant developmental anomalies. The most
striking abnormalities included anasarca, cleft palate, vertebral anomalies, rib anomalies, and serious
anomalies of the vessels of the heart. There are no adequate and well-controlled studies of either busulfan or
DMA in pregnant women. If BUSULFEX is used during pregnancy, or if the patient becomes pregnant while
receiving BUSULFEX, the patient should be apprised of the potential hazard to the fetus. Women of
childbearing potential should be advised to avoid becoming pregnant.
PRECAUTIONS
Hematologic: At the recommended dosage of BUSULFEX (busulfan) Injection, profound myelosuppression
is universal, and can manifest as neutropenia, thrombocytopenia, anemia, or a combination thereof. Patients
should be monitored for signs of local or systemic infection or bleeding. Their hematologic status should be
evaluated frequently.
Information for Patients: The increased risk of a second malignancy should be explained to the patient.
Laboratory Tests: Patients receiving BUSULFEX should be monitored daily with a complete blood count,
including differential count and quantitative platelet count, until engraftment has been demonstrated.
To detect hepatotoxicity, which may herald the onset of hepatic veno-occlusive disease, serum
transaminases, alkaline phosphatase, and bilirubin should be evaluated daily through BMT Day +28.
Drug Interactions: Itraconazole decreases busulfan clearance by up to 25%, and may produce an AUC
>1500 μM•min in some patients. Fluconazole, and the 5-HT3 antiemetics odansetron (Zofran ®) and
granisetron (Kytril®) have all been used with BUSULFEX® (busulfan).
Phenytoin increases the clearance of busulfan by 15% or more, possibly due to the induction of glutathione-Stransferase. Since the pharmacokinetics of BUSULFEX were studied in patients treated with phenytoin, the
clearance of BUSULFEX at the recommended dose may be lower and exposure (AUC) higher in patients not
treated with phenytoin.
Because busulfan is eliminated from the body via conjugation with glutathione, use of acetaminophen prior to
(<72 hours) or concurrent with BUSULFEX may result in reduced busulfan clearance based upon the known
property of acetaminophen to decrease glutathione levels in the blood and tissues.
Pregnancy: Pregnancy Category D. See WARNINGS.
Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs are
excreted in human milk and because of the potential for tumorgenicity shown for busulfan in human and
animal studies, a decision should be made whether to discontinue nursing or to discontinue the drug, taking
into account the importance of the drug to the mother.
Special Populations
Pediatrics: The effectiveness of BUSULFEX in the treatment of CML has not been specifically studied in
pediatric patients. An open-label, uncontrolled study evaluated the pharmacokinetics of BUSULFEX in 24
pediatric patients receiving BUSULFEX as part of a conditioning regimen administered prior to hematopoietic
progenitor cell transplantation for a variety of malignant hematologic (N=15) or non-malignant diseases (N=9).
Four (17%) patients died during the study. Two patients died within 28 days of transplant; one with
pneumonia and capillary leak syndrome, and the other with pneumonia and veno-occlusive disease. Two
patients died prior to day 100; one due to progressive disease and one due to multi-organ failure.
Adverse events were reported in all 24 patients during the study period (BMT day -10 through BMT day +28)
or post-study surveillance period (day +29 through +100). These included vomiting (100%), nausea (83%),
stomatitis (79%), hepatic veno-occlusive disease (HVOD) (21%), graft-versus host disease (GVHD) (25%),
and pneumonia (21%). For additional information see Full Prescribing Information, Special Populations Pediatric section.
Instructions for Drug Administration and Blood Sample Collection for Therapeutic Drug Monitoring:
See Full Prescribing Information.
Geriatric: Five of sixty-one patients treated in the BUSULFEX clinical trial were over the age of 55 (range
57-64). All achieved myeloablation and engraftment.
Gender, Race: Adjusting BUSULFEX dosage based on gender or race has not been adequately studied.
Renal Insufficiency: BUSULFEX has not been studied in patients with renal impairment.
Hepatic Insufficiency: BUSULFEX has not been administered to patients with hepatic insufficiency.
Other: Busulfan may cause cellular dysplasia in many organs. Cytologic abnormalities characterized by
giant, hyperchromatic nuclei have been reported in lymph nodes, pancreas, thyroid, adrenal glands, liver,
lungs and bone marrow. This cytologic dysplasia may be severe enough to cause difficulty in the
interpretation of exfoliative cytologic examinations of the lungs, bladder, breast and the uterine cervix.
ADVERSE REACTIONS
Dimethylacetamide (DMA), the solvent used in the BUSULFEX formulation, was studied in 1962 as a potential
cancer chemotherapy drug. In a Phase 1 trial, the maximum tolerated dose (MTD) was 14.8 g/m 2/d for four
days. The daily recommended dose of BUSULFEX contains DMA equivalent to 42% of the MTD on a mg/m 2
basis. The dose-limiting toxicities in the Phase 1 study were hepatotoxicity as evidenced by increased liver
transaminase (SGOT) levels and neurological symptoms as evidenced by hallucinations. The hallucinations
had a pattern of onset at one day post completion of DMA administration and were associated with EEG
changes. The lowest dose at which hallucinations were recognized was equivalent to 1.9 times that delivered
in a conditioning regimen utilizing BUSULFEX 0.8 mg/kg every 6 hours x 16 doses. Other neurological
toxicities included somnolence, lethargy, and confusion. The relative contribution of DMA and/or other
concomitant medications to neurologic and hepatic toxicities observed with BUSULFEX is difficult to
ascertain.
Treatment with BUSULFEX at the recommended dose and schedule will result in profound myelosuppression
in 100% of patients, including granulocytopenia, thrombocytopenia, anemia, or a combined loss of formed
elements of the blood.
Adverse reaction information is primarily derived from the clinical study (N=61) of BUSULFEX and the data
obtained for high-dose oral busulfan conditioning in the setting of randomized, controlled trials identified
through a literature review.
BUSULFEX Clinical Trials: In the BUSULFEX (busulfan) Injection allogeneic stem cell transplantation
clinical trial, all patients were treated with BUSULFEX 0.8 mg/kg as a two-hour infusion every six hours for 16
doses over four days, combined with cyclophosphamide 60 mg/kg x 2 days. Ninety-three percent (93%) of
evaluable patients receiving this dose of BUSULFEX maintained an AUC less than 1,500 μM•min for dose 9,
which has generally been considered the level that minimizes the risk of HVOD.
Table 1: Summary of the Incidence (≥20%) of Non-Hematologic Adverse Events through BMT Day +28
in Patients who Received BUSULFEX Prior to Allogeneic Hematopoietic Progenitor Cell
Transplantation
Non-Hematological
Percent
Non-Hematological
Percent
Adverse Events*
Incidence
Adverse Events*
Incidence
METABOLIC AND
BODY AS A WHOLE
NUTRITIONAL SYSTEM
Fever
80
Hypomagnesemia
77
Headache
69
Hyperglycemia
66
Asthenia
51
Hypokalemia
64
Chills
46
Hypocalcemia
49
Pain
44
Hyperbilirubinemia
49
Edema General
28
Edema
36
Allergic Reaction
26
SGPT Elevation
31
Chest Pain
26
Creatinine Increased
21
Inflammation at Injection Site
25
NERVOUS SYSTEM
Back Pain
23
Insomnia
84
CARDIOVASCULAR SYSTEM
Anxiety
72
Tachycardia
44
Dizziness
30
Hypertension
36
Depression
23
Thrombosis
33
RESPIRATORY SYSTEM
Vasodilation
25
Rhinitis
44
DIGESTIVE SYSTEM
Lung Disorder
34
Nausea
98
Cough
28
Stomatitis (Mucositis)
97
Epistaxis
25
Vomiting
95
Dyspnea
25
Anorexia
85
SKIN AND APPENDAGES
Diarrhea
84
Rash
57
Abdominal Pain
72
Pruritus
28
Dyspepsia
44
Constipation
38
Dry Mouth
26
Rectal Disorder
25
Abdominal Enlargement
23
*Includes all reported adverse events regardless of severity (toxicity grades 1-4)
The following sections describe clinically significant events occurring in the BUSULFEX® (busulfan) clinical
trials, regardless of drug attribution. For pediatric information, see Special Populations – Pediatric section.
Hematologic: At the indicated dose and schedule, BUSULFEX produced profound myelosuppression in
100% of patients. Following hematopoietic progenitor cell infusion, recovery of neutrophil counts to
≥500 cells/mm3 occurred at median day 13 when prophylactic G-CSF was administered to the majority of
participants on the study. The median number of platelet transfusions per patient on study was 6, and the
median number of red blood cell transfusions on study was 4. Prolonged prothrombin time was reported in
one patient (2%).
Gastrointestinal: Gastrointestinal toxicities were frequent and generally considered to be related to the drug.
Few were categorized as serious. Mild or moderate nausea occurred in 92% of patients in the allogeneic
clinical trial, and mild or moderate vomiting occurred in 95% through BMT Day +28; nausea was severe in
7%. The incidence of vomiting during BUSULFEX administration (BMT Day –7 to –4) was 43% in the
allogeneic clinical trial. Grade 3-4 stomatitis developed in 26% of the participants, and Grade 3 esophagitis
developed in 2%. Grade 3-4 diarrhea was reported in 5% of the allogeneic study participants, while mild or
moderate diarrhea occurred in 75%. Mild or moderate constipation occurred in 38% of patients; ileus
developed in 8% and was severe in 2%. Forty-four percent (44%) of patients reported mild or moderate
dyspepsia. Two percent (2%) of patients experienced mild hematemesis. Pancreatitis developed in 2% of
patients. Mild or moderate rectal discomfort occurred in 24% of patients. Severe anorexia occurred in 21% of
patients and was mild/moderate in 64%.
Hepatic: Hyperbilirubinemia occurred in 49% of patients in the allogeneic BMT trial. Grade 3/4
hyperbilirubinemia occurred in 30% of patients within 28 days of transplantation and was considered lifethreatening in 5% of these patients. Hyperbilirubinemia was associated with graft-versus-host disease in six
patients and with hepatic veno-occlusive disease in 5 patients. Grade 3/4 SGPT elevations occurred in 7% of
patients. Alkaline phosphatase increases were mild or moderate in 15% of patients. Mild or moderate
jaundice developed in 12% of patients, and mild or moderate hepatomegaly developed in 6%.
Hepatic veno-occlusive disease: Hepatic veno-occlusive disease (HVOD) is a recognized potential
complication of conditioning therapy prior to transplant. Based on clinical examination and laboratory findings,
hepatic veno-occlusive disease was diagnosed in 8% (5/61) of patients treated with BUSULFEX in the setting
of allogeneic transplantation, was fatal in 2/5 cases (40%), and yielded an overall mortality from HVOD in the
entire study population of 2/61 (3%). Three of the five patients diagnosed with HVOD were retrospectively
found to meet the Jones’ criteria.
Graft-versus-host disease: Graft-versus-host disease developed in 18% of patients (11/61) receiving
allogeneic transplants; it was severe in 3%, and mild or moderate in 15%. There were 3 deaths (5%)
attributed to GVHD.
Edema: Patients receiving allogeneic transplant exhibited some form of edema (79%), hypervolemia, or
documented weight increase (8%); all events were reported as mild or moderate.
Infection/Fever: Fifty-one percent (51%) of patients experienced one or more episodes of infection.
Pneumonia was fatal in one patient (2%) and life-threatening in 3% of patients. Fever was reported in 80% of
patients; it was mild or moderate in 78% and severe in 3%. Forty-six percent (46%) of patients experienced
chills.
Cardiovascular: Mild or moderate tachycardia was reported in 44% of patients. In 7 patients (11%) it was
first reported during BUSULFEX administration. Other rhythm abnormalities, which were all mild or moderate,
included arrhythmia (5%), atrial fibrillation (2%), ventricular extrasystoles (2%), and third degree heart block
(2%). Mild or moderate thrombosis occurred in 33% of patients, and all episodes were associated with the
central venous catheter. Hypertension was reported in 36% of patients and was Grade 3/4 in 7%.
Hypotension occurred in 11% of patients and was Grade 3/4 in 3%. Mild vasodilation (flushing and hot
flashes) was reported in 25% of patients. Other cardiovascular events included cardiomegaly (5%), mild ECG
abnormality (2%), Grade 3/4 left-sided heart failure in one patient (2%), and moderate pericardial effusion
(2%). These events were reported primarily in the post-cyclophosphamide phase.
Pulmonary: Mild or moderate dyspnea occurred in 25% of patients and was severe in 2%. One patient (2%)
experienced severe hyperventilation; and in 2 (3%) additional patients it was mild or moderate. Mild rhinitis
and mild or moderate cough were reported in 44% and 28% of patients, respectively. Mild epistaxis events
were reported in 25%. Three patients (5%) on the allogeneic study developed documented alveolar
hemorrhage. All required mechanical ventilatory support and all died. Non-specific interstitial fibrosis was
found on wedge biopsies performed with video assisted thoracoscopy in one patient on the allogeneic study
who subsequently died from respiratory failure on BMT Day +98. Other pulmonary events, reported as mild or
moderate, included pharyngitis (18%), hiccup (18%), asthma (8%), atelectasis (2%), pleural effusion (3%),
hypoxia (2%), hemoptysis (3%), and sinusitis (3%).
Neurologic: The most commonly reported adverse events of the central nervous system were insomnia
(84%), anxiety (75%), dizziness (30%), and depression (23%). Severity was mild or moderate except for one
patient (1%) who experienced severe insomnia. One patient (1%) developed a life-threatening cerebral
hemorrhage and a coma as a terminal event following multi-organ failure after HVOD. Other events
considered severe included delirium (2%), agitation (2%), and encephalopathy (2%). The overall incidence of
confusion was 11%, and 5% of patients were reported to have experienced hallucinations. The patient who
developed delirium and hallucination on the allogeneic study had onset of confusion at the completion of
BUSULFEX (busulfan) Injection. The overall incidence of lethargy in the allogeneic BUSULFEX clinical trial
was 7%, and somnolence was reported in 2%. One patient (2%) treated in an autologous transplantation
study experienced a seizure while receiving cyclophosphamide, despite prophylactic treatment with
phenytoin.
Renal: Creatinine was mildly or moderately elevated in 21% of patients. BUN was increased in 3% of
patients and to a Grade 3/4 level in 2%. Seven percent of patients experienced dysuria, 15% oliguria, and 8%
hematuria. There were 4 (7%) Grade 3/4 cases of hemorrhagic cystitis in the allogeneic clinical trial.
Skin: Rash (57%) and pruritus (28%) were reported; both conditions were predominantly mild. Alopecia was
mild in 15% of patients and moderate in 2%. Mild vesicular rash was reported in 10% of patients and mild or
moderate maculopapular rash in 8%. Vesiculo-bullous rash was reported in 10%, and exfoliative dermatitis in
5%. Erythema nodosum was reported in 2%, acne in 7%, and skin discoloration in 8%.
Metabolic: Hyperglycemia was observed in 67% of patients and Grade 3/4 hyperglycemia was reported in
15%. Hypomagnesemia was mild or moderate in 77% of patients; hypokalemia was mild or moderate in 62%
and severe in 2%; hypocalcemia was mild or moderate in 46% and severe in 3%; hypophosphatemia was
mild or moderate in 17%; and hyponatremia was reported in 2%.
Other: Other reported events included headache (mild or moderate 64%, severe 5%), abdominal pain (mild
or moderate 69%, severe 3%), asthenia (mild or moderate 49%, severe 2%), unspecified pain (mild or
moderate 43%, severe 2%), allergic reaction (mild or moderate 24%, severe 2%), injection site inflammation
(mild or moderate 25%), injection site pain (mild or moderate 15%), chest pain (mild or moderate 26%), back
pain (mild or moderate 23%), myalgia (mild or moderate 16%), arthralgia (mild or moderate 13%), and ear
disorder in 3%.
Deaths: There were two deaths through BMT Day +28 in the allogeneic transplant setting. There were an
additional six deaths BMT Day +29 through BMT Day +100 in the allogeneic transplant setting.
Post-Marketing Experience: The following adverse reactions (reported as MedRA terms) have been
identified during post-approval use of BUSULFEX (busulfan) Injection: febrile neutropenia; tumor lysis
syndrome; thrombotic micro-angiopathy (TMA); severe bacterial, viral (e.g., cytomegalovirus viraemia) and
fungal infections; and sepsis. Because these reactions are reported voluntarily from a population of uncertain
size, it is not always possible to establish a causal relationship to drug exposure.
Oral Busulfan Literature Review: A literature review identified four randomized, controlled trials that
evaluated a high-dose oral busulfan-containing conditioning regimen for allogeneic bone marrow
transplantation in the setting of CML (see CLINICAL STUDIES, in Full prescribing Information). The safety
outcomes reported in those trials are summarized in Table 2 below for a mixed population of hematological
malignancies (AML, CML, and ALL).
Table 2: Summary of safety analyses from the randomized, controlled trials utilizing a high dose oral
busulfan-containing conditioning regimen that were identified in a literature review.
TRM*
Death≤100d
=4.1%
(3/73)
Clift : CML Chronic Phase
GVHD***
Pulmonary
VOD**
Acute≥Grade 2
=35%
Chronic=41%
(30/73)
No Report
1 death from
Idiopathic
Interstitial
Pneumonitis
And
1 death from
Pulmonary
Fibrosis
Hemorrhagic
Cystitis
Seizure
No Report
No Report
Hemorrhagic
Cystitis
Seizure
10.8%
(7/65)
No report
Devergie: CML Chronic Phase
TRM
VOD
GVHD
Pulmonary
Interstitial
Acute≥Grade 2
Pneumonitis
=41%
=16.9%
(24/59 at risk)
(11/65)
Ringden: CML, AML, ALL
38%
7.7% (5/65)
Deaths=4.6%
(3/65)
TRM
VOD
GVHD
Pulmonary
Hemorrhagic
Cystitis
Seizure
28%
12%
Acute≥Grade 2
=26%
Chronic=45%
Interstitial
Pneumonitis
=14%
24%
6%
TRM
VOD
Blume: CML, AML, ALL
No Report
Deaths=4.9%
GVHD
Pulmonary
Hemorrhagic
Cystitis
Seizure
Acute≥Grade 2
=22%
(13/58 at risk)
Chronic=31%
(14/45 at risk)
No Report
No Report
No Report
*TRM = Transplantation Related Mortality
**VOD = Veno-Occlusive Disease of the liver
***GVHD = Graft versus Host Disease
OVERDOSAGE
There is no known antidote to BUSULFEX® (busulfan) other than hematopoietic progenitor cell
transplantation. In the absence of hematopoietic progenitor cell transplantation, the recommended dosage for
BUSULFEX would constitute an overdose of busulfan. The principal toxic effect is profound bone marrow
hypoplasia/aplasia and pancytopenia, but the central nervous system, liver, lungs, and gastrointestinal tract
may be affected. The hematologic status should be closely monitored and vigorous supportive measures
instituted as medically indicated. Survival after a single 140 mg dose of Myleran ® Tablets in an 18 kg, 4-year
old child has been reported. Inadvertent administration of a greater than normal dose of oral busulfan
(2.1 mg/kg; total dose of 23.3 mg/kg) occurred in a 2-year old child prior to a scheduled bone marrow
transplant without sequelae. An acute dose of 2.4 g was fatal in a 10-year old boy. There is one report that
busulfan is dialyzable, thus dialysis should be considered in the case of overdose. Busulfan is metabolized by
conjugation with glutathione, thus administration of glutathione may be considered.
Distributed and Marketed by:
Otsuka America Pharmaceutical, Inc.
Rockville, MD 20850
Manufactured by:
Ben Venue Labs, Inc.
Bedford, OH 44146
Part No. 06US11L-0497B
Revision Date: April 2011
© 2011 Otsuka Pharmaceutical Co., Ltd., Tokyo, 101-8535 Japan
For questions of a medical nature call 1-800-438-6141, select option 2.
TREANDA® is her chemo.
This is her therapy.
Single-agent TREANDA tripled median PFS in patients with CLL*
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Modifications to IWG-RC specified that persistently positive bone marrow in patients who met all other criteria for complete
response (CR) would be scored as partial response (PR). Bone marrow sample lengths were not required to be ≥20 mm.
s)N SINGLEARM STUDIES OF PATIENTS WITH INDOLENT "CELL
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Important Safety Information
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LEARN MORE AT WWW.TREANDA.COM
Please see accompanying brief summary of full Prescribing Information.
Oncology
¥#EPHALON)NCISAWHOLLYOWNEDSUBSIDIARYOF4EVA0HARMACEUTICAL)NDUSTRIES,TD
!LLRIGHTSRESERVED42%.OVEMBER
Built for Action®
Brief Summary of Prescribing Information
INDICATIONS AND USAGE: TREANDA is indicated for the treatment of patients with chronic lymphocytic
leukemia (CLL). Efficacy relative to first line therapies other than chlorambucil has not been established.
TREANDA for Injection is indicated for the treatment of patients with indolent B-cell non-Hodgkin’s
lymphoma (NHL) that has progressed during or within six months of treatment with rituximab or a
rituximab-containing regimen.
CONTRAINDICATIONS: TREANDA is contraindicated in patients with a known hypersensitivity
(eg, anaphylactic and anaphylactoid reactions) to bendamustine or mannitol. [See Warnings and
Precautions]
WARNINGS AND PRECAUTIONS: Myelosuppression. Patients treated with TREANDA are likely to
experience myelosuppression. In the two NHL studies, 98% of patients had Grade 3-4 myelosuppression.
Three patients (2%) died from myelosuppression-related adverse reactions; one each from neutropenic
sepsis, diffuse alveolar hemorrhage with Grade 3 thrombocytopenia, and pneumonia from an
opportunistic infection (CMV). In the event of treatment-related myelosuppression, monitor leukocytes,
platelets, hemoglobin (Hgb), and neutrophils closely. In the clinical trials, blood counts were monitored
every week initially. Hematologic nadirs were observed predominantly in the third week of therapy.
Hematologic nadirs may require dose delays if recovery to the recommended values have not occurred
by the first day of the next scheduled cycle. Prior to the initiation of the next cycle of therapy, the ANC
should be ≥ 1 x 109/L and the platelet count should be ≥ 75 x 109/L. [See Dosage and Administration].
Infections. Infection, including pneumonia and sepsis, has been reported in patients in clinical trials
and in post-marketing reports. Infection has been associated with hospitalization, septic shock and
death. Patients with myelosuppression following treatment with TREANDA are more susceptible to
infections. Patients with myelosuppression following TREANDA treatment should be advised to contact
a physician if they have symptoms or signs of infection. Infusion Reactions and Anaphylaxis. Infusion
reactions to TREANDA have occurred commonly in clinical trials. Symptoms include fever, chills,
pruritus and rash. In rare instances severe anaphylactic and anaphylactoid reactions have occurred,
particularly in the second and subsequent cycles of therapy. Monitor clinically and discontinue drug
for severe reactions. Patients should be asked about symptoms suggestive of infusion reactions after
their first cycle of therapy. Patients who experienced Grade 3 or worse allergic-type reactions were not
typically rechallenged. Measures to prevent severe reactions, including antihistamines, antipyretics and
corticosteroids should be considered in subsequent cycles in patients who have previously
experienced Grade 1 or 2 infusion reactions. Discontinuation should be considered in patients with
Grade 3 or 4 infusion reactions. Tumor Lysis Syndrome. Tumor lysis syndrome associated with
TREANDA treatment has been reported in patients in clinical trials and in post-marketing reports. The
onset tends to be within the first treatment cycle of TREANDA and, without intervention, may lead to
acute renal failure and death. Preventive measures include maintaining adequate volume status, and
close monitoring of blood chemistry, particularly potassium and uric acid levels. Allopurinol has also
been used during the beginning of TREANDA therapy. However, there may be an increased risk of
severe skin toxicity when TREANDA and allopurinol are administered concomitantly. Skin Reactions.
A number of skin reactions have been reported in clinical trials and post-marketing safety reports.
These events have included rash, toxic skin reactions and bullous exanthema. Some events occurred
when TREANDA was given in combination with other anticancer agents, so the precise relationship
to TREANDA is uncertain. In a study of TREANDA (90 mg/m2) in combination with rituximab, one case
of toxic epidermal necrolysis (TEN) occurred. TEN has been reported for rituximab (see rituximab
package insert). Cases of Stevens-Johnson syndrome (SJS) and TEN, some fatal, have been reported
when TREANDA was administered concomitantly with allopurinol and other medications known to
cause these syndromes. The relationship to TREANDA cannot be determined. Where skin reactions
occur, they may be progressive and increase in severity with further treatment. Therefore, patients
with skin reactions should be monitored closely. If skin reactions are severe or progressive, TREANDA
should be withheld or discontinued. Other Malignancies. There are reports of pre-malignant and
malignant diseases that have developed in patients who have been treated with TREANDA, including
myelodysplastic syndrome, myeloproliferative disorders, acute myeloid leukemia and bronchial
carcinoma. The association with TREANDA therapy has not been determined. Extravasation. There
are postmarketing reports of bendamustine extravasations resulting in hospitalizations from
erythema, marked swelling, and pain. Precautions should be taken to avoid extravasations, including
monitoring of the intravenous infusion site for redness, swelling, pain, infection, and necrosis during
and after administration of TREANDA. Use in Pregnancy. TREANDA can cause fetal harm when
administered to a pregnant woman. Single intraperitoneal doses of bendamustine in mice and rats
administered during organogenesis caused an increase in resorptions, skeletal and visceral
malformations, and decreased fetal body weights.
ADVERSE REACTIONS: The data described below reflect exposure to TREANDA in 349 patients who
participated in an actively-controlled trial (N=153) for the treatment of CLL and two single-arm
studies (N=176) for the treatment of indolent B-cell NHL. 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 practice. The following serious adverse reactions have been associated with TREANDA
in clinical trials and are discussed in greater detail in other sections [See Warnings and
Precautions] of the label: Myelosuppression; Infections; Infusion Reactions and Anaphylaxis;
Tumor Lysis Syndrome; Skin Reactions; Other Malignancies. Clinical Trials Experience in CLL.
The data described below reflect exposure to TREANDA in 153 patients. TREANDA was studied in
an active-controlled trial. The population was 45-77 years of age, 63% male, 100% white, and had
treatment naïve CLL. All patients started the study at a dose of 100 mg/m2 intravenously over 30
minutes on days 1 and 2 every 28 days. Adverse reactions were reported according to NCI CTC
v.2.0. In the randomized CLL clinical study, non-hematologic adverse reactions (any grade) in the
TREANDA group that occurred with a frequency greater than 15% were pyrexia (24%), nausea
(20%), and vomiting (16%). Other adverse reactions seen frequently in one or more studies
included asthenia, fatigue, malaise, and weakness; dry mouth; somnolence; cough; constipation;
headache; mucosal inflammation; and stomatitis. Worsening hypertension was reported in 4
patients treated with TREANDA in the randomized CLL clinical study and none treated with
chlorambucil. Three of these 4 adverse reactions were described as a hypertensive crisis and were
managed with oral medications and resolved. The most frequent adverse reactions leading to study
withdrawal for patients receiving TREANDA were hypersensitivity (2%) and pyrexia (1%). Table 1
contains the treatment emergent adverse reactions, regardless of attribution, that were reported in
≥ 5% of patients in either treatment group in the randomized CLL clinical study.
Table 1: Non-Hematologic Adverse Reactions Occurring in Randomized CLL Clinical Study in
at Least 5% of Patients
Number (%) of patients
TREANDA
Chlorambucil
(N=153)
(N=143)
System organ class
Preferred term
All Grades Grade 3/4
All Grades
Grade 3/4
Total number of patients with at
least 1 adverse reaction
121 (79)
52 (34)
96 (67)
25 (17)
Gastrointestinal disorders
Nausea
31 (20)
1 (<1)
21 (15)
1 (<1)
Vomiting
24 (16)
1 (<1)
9 (6)
0
Diarrhea
14 (9)
2 (1)
5 (3)
0
Table 1: Non-Hematologic Adverse Reactions Occurring in Randomized CLL Clinical Study
in at Least 5% of Patients (continued)
Number (%) of patients
TREANDA
Chlorambucil
(N=153)
(N=143)
System organ class
Preferred term
All Grades
Grade 3/4 All Grades Grade 3/4
General disorders and administration
site conditions
Pyrexia
36 (24)
6 (4)
8 (6)
2 (1)
Fatigue
14 (9)
2 (1)
8 (6)
0
Asthenia
13 (8)
0
6 (4)
0
Chills
9 (6)
0
1 (<1)
0
Immune system disorders
Hypersensitivity
7 (5)
2 (1)
3 (2)
0
Infections and infestations
Nasopharyngitis
10 (7)
0
12 (8)
0
Infection
9 (6)
3 (2)
1 (<1)
1 (<1)
Herpes simplex
5 (3)
0
7 (5)
0
Investigations
Weight decreased
11 (7)
0
5 (3)
0
Metabolism and nutrition disorders
Hyperuricemia
11 (7)
3 (2)
2 (1)
0
Respiratory, thoracic and
mediastinal disorders
Cough
6 (4)
1 (<1)
7 (5)
1 (<1)
Skin and subcutaneous tissue disorders
Rash
12 (8)
4 (3)
7 (5)
3 (2)
Pruritus
8 (5)
0
2 (1)
0
The Grade 3 and 4 hematology laboratory test values by treatment group in the randomized CLL
clinical study are described in Table 2. These findings confirm the myelosuppressive effects seen
in patients treated with TREANDA. Red blood cell transfusions were administered to 20% of
patients receiving TREANDA compared with 6% of patients receiving chlorambucil.
Table 2: Incidence of Hematology Laboratory Abnormalities in Patients Who Received
TREANDA or Chlorambucil in the Randomized CLL Clinical Study
Laboratory Abnormality
Hemoglobin Decreased
Platelets Decreased
Leukocytes Decreased
Lymphocytes Decreased
Neutrophils Decreased
TREANDA
(N=150)
All Grades
Grade 3/4
n (%)
n (%)
134 (89)
20 (13)
116 (77)
16 (11)
92 (61)
42 (28)
102 (68)
70 (47)
113 (75)
65 (43)
Chlorambucil
(N=141)
All Grades
Grade 3/4
n (%)
n (%)
115 (82)
12 (9)
110 (78)
14 (10)
26 (18)
4 (3)
27 (19)
6 (4)
86 (61)
30 (21)
In the randomized CLL clinical study, 34% of patients had bilirubin elevations, some without
associated significant elevations in AST and ALT. Grade 3 or 4 increased bilirubin occurred in 3% of
patients. Increases in AST and ALT of Grade 3 or 4 were limited to 1% and 3% of patients,
respectively. Patients treated with TREANDA may also have changes in their creatinine levels. If
abnormalities are detected, monitoring of these parameters should be continued to ensure that
significant deterioration does not occur. Clinical Trials Experience in NHL. The data described
below reflect exposure to TREANDA in 176 patients with indolent B-cell NHL treated in two singlearm studies. The population was 31-84 years of age, 60% male, and 40% female. The race
distribution was 89% White, 7% Black, 3% Hispanic, 1% other, and <1% Asian. These patients
received TREANDA at a dose of 120 mg/m2 intravenously on Days 1 and 2 for up to 8 21-day cycles.
The adverse reactions occurring in at least 5% of the NHL patients, regardless of severity, are
shown in Table 3. The most common non-hematologic adverse reactions (≥30%) were nausea
(75%), fatigue (57%), vomiting (40%), diarrhea (37%) and pyrexia (34%). The most common
non-hematologic Grade 3 or 4 adverse reactions (≥5%) were fatigue (11%), febrile neutropenia
(6%), and pneumonia, hypokalemia and dehydration, each reported in 5% of patients.
Table 3: Non-Hematologic Adverse Reactions Occurring in at Least 5% of NHL Patients
Treated With TREANDA by System Organ Class and Preferred Term (N=176)
System organ class
Preferred term
Total number of patients with
at least 1 adverse reaction
Cardiac disorders
Tachycardia
Gastrointestinal disorders
Nausea
Vomiting
Diarrhea
Constipation
Stomatitis
Abdominal pain
Dyspepsia
Gastroesophageal reflux disease
Dry mouth
Abdominal pain upper
Abdominal distension
General disorders and administration
site conditions
Fatigue
Pyrexia
Chills
Edema peripheral
Asthenia
Chest pain
Infusion site pain
Pain
Catheter site pain
Number (%) of patients*
All Grades
Grade 3/4
176 (100)
94 (53)
13 (7)
0
132 (75)
71 (40)
65 (37)
51 (29)
27 (15)
22 (13)
20 (11)
18 (10)
15 (9)
8 (5)
8 (5)
7 (4)
5 (3)
6 (3)
1 (<1)
1 (<1)
2 (1)
0
0
1 (<1)
0
0
101 (57)
59 (34)
24 (14)
23 (13)
19 (11)
11 (6)
11 (6)
10 (6)
8 (5)
19 (11)
3 (2)
0
1 (<1)
4 (2)
1 (<1)
0
0
0
Table 3: Non-Hematologic Adverse Reactions Occurring in at Least 5% of NHL Patients
Treated With TREANDA by System Organ Class and Preferred Term (N=176)
(continued)
System organ class
Number (%) of patients*
Preferred term
All Grades
Grade 3/4
Infections and infestations
Herpes zoster
18 (10)
5 (3)
Upper respiratory tract infection
18 (10)
0
Urinary tract infection
17 (10)
4 (2)
Sinusitis
15 (9)
0
Pneumonia
14 (8)
9 (5)
Febrile Neutropenia
11 (6)
11 (6)
Oral Candidiasis
11 (6)
2 (1)
Nasopharyngitis
11 (6)
0
Investigations
Weight decreased
31 (18)
3 (2)
Metabolism and nutrition disorders
Anorexia
40 (23)
3 (2)
Dehydration
24 (14)
8 (5)
Decreased appetite
22 (13)
1 (<1)
Hypokalemia
15 (9)
9 (5)
Musculoskeletal and connective tissue disorders
Back pain
25 (14)
5 (3)
Arthralgia
11 (6)
0
Pain in extremity
8 (5)
2 (1)
Bone pain
8 (5)
0
Nervous system disorders
Headache
36 (21)
0
Dizziness
25 (14)
0
Dysgeusia
13 (7)
0
Psychiatric disorders
Insomnia
23 (13)
0
Anxiety
14 (8)
1 (<1)
Depression
10 (6)
0
Respiratory, thoracic and mediastinal disorders
Cough
38 (22)
1 (<1)
Dyspnea
28 (16)
3 (2)
Pharyngolaryngeal pain
14 (8)
1 (<1)
Wheezing
8 (5)
0
Nasal congestion
8 (5)
0
Skin and subcutaneous tissue disorders
Rash
28 (16)
1 (<1)
Pruritus
11 (6)
0
Dry skin
9 (5)
0
Night sweats
9 (5)
0
Hyperhidrosis
8 (5)
0
Vascular disorders
Hypotension
10 (6)
2 (1)
*Patients may have reported more than 1 adverse reaction.
NOTE: Patients counted only once in each preferred term category and once in each system
organ class category.
Hematologic toxicities, based on laboratory values and CTC grade, in NHL patients treated in both
single arm studies combined are described in Table 4. Clinically important chemistry laboratory
values that were new or worsened from baseline and occurred in >1% of patients at grade 3 or 4,
in NHL patients treated in both single arm studies combined were hyperglycemia (3%), elevated
creatinine (2%), hyponatremia (2%), and hypocalcemia (2%).
Table 4: Incidence of Hematology Laboratory Abnormalities in Patients Who Received
TREANDA in the NHL Studies
Percent of patients
All Grades
Grade 3/4
99
94
94
56
88
11
86
60
86
25
Hematology Variable
Lymphocytes Decreased
Leukocytes Decreased
Hemoglobin Decreased
Neutrophils Decreased
Platelets Decreased
TREANDA administration should be delayed in the event of Grade 4 hematologic toxicity or
clinically significant ≥ Grade 2 non-hematologic toxicity. Once non-hematologic toxicity has
recovered to ≤ Grade 1 and/or the blood counts have improved [Absolute Neutrophil Count (ANC)
≥ 1 x 109/L, platelets ≥ 75 x 109/L], TREANDA can be reinitiated at the discretion of the treating
physician. In addition, dose reduction may be warranted. [See Warnings and Precautions] Dose
modifications for hematologic toxicity: for Grade 3 or greater toxicity, reduce the dose to
50 mg/m2 on Days 1 and 2 of each cycle; if Grade 3 or greater toxicity recurs, reduce the dose to
25 mg/m2 on Days 1 and 2 of each cycle. Dose modifications for non-hematologic toxicity: for
clinically significant Grade 3 or greater toxicity, reduce the dose to 50 mg/m2 on Days 1 and 2 of
each cycle. Dose re-escalation in subsequent cycles may be considered at the discretion of the
treating physician. Dosing Instructions for NHL. Recommended Dosage: The recommended dose
is 120 mg/m2 administered intravenously over 60 minutes on Days 1 and 2 of a 21-day cycle, up
to 8 cycles. Dose Delays, Dose Modifications and Reinitiation of Therapy for NHL: TREANDA
administration should be delayed in the event of a Grade 4 hematologic toxicity or clinically
significant ≥ Grade 2 non-hematologic toxicity. Once non-hematologic toxicity has recovered to
≤ Grade 1 and/or the blood counts have improved [Absolute Neutrophil Count (ANC) ≥ 1 x 109/L,
platelets ≥ 75 x 109/L], TREANDA can be reinitiated at the discretion of the treating physician. In
addition, dose reduction may be warranted. [See Warnings and Precautions] Dose modifications
for hematologic toxicity: for Grade 4 toxicity, reduce the dose to 90 mg/m2 on Days 1 and 2 of each
cycle; if Grade 4 toxicity recurs, reduce the dose to 60 mg/m2 on Days 1 and 2 of each cycle. Dose
modifications for non-hematologic toxicity: for Grade 3 or greater toxicity, reduce the dose to
90 mg/m2 on Days 1 and 2 of each cycle; if Grade 3 or greater toxicity recurs, reduce the dose to
60 mg/m2 on Days 1 and 2 of each cycle. Reconstitution/Preparation for Intravenous Administration.
M D6AE:42==JC64@?DE:EFE66249,*&G:2=2D7@==@HDM>8,*&G:2=55>$@7@?=J
Sterile Water for Injection, USP M >8 ,*& G:2= 55 >$ @7 @?=J Sterile Water for
Injection, USP. Shake well to yield a clear, colorless to a pale yellow solution with a bendamustine
HCl concentration of 5 mg/mL. The lyophilized powder should completely dissolve in 5 minutes. If
particulate matter is observed, the reconstituted product should not be used.
MD6AE:42==JH:E95C2HE96G@=F>6?665657@CE96C6BF:C655@D632D65@?>8
>$4@?46?EC2E:@?
and immediately transfer to a 500 mL infusion bag of 0.9% Sodium Chloride Injection, USP
(normal saline). As an alternative to 0.9% Sodium Chloride Injection, USP (normal saline), a 500
mL infusion bag of 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, may be considered. The
resulting final concentration of bendamustine HCl in the infusion bag should be within 0.2–0.6 mg/
mL. The reconstituted solution must be transferred to the infusion bag within 30 minutes of
reconstitution. After transferring, thoroughly mix the contents of the infusion bag. The admixture
D9@F=53624=62C2?54@=@C=6DDE@D=:89E=JJ6==@HD@=FE:@?M-D6+E6C:=6/2E6C7@C"?;64E:@?-+(
for reconstitution and then either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45%
Sodium Chloride Injection, USP, for dilution, as outlined above. No other diluents have been shown
E@364@>A2E:3=6M(2C6?E6C2=5CF8AC@5F4EDD9@F=536:?DA64E65G:DF2==J7@CA2CE:4F=2E6>2EE6C2?5
discoloration prior to administration whenever solution and container permit. Any unused solution
should be discarded according to institutional procedures for antineoplastics. Admixture Stability.
TREANDA contains no antimicrobial preservative. The admixture should be prepared as close as
possible to the time of patient administration. Once diluted with either 0.9% Sodium Chloride Injection,
USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, the final admixture is stable for 24 hours
when stored refrigerated (2-8°C or 36-47°F) or for 3 hours when stored at room temperature (15-30°C
or 59-86°F) and room light. Administration of TREANDA must be completed within this period.
DOSAGE FORMS AND STRENGTHS: TREANDA for Injection single-use vial containing either 25 mg
or 100 mg of bendamustine HCl as white to off-white lyophilized powder.
HOW SUPPLIED/STORAGE AND HANDLING: Safe Handling and Disposal. As with other
potentially toxic anticancer agents, care should be exercised in the handling and preparation of
solutions prepared from TREANDA. The use of gloves and safety glasses is recommended to avoid
exposure in case of breakage of the vial or other accidental spillage. If a solution of TREANDA
contacts the skin, wash the skin immediately and thoroughly with soap and water. If TREANDA
contacts the mucous membranes, flush thoroughly with water. Procedures for the proper handling
and disposal of anticancer drugs should be considered. Several guidelines on the subject have been
published. There is no general agreement that all of the procedures recommended in the guidelines
are necessary or appropriate. How Supplied. TREANDA (bendamustine hydrochloride) for Injection
is supplied in individual cartons as follows: NDC 63459-390-08 TREANDA (bendamustine
hydrochloride) for Injection, 25 mg in 8 mL amber single-use vial and NDC 63459-391-20
TREANDA (bendamustine hydrochloride) for Injection, 100 mg in 20 mL amber single-use vial.
Storage. TREANDA may be stored up to 25°C (77°F) with excursions permitted up to 30°C (86°F)
(see USP Controlled Room Temperature). Retain in original package until time of use to protect
from light.
In both studies, serious adverse reactions, regardless of causality, were reported in 37% of patients
receiving TREANDA. The most common serious adverse reactions occurring in ≥ 5% of patients were
febrile neutropenia and pneumonia. Other important serious adverse reactions reported in clinical
trials and/or post-marketing experience were acute renal failure, cardiac failure, hypersensitivity,
skin reactions, pulmonary fibrosis, and myelodysplastic syndrome. Serious drug-related adverse
reactions reported in clinical trials included myelosuppression, infection, pneumonia, tumor lysis
syndrome, and infusion reactions. [See Warnings and Precautions] Adverse reactions occurring
less frequently but possibly related to TREANDA treatment were hemolysis, dysgeusia/taste
disorder, atypical pneumonia, sepsis, herpes zoster, erythema, dermatitis, and skin necrosis. PostMarketing Experience. The following adverse reactions have been identified during post-approval
use of TREANDA. Because these reactions are reported voluntarily from a population of uncertain
size, it is not always possible to reliably estimate their frequency or establish a causal
relationship to drug exposure: anaphylaxis; and injection or infusion site reactions including
pruritus, irritation, pain, and swelling. Skin reactions including SJS and TEN have occurred when
TREANDA was administered concomitantly with allopurinol and other medications known to
cause these syndromes. [See Warnings and Precautions]
OVERDOSAGE: The intravenous LD of bendamustine HCl is 240 mg/m2 in the mouse and rat.
Toxicities included sedation, tremor, ataxia, convulsions and respiratory distress. Across all clinical
experience, the reported maximum single dose received was 280 mg/m2. Three of four patients
treated at this dose showed ECG changes considered dose-limiting at 7 and 21 days post-dosing.
These changes included QT prolongation (one patient), sinus tachycardia (one patient), ST and T
wave deviations (two patients), and left anterior fascicular block (one patient). Cardiac enzymes and
ejection fractions remained normal in all patients. No specific antidote for TREANDA overdose is
known. Management of overdosage should include general supportive measures, including
monitoring of hematologic parameters and ECGs.
50
DOSAGE AND ADMINISTRATION: Dosing Instructions for CLL. Recommended Dosage: The
recommended dose is 100 mg/m2 administered intravenously over 30 minutes on Days 1 and 2 of
a 28-day cycle, up to 6 cycles. Dose Delays, Dose Modifications and Reinitiation of Therapy for CLL:
Manufactured by:
Pharmachemie B.V.
The Netherlands
Manufactured for:
Cephalon, Inc.
Frazer, PA 19355
TREANDA is a trademark of Cephalon, Inc., or its affiliates.
©2008-2011 Cephalon, Inc., or its affiliates.
TRE-2263
(Label Code: 00016287.03)
This brief summary is based on TREANDA full Prescribing Information.
March 2011
All rights reserved.
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For chronic lymphocytic leukemia (CLL)
refractory to fludarabine and alemtuzumab
EXPAND YOUR OPTIONS
A study population in need of additional treatment options1,2
5
median
prior therapies
59%
of patients received prior rituximab
93%
of patients received prior alkylating agents
100%
of patients received prior fludarabine and alemtuzumab
The following serious adverse events (AEs) are discussed in greater detail below:
Infusion reactions, cytopenias, progressive multifocal leukoencephalopathy, hepatitis B
infection and reactivation, and intestinal obstruction.
To learn more, please visit www.ARZERRA.com.
Indication
ARZERRA (ofatumumab) is indicated for the treatment
of patients with chronic lymphocytic leukemia (CLL)
refractory to fludarabine and alemtuzumab.
The effectiveness of ARZERRA is based on the
demonstration of durable objective responses. No
data demonstrate an improvement in disease-related
symptoms or increased survival with ARZERRA.
Important Safety Information
Infusion Reactions
ARZERRA can cause serious infusion reactions manifesting
as bronchospasm, dyspnea, laryngeal edema, pulmonary
edema, flushing, hypertension, hypotension, syncope,
cardiac ischemia/infarction, back pain, abdominal pain,
pyrexia, rash, urticaria, and angioedema. Infusion reactions
occur more frequently with the first 2 infusions. Premedicate
with acetaminophen, an antihistamine, and a corticosteroid.
Interrupt infusion for infusion reactions of any severity.
Institute medical management for severe infusion reactions
including angina, or other signs and symptoms of myocardial
ischemia. In a study of patients with moderate to severe
chronic obstructive pulmonary disease, an indication for
which ARZERRA is not approved, 2 of 5 patients developed
Grade 3 bronchospasm during infusion. Infusion reactions
occurred in 44% of patients on the day of the first infusion
(300 mg), 29% on the day of the second infusion (2,000 mg),
and less frequently during subsequent infusions.
Cytopenias
Prolonged (≥1 week) severe neutropenia and
thrombocytopenia can occur with ARZERRA. Monitor
complete blood counts (CBC) and platelet counts at regular
intervals during therapy, and increase the frequency of
monitoring in patients who develop Grade 3 or 4 cytopenias.
Of 108 patients with normal neutrophil counts at baseline,
45 (42%) developed ≥Grade 3 neutropenia. Nineteen (18%)
developed Grade 4 neutropenia. Some patients experienced
new onset Grade 4 neutropenia >2 weeks in duration.
Progressive Multifocal Leukoencephalopathy
Progressive multifocal leukoencephalopathy (PML),
including fatal PML, can occur with ARZERRA. Consider
PML in any patient with new onset of or changes in
pre-existing neurological signs or symptoms. Discontinue
ARZERRA if PML is suspected and initiate evaluation for
PML including consultation with a neurologist, brain MRI,
and lumbar puncture.
Hepatitis B Infection and Reactivation
Fulminant and fatal hepatitis B virus (HBV) infection and
reactivation can occur in patients following treatment with
ARZERRA. Screen patients at high risk of HBV infection
before initiation of ARZERRA. Closely monitor carriers of
hepatitis B for clinical and laboratory signs of active HBV
infection during treatment with ARZERRA and for 6 to 12
months following the last infusion of ARZERRA. Discontinue
ARZERRA in patients who develop viral hepatitis or
When treated with ARZERRA monotherapy, 42% of patients with
CLL refractory to fludarabine and alemtuzumab achieved a partial response1
Patients had received a median of 5 prior therapies
Overall response rate with ARZERRA
60
50
40
42%
The investigator-determined overall response rate
in patients with CLL refractory to fludarabine and
alemtuzumab was 42% (99% CI: 26, 60)
There were no complete responses
The effectiveness of ARZERRA is based on the
demonstration of durable objective responses
30
20
10
FLUDARABINE AND
ALEMTUZUMAB REFRACTORY
(n=59)
reactivation of viral hepatitis, and institute appropriate
treatment. Insufficient data exist regarding the safety of
administration of ARZERRA in patients with active hepatitis.
Intestinal Obstruction
Obstruction of the small intestine can occur in patients
receiving ARZERRA. Perform a diagnostic evaluation if
obstruction is suspected.
Immunizations
The safety of immunization with live viral vaccines during or
following administration of ARZERRA has not been studied.
Do not administer live viral vaccines to patients who have
recently received ARZERRA. The ability to generate an
immune response to any vaccine following administration
of ARZERRA has not been studied.
Most Common Adverse Reactions
In the pivotal study (total population, n=154) the most
common adverse reactions (≥10%, all grades) were
neutropenia, followed by pneumonia (23%), pyrexia (20%),
cough (19%), diarrhea (18%), anemia (16%), fatigue (15%),
dyspnea (14%), rash (14%), nausea (11%), bronchitis (11%),
and upper respiratory tract infections (11%).
Most Common Serious Adverse Reactions
In the pivotal study (total population, n=154), where
ARZERRA was administered at 2,000 mg beginning with the
second dose for 11 doses, the most common serious adverse
No data demonstrate an improvement in disease-related
symptoms or increased survival with ARZERRA
6.5 months—median duration of response
(95% CI: 5.8, 8.3)
reactions were infections (including pneumonia and sepsis),
neutropenia, and pyrexia.
A total of 108 patients (70%) experienced bacterial, viral, or
fungal infections. A total of 45 patients (29%) experienced
≥Grade 3 infections, of which 19 (12%) were fatal. The
proportion of fatal infections in the fludarabine- and
alemtuzumab-refractory group was 17%.
Please see Brief Summary of Prescribing Information on
adjacent pages.
How Supplied: Available as 2 different single-use glass vials
for dilution and intravenous administration. Each vial contains
either 100 mg ofatumumab in 5 mL of solution or 1,000 mg
ofatumumab in 50 mL of solution.
References: 1. ARZERRA (ofatumumab) [package insert]. Research Triangle Park,
NC: GlaxoSmithKline; 2011. 2. Tam CS, O’Brien S, Lerner S, et al. Leuk Lymph.
2007;48(10):1931-1939.
BRIEF SUMMARY
ARZERRA® (ofatumumab) Injection, for intravenous infusion
Table 1. Incidence of All Adverse Reactions Occurring in ≥5% of Patients
in Study 1 and in the Fludarabine- and Alemtuzumab-Refractory Subset
of Study 1 (MedDRA 9.0)
The following is a brief summary only; see full prescribing information for
complete product information.
1 INDICATIONS AND USAGE
ARZERRA® (ofatumumab) is indicated for the treatment of patients
with chronic lymphocytic leukemia (CLL) refractory to fludarabine and
alemtuzumab. The effectiveness of ARZERRA is based on the demonstration
of durable objective responses [see Clinical Studies (14) of full prescribing
information]. No data demonstrate an improvement in disease-related
symptoms or increased survival with ARZERRA.
4 CONTRAINDICATIONS
None.
5 WARNINGS AND PRECAUTIONS
5.1 Infusion Reactions ARZERRA can cause serious infusion reactions
manifesting as bronchospasm, dyspnea, laryngeal edema, pulmonary edema,
flushing, hypertension, hypotension, syncope, cardiac ischemia/infarction,
back pain, abdominal pain, pyrexia, rash, urticaria, and angioedema. Infusion
reactions occur more frequently with the first 2 infusions [see Adverse
Reactions (6.1)]. Premedicate with acetaminophen, an antihistamine, and a
corticosteroid [see Dosage and Administration (2.1, 2.4) of full prescribing
information]. Interrupt infusion for infusion reactions of any severity. Institute
medical management for severe infusion reactions including angina or other
signs and symptoms of myocardial ischemia [see Dosage and Administration
(2.3) of full prescribing information]. In a study of patients with moderate
to severe chronic obstructive pulmonary disease, an indication for which
ARZERRA is not approved, 2 of 5 patients developed Grade 3 bronchospasm
during infusion. 5.2 Cytopenias Prolonged (≥1 week) severe neutropenia and
thrombocytopenia can occur with ARZERRA. Monitor complete blood counts
(CBC) and platelet counts at regular intervals during therapy, and increase
the frequency of monitoring in patients who develop Grade 3 or 4 cytopenias.
5.3 Progressive Multifocal Leukoencephalopathy Progressive multifocal
leukoencephalopathy (PML), including fatal PML, can occur with ARZERRA.
Consider PML in any patient with new onset of or changes in pre-existing
neurological signs or symptoms. Discontinue ARZERRA if PML is suspected,
and initiate evaluation for PML including consultation with a neurologist,
brain MRI, and lumbar puncture. 5.4 Hepatitis B Infection and Reactivation
Fulminant and fatal hepatitis B virus (HBV) infection and reactivation can
occur in patients following treatment with ARZERRA. Screen patients at high
risk of HBV infection before initiation of ARZERRA. Closely monitor carriers
of hepatitis B for clinical and laboratory signs of active HBV infection during
treatment with ARZERRA and for 6 to 12 months following the last infusion
of ARZERRA. Discontinue ARZERRA in patients who develop viral hepatitis or
reactivation of viral hepatitis, and institute appropriate treatment. Insufficient
data exist regarding the safety of administration of ARZERRA in patients with
active hepatitis. 5.5 Intestinal Obstruction Obstruction of the small intestine
can occur in patients receiving ARZERRA. Perform a diagnostic evaluation
if obstruction is suspected. 5.6 Immunizations The safety of immunization
with live viral vaccines during or following administration of ARZERRA has
not been studied. Do not administer live viral vaccines to patients who have
recently received ARZERRA. The ability to generate an immune response to
any vaccine following administration of ARZERRA has not been studied.
6 ADVERSE REACTIONS
The following serious adverse reactions are discussed in greater detail in
other sections of the labeling:
t Infusion Reactions [see Warnings and Precautions (5.1)]
t Cytopenias [see Warnings and Precautions (5.2)]
t P rogressive Multifocal Leukoencephalopathy [see Warnings and
Precautions (5.3)]
t Hepatitis B Reactivation [see Warnings and Precautions (5.4)]
t Intestinal Obstruction [see Warnings and Precautions (5.5)]
The most common adverse reactions (≥10%) in Study 1 were neutropenia,
pneumonia, pyrexia, cough, diarrhea, anemia, fatigue, dyspnea, rash,
nausea, bronchitis, and upper respiratory tract infections. The most common
serious adverse reactions in Study 1 were infections (including pneumonia
and sepsis), neutropenia, and pyrexia. Infections were the most common
adverse reactions leading to drug discontinuation in Study 1. 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 practice. The safety of monotherapy
with ARZERRA was evaluated in 181 patients with relapsed or refractory
CLL in 2 open-label, non-randomized, single-arm studies. In these studies,
ARZERRA was administered at 2,000 mg beginning with the second dose
for 11 doses (Study 1 [n = 154]) or 3 doses (Study 2 [n = 27]). The data
described in Table 1 and other sections below are derived from 154 patients
in Study 1. All patients received 2,000 mg weekly from the second dose
onward. Ninety percent of patients received at least 8 infusions of ARZERRA
and 55% received all 12 infusions. The median age was 63 years (range: 41
to 86 years), 72% were male, and 97% were White.
Total Population
(n = 154)
Fludarabine- and
AlemtuzumabRefractory
(n = 59)
Grade
All
≥3
Grades
%
%
Grade
All
≥3
Grades
Body System/
%
%
Adverse Event
Infections and infestations
Pneumoniaa
23
14
25
15
Upper respiratory tract
11
0
3
0
infection
Bronchitis
11
<1
19
2
Sepsisb
8
8
10
10
Nasopharyngitis
8
0
8
0
Herpes zoster
6
1
7
2
Sinusitis
5
2
3
2
Blood and lymphatic
system disorders
Anemia
16
5
17
8
Psychiatric disorders
Insomnia
7
0
10
0
Nervous system disorders
Headache
6
0
7
0
Cardiovascular disorders
Hypertension
5
0
8
0
Hypotension
5
0
3
0
Tachycardia
5
<1
7
2
Respiratory, thoracic, and
mediastinal disorders
Cough
19
0
19
0
Dyspnea
14
2
19
5
Gastrointestinal disorders
Diarrhea
18
0
19
0
Nausea
11
0
12
0
Skin and subcutaneous
tissue disorders
Rashc
14
<1
17
2
Urticaria
8
0
5
0
Hyperhidrosis
5
0
5
0
Musculoskeletal and
connective tissue disorders
Back pain
8
1
12
2
Muscle spasms
5
0
3
0
General disorders and
administration site
conditions
Pyrexia
20
3
25
5
Fatigue
15
0
15
0
Edema peripheral
9
<1
8
2
Chills
8
0
10
0
a
Pneumonia includes pneumonia, lung infection, lobar pneumonia, and
bronchopneumonia.
b
Sepsis includes sepsis, neutropenic sepsis, bacteremia, and septic shock.
c
Rash includes rash, rash macular, and rash vesicular.
Infusion Reactions: Infusion reactions occurred in 44% of patients on the
day of the first infusion (300 mg), 29% on the day of the second infusion
(2,000 mg), and less frequently during subsequent infusions. Infections: A
total of 108 patients (70%) experienced bacterial, viral, or fungal infections.
A total of 45 patients (29%) experienced ≥Grade 3 infections, of which 19
(12%) were fatal. The proportion of fatal infections in the fludarabine- and
alemtuzumab-refractory group was 17%. Neutropenia: Of 108 patients
with normal neutrophil counts at baseline, 45 (42%) developed ≥Grade 3
neutropenia. Nineteen (18%) developed Grade 4 neutropenia. Some patients
experienced new onset Grade 4 neutropenia >2 weeks in duration.
6.2 Immunogenicity There is a potential for immunogenicity with therapeutic
proteins such as ofatumumab. Serum samples from patients with CLL in
Study 1 were tested by enzyme-linked immunosorbent assay (ELISA) for
anti-ofatumumab antibodies during and after the 24-week treatment period.
Results were negative in 46 patients after the 8th infusion and in 33 patients
after the 12th infusion. Immunogenicity assay results are highly dependent on
several factors including assay sensitivity and specificity, assay methodology,
sample handling, timing of sample collection, concomitant medications, and
underlying disease. For these reasons, comparison of incidence of antibodies to
ARZERRA with the incidence of antibodies to other products may be misleading.
7 DRUG INTERACTIONS
No formal drug-drug interaction studies have been conducted with ARZERRA.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy Pregnancy Category C: There are no adequate or well-controlled
studies of ofatumumab in pregnant women. A reproductive study in pregnant
cynomolgus monkeys that received ofatumumab at doses up to 3.5 times the
recommended human dose of ofatumumab did not demonstrate maternal
toxicity or teratogenicity. Ofatumumab crossed the placental barrier, and fetuses
exhibited depletion of peripheral B cells and decreased spleen and placental
weights. ARZERRA should be used during pregnancy only if the potential benefit
to the mother justifies the potential risk to the fetus. There are no human or
animal data on the potential short- and long-term effects of perinatal B-cell
depletion in offspring following in utero exposure to ofatumumab. Ofatumumab
does not bind normal human tissues other than B lymphocytes. It is not known
if binding occurs to unique embryonic or fetal tissue targets. In addition, the
kinetics of B-lymphocyte recovery are unknown in offspring with B-cell depletion
[see Nonclinical Toxicology (13.3)]. 8.3 Nursing Mothers It is not known whether
ofatumumab is secreted in human milk; however, human IgG is secreted in
human milk. Published data suggest that neonatal and infant consumption of
breast milk does not result in substantial absorption of these maternal antibodies
into circulation. Because the effects of local gastrointestinal and limited systemic
exposure to ofatumumab are unknown, caution should be exercised when
ARZERRA is administered to a nursing woman. 8.4 Pediatric Use Safety and
effectiveness of ARZERRA have not been established in children. 8.5 Geriatric
Use Clinical studies of ARZERRA did not include sufficient numbers of subjects
aged 65 and over to determine whether they respond differently from younger
subjects [see Clinical Pharmacology (12.3) of full prescribing information].
8.6 Renal Impairment No formal studies of ARZERRA in patients with renal
impairment have been conducted [see Clinical Pharmacology (12.3) of full
prescribing information]. 8.7 Hepatic Impairment No formal studies of ARZERRA
in patients with hepatic impairment have been conducted.
10 OVERDOSAGE
No data are available regarding overdosage with ARZERRA.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No carcinogenicity
or mutagenicity studies of ofatumumab have been conducted. In a repeat-dose
toxicity study, no tumorigenic or unexpected mitogenic responses were noted in
cynomolgus monkeys treated for 7 months with up to 3.5 times the human dose
of ofatumumab. Effects on male and female fertility have not been evaluated
in animal studies. 13.3 Reproductive and Developmental Toxicology
Pregnant cynomolgus monkeys dosed with 0.7 or 3.5 times the human dose
of ofatumumab weekly during the period of organogenesis (gestation days
20 to 50) had no maternal toxicity or teratogenicity. Both dose levels of
ofatumumab depleted circulating B cells in the dams, with signs of initial
B cell recovery 50 days after the final dose. Following Caesarean section
at gestational day 100, fetuses from ofatumumab-treated dams exhibited
decreases in mean peripheral B-cell counts (decreased to approximately
10% of control values), splenic B-cell counts (decreased to approximately
15 to 20% of control values), and spleen weights (decreased by 15% for the
low-dose and by 30% for the high-dose group, compared to control values).
Fetuses from treated dams exhibiting anti-ofatumumab antibody responses
had higher B cell counts and higher spleen weights compared to the fetuses
from other treated dams, indicating partial recovery in those animals
developing anti-ofatumumab antibodies. When compared to control animals,
fetuses from treated dams in both dose groups had a 10% decrease in mean
placental weights. A 15% decrease in mean thymus weight compared to
the controls was also observed in fetuses from dams treated with 3.5 times
the human dose of ofatumumab. The biological significance of decreased
placental and thymic weights is unknown. The kinetics of B-lymphocyte
recovery and the potential long-term effects of perinatal B-cell depletion in
offspring from ofatumumab-treated dams have not been studied in animals.
17 PATIENT COUNSELING INFORMATION
Advise patients to contact a healthcare professional for any of the following:
t 4JHOTBOETZNQUPNTPGJOGVTJPOSFBDUJPOTJODMVEJOHGFWFSDIJMMTSBTI
or breathing problems within 24 hours of infusion [see Warnings and
Precautions (5.1) and Adverse Reactions (6.1)]
t #MFFEJOHFBTZCSVJTJOHQFUFDIJBFQBMMPSXPSTFOJOHXFBLOFTTPSGBUJHVF
[see Warnings and Precautions (5.2)]
t 4JHOTPGJOGFDUJPOTJODMVEJOHGFWFSBOEDPVHI[see Warnings and
Precautions (5.2) and Adverse Reactions (6.1)]
t /FXOFVSPMPHJDBMTZNQUPNTTVDIBTDPOGVTJPOEJ[[JOFTTPSMPTTPG
balance, difficulty talking or walking, or vision problems [see Warnings and
Precautions (5.3)]
t 4ZNQUPNTPGIFQBUJUJTJODMVEJOHXPSTFOJOHGBUJHVFPSZFMMPXEJTDPMPSBUJPO
of skin or eyes [see Warnings and Precautions (5.4)]
t /FXPSXPSTFOJOHBCEPNJOBMQBJOPSOBVTFB[see Warnings and
Precautions (5.5)]
t 1SFHOBODZPSOVSTJOH [see Use in Specific Populations (8.1, 8.3)]
Advise patients of the need for:
t 1FSJPEJDNPOJUPSJOHGPSCMPPEDPVOUT [see Warnings and Precautions (5.2)]
t "WPJEJOHWBDDJOBUJPOXJUIMJWFWJSBMWBDDJOFT [see Warnings and
Precautions (5.6)]
Manufactured by:
GLAXO GROUP LIMITED
Greenford, Middlesex, UB6 0NN, United Kingdom
U.S. Lic. 1809
Distributed by:
GlaxoSmithKline
Research Triangle Park, NC 27709
©2011, GlaxoSmithKline. All rights reserved.
September 2011
ARZ:6BRS
©2011 The GlaxoSmithKline Group of Companies
All rights reserved. Printed in USA. AZA293R0 September 2011
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BRIEF SUMMARY OF PRESCRIBING INFORMATION
Nplate® (romiplostim), for subcutaneous injection
WARNINGS AND PRECAUTIONS
Risk of Progression of Myelodysplastic Syndromes to
Acute Myelogenous Leukemia
Progression from myelodysplastic syndromes (MDS) to
acute myelogenous leukemia (AML) has been observed
in clinical trials with Nplate®. A randomized, double
blind, placebo controlled trial enrolling patients with
severe thrombocytopenia and International Prognostic
Scoring System (IPSS) low or intermediate-1 risk MDS
was terminated due to more cases of AML observed in
the romiplostim treatment arm. At the time of an interim
analysis, among 219 MDS patients randomized 2:1 to
treatment with Nplate® or placebo (147 Nplate®: 72 placebo),
11 patients showed progression to AML, including nine on
the Nplate® arm versus two on the placebo arm. In addition,
in peripheral blood counts, the percentage of circulating
myeloblasts increased to greater than 10% in 28 patients,
25 of whom were in the romiplostim treatment arm. Of the
28 patients who had an increase in circulating myeloblasts
to greater than 10%, eight of these patients were diagnosed
to have AML, and 20 patients had not progressed to AML.
In four patients, increased peripheral blood blast cell counts
decreased to baseline after discontinuation of Nplate®.
In a single-arm trial of Nplate® given to 72 patients with
thrombocytopenia related to MDS, eight (11%) patients
were reported as having possible disease progression, and
three patients had confirmation of AML during follow-up.
In addition, in three patients, increased peripheral blood
blast cell counts decreased to baseline after discontinuation
of Nplate®.
Nplate® is not indicated for the treatment of thrombocytopenia
due to MDS or any cause of thrombocytopenia other than
chronic ITP.
Thrombotic/Thromboembolic Complications
Thrombotic/thromboembolic complications may result
from increases in platelet counts with Nplate® use. Portal
vein thrombosis has been reported in patients with chronic
liver disease receiving Nplate®. Nplate® should be used with
caution in patients with ITP and chronic liver disease.
To minimize the risk for thrombotic/thromboembolic
complications, do not use Nplate® in an attempt to normalize
platelet counts. Follow the dose adjustment guidelines to
achieve and maintain a platelet count of * 50 x 109/L [see
Dosage and Administration].
Bone Marrow Reticulin Formation and Risk for Bone
Marrow Fibrosis
Nplate® administration may increase the risk for development
or progression of reticulin fiber formation within the bone
marrow. This formation may improve upon discontinuation
of Nplate®. In a clinical study, one patient with ITP and
hemolytic anemia developed marrow fibrosis with collagen
during Nplate therapy. Clinical studies are in progress
to assess the risk of bone marrow fibrosis and clinical
consequences with cytopenias.
If new or worsening morphological abnormalities or
cytopenia(s) occurs, consider a bone marrow biopsy to
include staining for fibrosis [see Adverse Reactions].
Worsened Thrombocytopenia after Cessation of Nplate®
In clinical studies of patients with chronic ITP who had
Nplate® discontinued, four of 57 patients developed
thrombocytopenia of greater severity than was present
prior to Nplate® therapy. This worsened thrombocytopenia
resolved within 14 days. Following discontinuation of
Nplate®, obtain weekly CBCs, including platelet counts, for
at least two weeks and consider alternative treatments for
worsening thrombocytopenia, according to current treatment
guidelines [see Adverse Reactions].
Lack or Loss of Response to Nplate®
Hyporesponsiveness or failure to maintain a platelet response
with Nplate® should prompt a search for causative factors,
including neutralizing antibodies to Nplate® [see Adverse
Reactions]. To detect antibody formation, submit blood
samples to Amgen (1-800-772-6436). Amgen will assay
these samples for antibodies to Nplate® and thrombopoietin
(TPO). Discontinue Nplate® if the platelet count does not
increase to a level sufficient to avoid clinically important
bleeding after 4 weeks at the highest weekly dose of 10 mcg/kg.
Laboratory Monitoring
Obtain CBCs, including platelet counts, weekly during the
dose adjustment phase of Nplate® therapy and then monthly
following establishment of a stable Nplate® dose. Obtain
CBCs, including platelet counts, weekly for at least two
weeks following discontinuation of Nplate® [see Dosage and
Administration and Warnings and Precautions].
ADVERSE REACTIONS
Clinical Studies Experience
Serious adverse reactions associated with Nplate® in IPT
clinical studies were bone marrow reticulin deposition and
worsening thrombocytopenia after Nplate® discontinuation
[see Warnings and Precautions].
The data described below reflect Nplate® exposure to 271
patients with chronic ITP, aged 18 to 88, of whom 62%
were female. Nplate® was studied in two randomized,
placebo-controlled, double-blind studies that were identical
in design, with the exception that Study 1 evaluated
nonsplenectomized patients with ITP and Study 2
evaluated splenectomized patients with ITP. Data are also
reported from an open-label, single-arm study in which
patients received Nplate® over an extended period of time.
Overall, Nplate® was administered to 114 patients for at least
52 weeks and 53 patients for at least 96 weeks.
Because clinical studies 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 practice.
In the placebo-controlled studies, headache was the most
commonly reported adverse drug reaction, occurring in
35% of patients receiving Nplate® and 32% of patients
receiving placebo. Headaches were usually of mild or
moderate severity. Table 2 presents adverse drug reactions
from Studies 1 and 2 with a * 5% higher patient incidence in
Nplate® versus placebo. The majority of these adverse drug
reactions were mild to moderate in severity.
Table 2. Adverse Drug Reactions Identified in
Two Placebo-Controlled Studies
Preferred Term
Arthralgia
Dizziness
Insomnia
Myalgia
Pain in Extremity
Abdominal Pain
Shoulder Pain
Dyspepsia
Paresthesia
Nplate®
(n = 84)
26%
17%
16%
14%
13%
11%
8%
7%
6%
Placebo
(n = 41)
20%
0%
7%
2%
5%
0%
0%
0%
0%
Among 142 patients with chronic ITP who received Nplate®
in the single-arm extension study, the incidence rates of
the adverse reactions occurred in a pattern similar to those
reported in the placebo-controlled clinical studies.
Postmarketing Experience
The following adverse reactions have been identified during
post approval use of Nplate®. Because these reactions are
reported voluntarily from a population of uncertain size, it is
not always possible to reliably estimate their frequency or
establish a causal relationship to drug exposure.
• Erythromelalgia
Immunogenicity
As with all therapeutic proteins, patients may develop
antibodies to the therapeutic protein. Patients were screened
for immunogenicity to romiplostim using a BIAcore-based
biosensor immunoassay. This assay is capable of detecting
both high- and low-affinity binding antibodies that bind to
romiplostim and cross-react with TPO. The samples from
patients that tested positive for binding antibodies were
further evaluated for neutralizing capacity using a cell-based
bioassay.
In clinical studies, the incidence of preexisting antibodies
to romiplostim was 8% (43/537) and the incidence of
binding antibody development during Nplate® treatment
was 6% (31/537). The incidence of preexisting antibodies
to endogenous TPO was 5% (29/537) and the incidence of
binding antibody development to endogenous TPO during
Nplate® treatment was 4% (21/537). Of the patients with
positive binding antibodies that developed to romiplostim
or to TPO, two (0.4%) patients had neutralizing activity to
romiplostim and none had neutralizing activity to TPO. No
correlation was observed between antibody activity and
clinical effectiveness or safety.
Immunogenicity assay results are highly dependent on the
sensitivity and specificity of the assay used in detection
and may be influenced by several factors, including sample
handling, concomitant medications, and underlying disease.
For these reasons, comparison of incidence of antibodies
to romiplostim with the incidence of antibodies to other
products may be misleading.
DRUG INTERACTIONS
No formal drug interaction studies of Nplate® have been
performed.
USE IN SPECIFIC POPULATIONS
Pregnancy
Pregnancy Category C
There are no adequate and well-controlled studies of
Nplate® use in pregnant women. In animal reproduction
and developmental toxicity studies, romiplostim crossed the
placenta, and adverse fetal effects included thrombocytosis,
postimplantation loss, and an increase in pup mortality.
Nplate® should be used during pregnancy only if the potential
benefit to the mother justifies the potential risk to the fetus.
Pregnancy Registry : A pregnancy registry has been
established to collect information about the effects of
Nplate® use during pregnancy. Physicians are encouraged
to register pregnant patients, or pregnant women may enroll
themselves in the Nplate® pregnancy registry by calling
1-800-77-AMGEN (1-800-772-6436).
In rat and rabbit developmental toxicity studies no
evidence of fetal harm was observed at romiplostim
doses up to 11 times (rats) and 82 times (rabbit) the
maximum human dose (MHD) based on systemic
exposure. In mice at doses 5 times the MHD, reductions
in maternal body weight and increased postimplantation
loss occurred.
In a prenatal and postnatal development study in rats, at
doses 11 times the MHD, there was an increase in perinatal
pup mortality. Romiplostim crossed the placental barrier in
rats and increased fetal platelet counts at clinically equivalent
and higher doses.
Nursing Mothers
It is not known whether Nplate® is excreted in human milk;
however, human IgG is excreted in human milk. Published
data suggest that breast milk antibodies do not enter the
neonatal and infant circulation in substantial amounts.
Because many drugs are excreted in human milk and
because of the potential for serious adverse reactions in
nursing infants from Nplate®, a decision should be made
whether to discontinue nursing or to discontinue Nplate®,
taking into account the importance of Nplate® to the mother
and the known benefits of nursing.
Pediatric Use
The safety and effectiveness in pediatric patients (< 18 years)
have not been established.
Geriatric Use
Of the 271 patients who received Nplate® in ITP clinical
studies, 55 (20%) were age 65 and over, and 27 (10%)
were 75 and over. No overall differences in safety or efficacy
have been observed between older and younger patients
in the placebo-controlled studies, but greater sensitivity
of some older individuals cannot be ruled out. In general,
dose adjustment for an elderly patient should be cautious,
reflecting the greater frequency of decreased hepatic, renal,
or cardiac function, and of concomitant disease or other
drug therapy.
Renal Impairment
No clinical studies were conducted in patients with renal
impairment. Use Nplate® with caution in this population.
Hepatic Impairment
No clinical studies were conducted in patients with hepatic
impairment. Use Nplate® with caution in this population.
OVERDOSAGE
In the event of overdose, platelet counts may increase
excessively and result in thrombotic/thromboembolic
complications. In this case, discontinue Nplate® and
monitor platelet counts. Reinitiate treatment with Nplate® in
accordance with dosing and administration recommendations
[see Dosage and Administration].
Rx Only. Consult package insert for complete Prescribing
Information.
Manufactured by:
Amgen Inc.
One Amgen Center Drive
Thousand Oaks, California 91320-1799
This product, its production, and/or its use may be covered
by one or more U.S. Patents, including U.S. Patent Nos.
6,835,809, 7,189,827, 7,994,117 and 8,044,174, as well as
other patents or patents pending.
© 2008-2011 Amgen Inc. All rights reserved.
www.Nplate.com
v4
IN CHRONIC ITP
WHAT
Live rep support. Clinical data. Patient resources.
Visit www.NplateHCP.com/Bvisit
C UNTS
Evidence. Experience. Efficacy.1-6
Nplate® is a thrombopoietin receptor agonist indicated for the treatment of thrombocytopenia in patients with chronic immune
thrombocytopenia (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy.
Nplate® is not indicated for the treatment of thrombocytopenia due to myelodysplastic syndrome (MDS) or any cause of
thrombocytopenia other than chronic ITP. Nplate® should be used only in patients with ITP whose degree of thrombocytopenia
and clinical condition increase the risk for bleeding. Nplate® should not be used in an attempt to normalize platelet counts.
IMPORTANT SAFETY INFORMATION
■ In Nplate® clinical trials of patients with myelodysplastic syndromes (MDS) and severe thrombocytopenia, progression
from MDS to acute myelogenous leukemia (AML) has been observed. Nplate® is not indicated for the treatment of
thrombocytopenia due to MDS or any cause of thrombocytopenia other than chronic ITP.
■ Additional serious adverse reactions associated with Nplate® are Thrombotic/Thromboembolic Complications, Bone Marrow
Reticulin Formation and Risk for Bone Marrow Fibrosis, Worsened Thrombocytopenia after Cessation of Nplate®, and Lack or
Loss of Response to Nplate®.
■ Obtain CBCs, including platelet counts, prior to initiation, throughout, and following discontinuation of Nplate® therapy.
■ In the placebo-controlled studies, headache was the most commonly reported adverse drug reaction.
Please see Brief Summary of Prescribing Information on adjacent page.
References: 1. Nplate® (romiplostim) prescribing information, Amgen. 2. Kuter DJ, Bussel JB, Lyons RM, et al.
Efficacy of romiplostim in patients with chronic immune thrombocytopenic purpura: a double-blind randomised
controlled trial. Lancet. 2008;371:395-403. 3. Kuter DJ, Rummel M, Boccia R, et al. Romiplostim or standard of care
in patients with immune thrombocytopenia. N Engl J Med. 2010;363:1889-1899. 4. Bussel JB, Kuter DJ, Pullarkat V,
Lyons RM, Guo M, Nichol JL. Safety and efficacy of long-term treatment with romiplostim in thrombocytopenic
patients with chronic ITP. Blood. 2009;113:2161-2171. 5. Kuter DJ, Bussel JB, Newland A, et al. Long-term efficacy
and safety of romiplostim treatment of adult patients with chronic immune thrombocytopenia (ITP): final report
from an open-label extension study. Blood. 2010;116:Abstract 68. Presented at 52nd American Society of Hematology
Annual Meeting and Exposition; Orlando, FL; December 4-7, 2010. 6. Data on file, Amgen.
© 2011 Amgen Inc. All rights reserved. 64397-R1-V1 12/11