Adverse Events Grding Crd Common Terminology Criteri for Adverse Events* In clinicl studies, 2 of the most common dverse events reported with ALAVEN were peripherl neuropthy nd neutropeni. 1 With this crd, you cn help trck nd mnge these dverse events by identifying their severity nd djusting the dose of ALAVEN s needed. Grding peripherl neuropthy 1,2 * Monitor ptients closely for signs of peripherl motor nd sensory neuropthy. Grde 1 Grde 2 Grde 3 Grde 4 Grde 5 Asymptomtic Motor: clinicl or dignostic observtions only; intervention not indicted Sensory: loss of deep tendon reflexes or presthesi Moderte symptoms; limiting instrumentl ADL Severe symptoms; limiting self-cre ADL Motor: ssistive device indicted Life-thretening consequences; urgent intervention indicted Deth ADL=ctivities of dily living. * Adpted from Common Terminology Criteri for Adverse Events version 4.3. Indictions Metsttic Brest Cncer ALAVEN (eribulin mesylte) Injection is indicted for the tretment of ptients with metsttic brest cncer (mbc) who hve previously received t lest 2 chemotherpeutic regimens for the tretment of metsttic disese. Prior therpy should hve included n nthrcycline nd txne in either the djuvnt or metsttic setting. Liposrcom ALAVEN is indicted for the tretment of ptients with unresectble or metsttic liposrcom who hve received prior nthrcycline-contining regimen. Importnt Sfety Informtion Wrnings nd Precutions Neutropeni: Severe neutropeni (ANC <5/mm 3 ) lsting >1 week occurred in 12% of ptients with mbc nd liposrcom or leiomyosrcom. Febrile neutropeni occurred in 5% of ptients with mbc nd 2 ptients (.4%) died from complictions. Febrile neutropeni occurred in.9% of ptients with liposrcom or leiomyosrcom, nd ftl neutropenic sepsis occurred in.9% of ptients. Ptients with mbc with elevted liver enzymes >3 ULN nd bilirubin >1.5 ULN experienced higher incidence of Grde 4 neutropeni nd febrile neutropeni thn ptients with norml levels. Monitor complete blood cell counts prior to ech dose, nd increse the frequency of monitoring in ptients who develop Grde 3 or 4 cytopenis. Dely dministrtion nd reduce subsequent doses in ptients who experience febrile neutropeni or Grde 4 neutropeni lsting >7 dys. Peripherl Neuropthy: Grde 3 peripherl neuropthy occurred in 8% of ptients with mbc (Grde 4=.4%) nd 22% developed new or worsening neuropthy tht hd not recovered within medin follow-up durtion of 269 dys (rnge 25-662 dys). Neuropthy lsting >1 yer occurred in 5% of ptients with mbc. Grde 3 peripherl neuropthy occurred in 3.1% of ptients with liposrcom nd leiomyosrcom receiving ALAVEN nd neuropthy lsting more thn 6 dys occurred in 58% (38/65) of ptients who hd neuropthy t the lst tretment visit. Ptients should be monitored for signs of peripherl motor nd sensory neuropthy. Withhold ALAVEN in ptients who experience Grde 3 or 4 peripherl neuropthy until resolution to Grde 2 or less. Plese see dditionl Importnt Sfety Informtion on reverse side nd ccompnying ALAVEN full Prescribing Informtion.
Grding neutropeni 1,2 * Monitor complete blood cell counts prior to ech dose, nd increse the frequency of monitoring in ptients who develop Grde 3 or 4 cytopenis. ANC decresed Grde 1 LLN to 1,5/mm 3 ; <LLN to 1.5 x 1 9 /L Grde 2 <1,5 to 1,/mm 3 ; <1.5 to 1. x 1 9 /L Grde 3 <1, to 5/mm 3 ; <1. to.5 x 1 9 /L Grde 4 <5/mm 3 ; <.5 x 1 9 /L Febrile neutropeni Grde 3 Grde 4 Grde 5 ANC <1,/mm 3 with single temperture of >38.3 C (11 F) or sustined temperture of 38 C (1.4 F) for more thn 1 hour Life-thretening consequences; urgent intervention indicted Deth ANC=bsolute neutrophil count; LLN=lower limit of norml. * Adpted from Common Terminology Criteri for Adverse Events version 4.3. Importnt Sfety Informtion (cont d) Embryo-Fetl Toxicity: ALAVEN cn cuse fetl hrm when dministered to pregnnt womn. Advise femles of reproductive potentil to use effective contrception during tretment with ALAVEN nd for t lest 2 weeks following the finl dose. Advise mles with femle prtners of reproductive potentil to use effective contrception during tretment with ALAVEN nd for 3.5 months following the finl dose. QT Prolongtion: Monitor for prolonged QT intervls in ptients with congestive hert filure, brdyrrhythmis, drugs known to prolong the QT intervl, nd electrolyte bnormlities. Correct hypoklemi or hypomgnesemi prior to inititing ALAVEN nd monitor these electrolytes periodiclly during therpy. Avoid in ptients with congenitl long QT syndrome. Adverse Rections In ptients with mbc receiving ALAVEN, the most common dverse rections ( 25%) were neutropeni (82%), nemi (58%), stheni/ftigue (54%), lopeci (45%), peripherl neuropthy (35%), nuse (35%), nd constiption (25%). Febrile neutropeni (4%) nd neutropeni (2%) were the most common serious dverse rections. The most common dverse rection resulting in discontinution ws peripherl neuropthy (5%). In ptients with liposrcom nd leiomyosrcom receiving ALAVEN, the most common dverse rections ( 25%) reported in ptients receiving ALAVEN were ftigue (62%), nuse (41%), lopeci (35%), constiption (32%), peripherl neuropthy (29%), bdominl pin (29%), nd pyrexi (28%). The most common ( 5%) Grde 3-4 lbortory bnormlities reported in ptients receiving ALAVEN were neutropeni (32%), hypoklemi (5.4%), nd hypoclcemi (5%). Neutropeni (4.9%) nd pyrexi (4.5%) were the most common serious dverse rections. The most common dverse rections resulting in discontinution were ftigue nd thrombocytopeni (.9% ech). Use in Specific Popultions Lcttion: Becuse of the potentil for serious dverse rections in brestfed infnts from eribulin mesylte, dvise women not to brestfeed during tretment with ALAVEN nd for 2 weeks fter the finl dose. eptic nd Renl Impirment: A reduction in strting dose is recommended for ptients with mild or moderte heptic impirment nd/or moderte or severe renl impirment. Plese see dditionl Importnt Sfety Informtion on reverse side nd ccompnying ALAVEN full Prescribing Informtion. References: 1. ALAVEN [pckge insert]. Woodcliff Lke, NJ: Eisi Inc; 216. 2. Ntionl Cncer Institute. Cncer Therpy Evlution Progrm, Common Terminology Criteri for Adverse Events v4.3. NI Publiction # 9-541. evs.nci.nih.gov/ftp1/ctcae/ctcae_4.3_21-6-14_quickreference_8.5x11.pdf. Published My 28, 29. Updted June 14, 21. Accessed Februry 23, 216. To report suspected dverse rections, contct Eisi Inc. t 1-888-274-2378 or the FDA t 1-8-FDA-188 or www.fda.gov/medwtch. ALAVEN is registered trdemrk used by Eisi Inc. under license from Eisi R&D Mngement Co., Ltd. 216 Eisi Inc. All rights reserved. Printed in USA/Mrch 216 ALA-US327
IGLIGTS F PRESCRIBING INFRMATIN These highlights do not include ll the informtion needed to use ALAVEN sfely nd effectively. See full prescribing informtion for ALAVEN. ALAVEN (eribulin mesylte) injection, for intrvenous use Initil U.S. Approvl: 21 RECENT MAJR CANGES Indictions nd Usge (1.2) 1/216 Wrnings nd Precutions (5.1, 5.2, 5.3) 1/216 INDICATINS AND USAGE ALAVEN is microtubule inhibitor indicted for the tretment of ptients with: Metsttic brest cncer who hve previously received t lest two chemotherpeutic regimens for the tretment of metsttic disese. Prior therpy should hve included n nthrcycline nd txne in either the djuvnt or metsttic setting. (1.1) Unresectble or metsttic liposrcom who hve received prior nthrcycline-contining regimen. (1.2) DSAGE AND ADMINISTRATIN Administer 1.4 mg/m 2 intrvenously over 2 to 5 minutes on Dys 1 nd 8 of 21-dy cycle. (2.1) Reduce dose in ptients with heptic impirment or with moderte or severe renl impirment. (2.1) Do not mix with other drugs or dminister with dextrose-contining solutions. (2.3) DSAGE FRMS AND STRENGTS Injection: 1 mg per 2 ml (.5 mg per ml) (3) CNTRAINDICATINS None (4) FULL PRESCRIBING INFRMATIN: CNTENTS* 1 INDICATINS AND USAGE 1.1 Metsttic Brest Cncer 1.2 Liposrcom 2 DSAGE AND ADMINISTRATIN 2.1 Recommended Dose 2.2 Dose Modifiction 2.3 Instructions for Preprtion nd Administrtion 3 DSAGE FRMS AND STRENGTS 4 CNTRAINDICATINS 5 WARNINGS AND PRECAUTINS 5.1 Neutropeni 5.2 Peripherl Neuropthy 5.3 Embryo-Fetl Toxicity 5.4 QT Prolongtion 6 ADVERSE REACTINS 6.1 Clinicl Trils Experience 6.2 Postmrketing Experience 7 DRUG INTERACTINS 7.1 Effects of ther Drugs on ALAVEN 7.2 Effects of ALAVEN on ther Drugs FULL PRESCRIBING INFRMATIN 1 INDICATINS AND USAGE 1.1 Metsttic Brest Cncer ALAVEN is indicted for the tretment of ptients with metsttic brest cncer who hve previously received t lest two chemotherpeutic regimens for the tretment of metsttic disese. Prior therpy should hve included n nthrcycline nd txne in either the djuvnt or metsttic setting [see Clinicl Studies (14.1)]. 1.2 Liposrcom ALAVEN is indicted for the tretment of ptients with unresectble or metsttic liposrcom who hve received prior nthrcycline-contining regimen [see Clinicl Studies (14.2)]. 2 DSAGE AND ADMINISTRATIN 2.1 Recommended Dose The recommended dose of ALAVEN is 1.4 mg/m 2 dministered intrvenously over 2 to 5 minutes on Dys 1 nd 8 of 21-dy cycle. The recommended dose of ALAVEN in ptients with mild heptic impirment (Child-Pugh A) is 1.1 mg/m 2 dministered intrvenously over 2 to 5 minutes on Dys 1 nd 8 of 21-dy cycle [see Use in Specific Popultions (8.6)]. The recommended dose of ALAVEN in ptients with moderte heptic impirment (Child-Pugh B) is.7 mg/m 2 dministered intrvenously over 2 to 5 minutes on Dys 1 nd 8 of 21-dy cycle [see Use in Specific Popultions (8.6)]. The recommended dose of ALAVEN in ptients with moderte or severe renl impirment (cretinine clernce (CLcr) 15-49 ml/min) is 1.1 mg/m 2 dministered intrvenously over 2 to 5 minutes on Dys 1 nd 8 of 21-dy cycle [see Use in Specific Popultions (8.7)]. 2.2 Dose Modifiction Assess for peripherl neuropthy nd obtin complete blood cell counts prior to ech dose. Recommended dose delys Do not dminister ALAVEN on Dy 1 or Dy 8 for ny of the following: ANC < 1,/mm 3 Pltelets < 75,/mm 3 Grde 3 or 4 non-hemtologicl toxicities. The Dy 8 dose my be delyed for mximum of 1 week. If toxicities do not resolve or improve to Grde 2 severity by Dy 15, omit the dose. WARNINGS AND PRECAUTINS Neutropeni: Monitor peripherl blood cell counts nd djust dose s pproprite. (5.1) Peripherl Neuropthy: Monitor for signs of neuropthy. Mnge with dose dely nd djustment. (5.2) Embryo-Fetl Toxicity: Cn cuse fetl hrm. Advise femles of reproductive potentil of the potentil risk to the fetus nd to use effective contrception. (5.3, 8.1, 8.3) QT Prolongtion: Monitor for prolonged QT intervls in ptients with congestive hert filure, brdyrrhythmis, drugs known to prolong the QT intervl, nd electrolyte bnormlities. Avoid in ptients with congenitl long QT syndrome. (5.4) ADVERSE REACTINS The most common dverse rections ( 25%) in metsttic brest cncer were neutropeni, nemi, stheni/ftigue, lopeci, peripherl neuropthy, nuse, nd constiption. (6.1) The most common dverse rections ( 25%) in liposrcom nd leiomyosrcom were ftigue, nuse, lopeci, constiption, peripherl neuropthy, bdominl pin, nd pyrexi. The most common ( 5%) Grde 3-4 lbortory bnormlities in liposrcom nd leiomyosrcom were neutropeni, hypoklemi, nd hypoclcemi. (6.1) To report SUSPECTED ADVERSE REACTINS, contct Eisi Inc. t (1-877-873-4724) or FDA t 1-8-FDA-188 or www.fd.gov/medwtch USE IN SPECIFIC PPULATINS Lcttion: Do not brestfeed. (8.2) eptic Impirment: A lower strting dose is recommended for ptients with mild (Child-Pugh A) nd moderte (Child-Pugh B) heptic impirment. Ptients with severe heptic impirment (Child-Pugh C) were not studied. (8.6) Renl Impirment: A lower strting dose is recommended for ptients with moderte (CLcr 3-49 ml/min) or severe (CLcr 15-29 ml/min) renl impirment. (8.7) See 17 for PATIENT CUNSELING INFRMATIN nd FDA-pproved Ptient Lbeling (Ptient Informtion). Revised: ctober 216 8 USE IN SPECIFIC PPULATINS 8.1 Pregnncy 8.2 Lcttion 8.3 Femles nd Mles of Reproductive Potentil 8.4 Peditric Use 8.5 Geritric Use 8.6 eptic Impirment 8.7 Renl Impirment 1 VERDSAGE 11 DESCRIPTIN 12 CLINICAL PARMACLGY 12.1 Mechnism of Action 12.2 Phrmcodynmics 12.3 Phrmcokinetics 13 NNCLINICAL TXICLGY 13.1 Crcinogenesis, Mutgenesis, Impirment of Fertility 14 CLINICAL STUDIES 14.1 Metsttic Brest Cncer 14.2 Liposrcom 16 W SUPPLIED/STRAGE AND ANDLING 17 PATIENT CUNSELING INFRMATIN *Sections or subsections omitted from the full prescribing informtion re not listed. If toxicities resolve or improve to Grde 2 severity by Dy 15, dminister ALAVEN t reduced dose nd initite the next cycle no sooner thn 2 weeks lter. Recommended dose reductions If dose hs been delyed for toxicity nd toxicities hve recovered to Grde 2 severity or less, resume ALAVEN t reduced dose s set out in Tble 1. Do not re-esclte ALAVEN dose fter it hs been reduced. Tble 1: Recommended Dose Reductions Recommended Event Description ALAVEN Dose Permnently reduce the 1.4 mg/m 2 ALAVEN dose for ny of the following: ANC <5/mm 3 for >7 dys ANC <1, /mm 3 with fever or infection Pltelets <25,/mm 3 1.1 mg/m 2 Pltelets <5,/mm 3 requiring trnsfusion Non-hemtologic Grde 3 or 4 toxicities mission or dely of Dy 8 ALAVEN dose in previous cycle for toxicity ccurrence of ny event requiring permnent dose reduction.7 mg/m while receiving 1.1 mg/m 2 2 ccurrence of ny event requiring permnent dose reduction Discontinue ALAVEN while receiving.7 mg/m 2 ANC = bsolute neutrophil count. Toxicities grded in ccordnce with Ntionl Cncer Institute (NCI) Common Terminology Criteri for Adverse Events (CTCAE) version 3.. 2.3 Instructions for Preprtion nd Administrtion Asepticlly withdrw the required mount of ALAVEN from the single-use vil nd dminister undiluted or diluted in 1 ml of.9% Sodium Chloride Injection, USP. Do not dilute in or dminister through n intrvenous line contining solutions with dextrose. Do not dminister in the sme intrvenous line concurrent with the other medicinl products.
Store undiluted ALAVEN in the syringe for up to 4 hours t room temperture or for up to 24 hours under refrigertion (4 F or 4 C). Store diluted solutions of ALAVEN for up to 4 hours t room temperture or up to 24 hours under refrigertion. Discrd unused portions of the vil. 3 DSAGE FRMS AND STRENGTS Injection: 1 mg/2 ml (.5 mg/ml). 4 CNTRAINDICATINS None. 5 WARNINGS AND PRECAUTINS 5.1 Neutropeni In Study 1, severe neutropeni (ANC < 5/mm 3 ) lsting more thn one week occurred in 12% (62/53) of ptients with metsttic brest cncer, leding to discontinution in <1% of ptients. Febrile neutropeni (fever 38.5 C with Grde 3 or 4 neutropeni) occurred in 5% (23/53) of ptients; two ptients (.4%) died from complictions of febrile neutropeni [see Adverse Rections (6.1)]. In Study 1, ptients with lnine minotrnsferse (ALT) or sprtte minotrnsferse (AST) > 3 ULN (upper limit of norml) experienced higher incidence of Grde 4 neutropeni nd febrile neutropeni thn ptients with norml minotrnsferse levels. Ptients with bilirubin > 1.5 ULN lso hd higher incidence of Grde 4 neutropeni nd febrile neutropeni. In Study 2, severe neutropeni (ANC < 5/mm 3 ) lsting more thn one week occurred in 12% (26/222) of ptients with liposrcom or leiomyosrcom. Febrile neutropeni occurred in.9% of ptients treted with ALAVEN nd ftl neutropenic sepsis in.9% [see Adverse Rections (6.1)]. Monitor complete blood counts prior to ech dose; increse the frequency of monitoring in ptients who develop Grde 3 or 4 cytopenis. Dely dministrtion of ALAVEN nd reduce subsequent doses in ptients who experience febrile neutropeni or Grde 4 neutropeni lsting longer thn 7 dys [see Dosge nd Administrtion (2.2)]. Clinicl studies of ALAVEN did not include ptients with bseline neutrophil counts below 1,5/mm 3. 5.2 Peripherl Neuropthy In Study 1, Grde 3 peripherl neuropthy occurred in 8% (4/53) of ptients, nd Grde 4 in.4% (2/53) of ptients with metsttic brest cncer (MBC). Peripherl neuropthy ws the most common toxicity leding to discontinution of ALAVEN (5% of ptients; 24/53) in Study 1. Neuropthy lsting more thn one yer occurred in 5% (26/53) of ptients. Twenty-two percent (19/53) of ptients developed new or worsening neuropthy tht hd not recovered within medin follow-up durtion of 269 dys (rnge 25-662 dys). In Study 2, Grde 3 peripherl neuropthy occurred in 3.1% (7/223) of ALAVEN-treted ptients. Peripherl neuropthy led to discontinution of ALAVEN in.9% of ptients. The medin time to first occurrence of peripherl neuropthy of ny severity ws 5 months (rnge: 3.5 months to 9 months). Neuropthy lsting more thn 6 dys occurred in 58% (38/65) of ptients. Sixty three percent (41/65) hd not recovered within medin follow-up durtion of 6.4 months (rnge: 27 dys to 29 months). Monitor ptients closely for signs of peripherl motor nd sensory neuropthy. Withhold ALAVEN in ptients who experience Grde 3 or 4 peripherl neuropthy, until resolution to Grde 2 or less [see Dosge nd Administrtion (2.2)]. 5.3 Embryo-Fetl Toxicity Bsed on findings from n niml reproduction study nd its mechnism of ction, ALAVEN cn cuse fetl hrm when dministered to pregnnt womn. There re no dequte nd well-controlled studies of ALAVEN in pregnnt women. In niml reproduction studies, eribulin mesylte cused embryo-fetl toxicity when dministered to pregnnt rts during orgnogenesis t doses below the recommended humn dose. Advise pregnnt women of the potentil risk to fetus. Advise femles of reproductive potentil to use effective contrception during tretment with ALAVEN nd for t lest 2 weeks following the finl dose. Advise mles with femle prtners of reproductive potentil to use effective contrception during tretment with ALAVEN nd for 3.5 months following the finl dose [see Use in Specific Popultions (8.1)]. 5.4 QT Prolongtion In n uncontrolled open-lbel ECG study in 26 ptients, QT prolongtion ws observed on Dy 8, independent of eribulin concentrtion, with no QT prolongtion observed on Dy 1. ECG monitoring is recommended if therpy is initited in ptients with congestive hert filure, brdyrrhythmis, drugs known to prolong the QT intervl, including Clss I nd III ntirrhythmics, nd electrolyte bnormlities. Correct hypoklemi or hypomgnesemi prior to inititing ALAVEN nd monitor these electrolytes periodiclly during therpy. Avoid ALAVEN in ptients with congenitl long QT syndrome. 6 ADVERSE REACTINS 6.1 Clinicl Trils Experience Becuse clinicl trils re conducted under widely vrying conditions, the dverse rection rtes observed in the clinicl trils of drug cnnot be directly compred to rtes in other clinicl trils nd my not reflect the rtes observed in clinicl prctice. The following dverse rections re discussed in detil in other sections of the lbeling: Neutropeni [see Wrnings nd Precutions (5.1)] Peripherl neuropthy [see Wrnings nd Precutions (5.2)] QT prolongtion [see Wrnings nd Precutions (5.4)] In clinicl trils, ALAVEN hs been dministered to 1963 ptients including 467 ptients exposed to ALAVEN for 6 months or longer. The mjority of the 1963 ptients were women (92%) with medin ge of 55 yers (rnge: 17 to 85 yers). The rcil nd ethnic distribution ws White (72%), Blck (4%), Asin (9%), nd other (3%). Metsttic Brest Cncer The most common dverse rections ( 25%) reported in ptients receiving ALAVEN were neutropeni, nemi, stheni/ftigue, lopeci, peripherl neuropthy, nuse, nd constiption. The most common serious dverse rections reported in ptients receiving ALAVEN were febrile neutropeni (4%) nd neutropeni (2%). The most common dverse rection resulting in discontinution of ALAVEN ws peripherl neuropthy (5%). The dverse rections described in Tble 2 were identified in 75 ptients treted in Study 1 [see Clinicl Studies (14.1)]. In Study 1, ptients were rndomized (2:1) to receive either ALAVEN (1.4 mg/m 2 on Dys 1 nd 8 of 21-dy cycle) or single gent tretment chosen by their physicin (control group). A totl of 53 ptients received ALAVEN nd 247 ptients in the control group received therpy consisting of chemotherpy [totl 97% (nthrcyclines 1%, cpecitbine 18%, gemcitbine 19%, txnes 15%, vinorelbine 25%, other chemotherpies 1%)] or hormonl therpy (3%). The medin durtion of exposure ws 118 dys for ptients receiving ALAVEN nd 63 dys for ptients receiving control therpy. Tble 2 reports the most common dverse rections occurring in t lest 1% of ptients in either group. Tble 2: Adverse Rections with Per-Ptient Incidence of t Lest 1% in Study 1 Adverse Rections ALAVEN Control Group n=53 n=247 All Grdes Grde 3 All Grdes Grde 3 Blood nd lymphtic system disorders b Neutropeni 82% 57% 53% 23% Anemi 58% 2% 55% 4% Nervous system disorders Peripherl neuropthy c 35% 8% 16% 2% edche 19% <1% 12% <1% Generl disorders Astheni/Ftigue 54% 1% 4% 11% Pyrexi 21% <1% 13% <1% Mucosl inflmmtion 9% 1% 1% 2% Gstrointestinl disorders Nuse 35% 1% 28% 3% Constiption 25% 1% 21% 1% Vomiting 18% 1% 18% 1% Dirrhe 18% 18% Musculoskeletl nd connective tissue disorders Arthrlgi/Mylgi 22% <1% 12% 1% Bck pin 16% 1% 7% 2% Bone pin 12% 2% 9% 2% Pin in extremity 11% 1% 1% 1% Metbolism nd nutrition disorders Decresed weight 21% 1% 14% <1% Anorexi 2% 1% 13% 1% Respirtory, thorcic, nd medistinl disorders Dyspne 16% 4% 13% 4% Cough 14% 9% Skin nd subcutneous tissue disorders Alopeci 45% NA d 1% NA d Infections Urinry Trct Infection 1% 1% 5% dverse rections were grded per Ntionl Cncer Institute Criteri for Adverse Events version 4.. b bsed upon lbortory dt. c includes peripherl neuropthy, peripherl sensorimotor neuropthy, peripherl motor neuropthy, polyneuropthy, peripherl sensory neuropthy, nd presthesi. d not pplicble; (grding system does not specify > Grde 2 for lopeci). Cytopenis: Grde 3 neutropeni occurred in 28% (143/53) of ptients who received ALAVEN in Study 1, nd 29% (144/53) of ptients experienced Grde 4 neutropeni. Febrile neutropeni occurred in 5% (23/53) of ptients; two ptients (.4%) died from complictions of febrile neutropeni. Dose reduction due to neutropeni ws required in 12% (62/53) of ptients nd discontinution ws required in <1% of ptients. The men time to ndir ws 13 dys nd the men time to recovery from severe neutropeni (<5/mm 3 ) ws 8 dys. Grde 3 or greter thrombocytopeni occurred in 1% (7/53) of ptients. G-CSF (grnulocyte colony-stimulting fctor) or GM-CSF (grnulocyte mcrophge colony-stimulting fctor) ws used in 19% of ptients who received ALAVEN. Peripherl Neuropthy: In Study 1, 17% of enrolled ptients hd Grde 1 peripherl neuropthy nd 3% of ptients hd Grde 2 peripherl neuropthy t bseline. Dose reduction due to peripherl neuropthy ws required by 3% (14/53) of ptients who received ALAVEN. Four percent (2/53) of ptients experienced peripherl motor neuropthy of ny grde nd 2% (8/53) of ptients developed Grde 3 peripherl motor neuropthy. Liver Function Test Abnormlities: Among ptients with Grde or 1 ALT levels t bseline, 18% of ALAVEN-treted ptients experienced Grde 2 or greter ALT elevtion. ne ALAVENtreted ptient without documented liver metstses hd concomitnt Grde 2 elevtions in bilirubin nd ALT; these bnormlities resolved nd did not recur with re-exposure to ALAVEN. Less Common Adverse Rections: The following dditionl dverse rections were reported in 5% to <1% of the ALAVEN-treted group: Eye Disorders: incresed lcrimtion Gstrointestinl Disorders: dyspepsi, bdominl pin, stomtitis, dry mouth Generl Disorders nd Administrtion Site Conditions: peripherl edem Infections nd Infesttions: upper respirtory trct infection Metbolism nd Nutrition Disorders: hypoklemi Musculoskeletl nd Connective Tissue Disorders: muscle spsms, musculr wekness Nervous System Disorders: dysgeusi, dizziness Psychitric Disorders: insomni, depression Skin nd Subcutneous Tissue Disorders: rsh Liposrcom The sfety of ALAVEN ws evluted in Study 2, n open-lbel, rndomized, multicenter, ctive-controlled tril, in which ptients were rndomized (1:1) to receive either ALAVEN 1.4 mg/m 2 on Dys 1 nd 8 of 21-dy cycle or dcrbzine t doses of 85 mg/m 2 (2%), 1 mg/m 2 (64%), or 12 mg/m 2 (16%) every 3 weeks. A totl of 223 ptients received ALAVEN nd 221 ptients received dcrbzine. Ptients were required to hve received t lest two prior systemic chemotherpy regimens. The tril excluded ptients with pre-existing Grde 3 peripherl neuropthy, known centrl nervous system metstsis, elevted serum bilirubin or significnt chronic liver disese, history of myocrdil infrction within 6 months, history of New York ert Assocition Clss II or IV hert filure, or crdic rrhythmi requiring tretment. The medin ge of the sfety popultion in Study 2 ws 56 yers (rnge: 24 to 83 yers); 67% femle; 73% White, 3% Blck or Africn Americn, 8% Asin/Pcific Islnder, nd 15% unknown; 99% received prior nthrcycline-contining regimen; nd 99% received 2 prior regimens. The medin durtion of exposure ws 2.3 months (rnge: 21 dys to 26 months) for ptients receiving ALAVEN [see Clinicl Studies (14.2)].
The most common dverse rections ( 25%) reported in ptients receiving ALAVEN were ftigue, nuse, lopeci, constiption, peripherl neuropthy, bdominl pin, nd pyrexi. The most common ( 5%) Grde 3-4 lbortory bnormlities reported in ptients receiving ALAVEN were neutropeni, hypoklemi, nd hypoclcemi. The most common serious dverse rections reported in ptients receiving ALAVEN were neutropeni (4.9%) nd pyrexi (4.5%). Permnent discontinution of ALAVEN for dverse rections occurred in 8% of ptients. The most common dverse rections resulting in discontinution of ALAVEN were ftigue nd thrombocytopeni (.9% ech). Twenty-six percent of ptients required t lest one dose reduction. The most frequent dverse rections tht led to dose reduction were neutropeni (18%) nd peripherl neuropthy (4.%). Tble 3 summrizes the incidence of dverse rections occurring in t lest 1% of ptients in the ALAVEN-treted rm in Study 2. Tble 3: Adverse Rections ccurring in 1% (ll Grdes) of Ptients Treted on the ALAVEN rm nd t igher Incidence thn in the Dcrbzine Arm (Between Arm Difference of 5% for All Grdes or 2% for Grdes 3 nd 4) (Study 2) b ALAVEN Dcrbzine Adverse Rection n=223 n=221 All Grdes Grdes 3-4 All Grdes Grdes 3-4 Nervous system disorders Peripherl Neuropthy c 29% 3.1% 8%.5% edche 18% % 1% % Generl disorders Pyrexi 28%.9% 14%.5% Gstrointestinl disorders Constiption 32%.9% 26%.5% Abdominl pin d 29% 1.8% 23% 4.1% Stomtitis 14%.9% 5%.5% Skin nd subcutneous tissue disorders Alopeci 35% NA e 2.7% NA e Infections Urinry trct infection 11% 2.2% 5%.5% Adverse rections were grded per Ntionl Cncer Institute Criteri for Adverse Events version 4.3 (NCI CTCAE v4.3). b Sfety dt from one study site enrolling six ptients were excluded. c Includes peripherl neuropthy, peripherl sensorimotor neuropthy, peripherl motor neuropthy, polyneuropthy, peripherl sensory neuropthy, nd presthesi. d Includes bdominl pin, upper bdominl pin, lower bdominl pin, bdominl discomfort. e Not pplicble; (grding system does not specify > Grde 2 for lopeci). ther cliniclly importnt dverse rections occurring in 1% of the ALAVEN-treted ptients were: Gstrointestinl Disorders: nuse (41%); vomiting (19%), dirrhe (17%) Generl Disorders: stheni/ftigue (62%); peripherl edem (12%) Metbolism nd Nutrition Disorders: decresed ppetite (19%) Musculoskeletl nd Connective Tissue Disorders: rthrlgi/mylgi (16%); bck pin (16%) Respirtory Disorders: cough (18%) Less Common Adverse Rections: The following dditionl cliniclly importnt dverse rections were reported in 5% to <1% of the ALAVEN-treted group: Blood nd Lymphtic System Disorders: thrombocytopeni Eye Disorders: incresed lcrimtion Gstrointestinl Disorders: dyspepsi Metbolism nd Nutrition Disorders: hyperglycemi Musculoskeletl nd Connective Tissue Disorders: muscle spsms, musculoskeletl pin Nervous System Disorders: dizziness, dysgeusi Psychitric Disorders: insomni, nxiety Respirtory, Thorcic, nd Medistinl Disorders: orophryngel pin Vsculr Disorders: hypotension Tble 4: Lbortory Abnormlities ccurring in 1% (ll Grdes) of Ptients Treted on the ALAVEN rm nd t igher Incidence thn in the Dcrbzine Arm (Between Arm Difference of 5% for All Grdes or 2% for Grdes 3 nd 4) (Study 2) Lbortory Abnormlity lven Dcrbzine All Grdes Grdes 3-4 All Grdes Grdes 3-4 emtology Anemi 7% 4.1% 52% 6% Neutropeni 63% 32% 3% 8.9% Chemistry Incresed lnine minotrnsferse (ALT) 43% 2.3% 28% 2.3% Incresed sprtte minotrnsferse (AST) 36%.9% 16%.5% ypoklemi 3% 5.4% 14% 2.8% ypoclcemi 28% 5% 18% 1.4% ypophosphtemi 2% 3.2% 11% 1.4% Ech test incidence is bsed on the number of ptients who hd both bseline nd t lest one on-study mesurement nd t lest 1 grde increse from bseline. lven group (rnge 221-222) nd dcrbzine group (rnge 214-215) Lbortory results were grded per NCI CTCAE v4.3. 6.2 Postmrketing Experience The following dverse drug rections hve been identified during post-pprovl of ALAVEN. Becuse these rections re reported voluntrily from popultion of uncertin size, it is not lwys possible to relibly estimte their frequency or estblish cusl reltionship to drug exposure. Blood nd Lymphtic System Disorders: lymphopeni Gstrointestinl Disorders: pncretitis eptobiliry Disorders: heptotoxicity Immune System Disorders: drug hypersensitivity Infections nd Infesttions: pneumoni, sepsis/neutropenic sepsis Metbolism nd Nutrition Disorders: hypomgnesemi, dehydrtion Respirtory, thorcic nd medistinl disorders: interstitil lung disese Skin nd Subcutneous Tissue Disorders: pruritus, Stevens-Johnson syndrome, toxic epiderml necrolysis 7 DRUG INTERACTINS 7.1 Effects of ther Drugs on ALAVEN No drug-drug interctions re expected with CYP3A4 inhibitors, CYP3A4 inducers or P-glycoprotein (P-gp) inhibitors. Cliniclly meningful differences in exposure (AUC) were not observed in ptients with dvnced solid tumors when ALAVEN ws dministered with or without ketoconzole ( strong inhibitor of CYP3A4 nd P-gp inhibitor) nd when ALAVEN ws dministered with or without rifmpin ( CYP3A4 inducer) [see Clinicl Phrmcology (12.3)]. 7.2 Effect of ALAVEN on ther Drugs Eribulin does not inhibit CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A4 enzymes or induce CYP1A2, CYP2C9, CYP2C19 or CYP3A4 enzymes t relevnt clinicl concentrtions. Eribulin is not expected to lter the plsm concentrtions of drugs tht re substrtes of these enzymes [see Clinicl Phrmcology (12.3)]. 8 USE IN SPECIFIC PPULATINS 8.1 Pregnncy Risk Summry Bsed on findings from n niml reproduction study nd its mechnism of ction, ALAVEN cn cuse fetl hrm when dministered to pregnnt womn [see Clinicl Phrmcology (12.1)]. There re no vilble dt on the use of ALAVEN during pregnncy. In n niml reproduction study, eribulin mesylte cused embryo-fetl toxicity when dministered to pregnnt rts during orgnogenesis t doses below the recommended humn dose [see Dt]. Advise pregnnt women of the potentil risk to fetus. The estimted bckground risks of mjor birth defects nd miscrrige for the indicted popultions re unknown. In the U.S. generl popultion, the estimted bckground risk of mjor birth defects nd miscrrige in cliniclly-recognized pregnncies is 2% to 4% nd 15% to 2%, respectively. Dt Animl Dt In n embryo-fetl developmentl toxicity study, pregnnt rts received intrvenous infusion of eribulin mesylte during orgnogenesis (Gesttion Dys 8, 1, nd 12) t doses pproximtely.4,.13,.43 nd.64 times the recommended humn dose, bsed on body surfce re. Incresed bortion nd severe fetl externl or soft tissue mlformtions, including the bsence of lower jw nd tongue, or stomch nd spleen, were observed t doses.64 times the recommended humn dose of 1.4 mg/m 2 bsed on body surfce re. Incresed embryo-fetl deth/resorption, reduced fetl weights, nd minor skeletl nomlies consistent with developmentl dely were lso reported t doses t or bove mternlly toxic dose of pproximtely.43 times the recommended humn dose. 8.2 Lcttion Risk Summry There is no informtion regrding the presence of eribulin mesylte or its metbolites in humn milk, the effects on the brestfed infnt, or the effects on milk production. No lcttion studies in nimls were conducted. Becuse of the potentil for serious dverse rections in brestfed infnts from eribulin mesylte, dvise women not to brestfeed during tretment with ALAVEN nd for 2 weeks fter the finl dose. 8.3 Femles nd Mles of Reproductive Potentil Contrception Femles Bsed on findings from n niml reproduction study nd its mechnism of ction, ALAVEN cn cuse fetl hrm when dministered to pregnnt womn [see Use in Specific Popultions (8.1)]. Advise femles of reproductive potentil to use effective contrception during tretment with ALAVEN nd for t lest 2 weeks following the finl dose. Mles Bsed on its mechnism of ction, dvise mles with femle prtners of reproductive potentil to use effective contrception during tretment with ALAVEN nd for 3.5 months following the finl dose. Infertility Mles Bsed on niml dt, ALAVEN my result in dmge to mle reproductive tissues leding to impired fertility of unknown durtion [see Nonclinicl Toxicology (13.1)]. 8.4 Peditric Use The sfety nd effectiveness of ALAVEN in peditric ptients below the ge of 18 yers hve not been estblished. 8.5 Geritric Use Study 1 did not include sufficient numbers of subjects with metsttic brest cncer ged 65 yers nd older to determine whether they respond differently from younger subjects. f the 827 subjects who received the recommended dose nd schedule of ALAVEN in clinicl studies with dvnced brest cncer, 15% (121/827) were 65 nd older, nd 2% (17/827) ptients were 75 nd older. No overll differences in sfety were observed between these subjects nd younger subjects. Clinicl studies of ALAVEN did not include sufficient number of subjects in Study 2 ged 65 yers nd older to determine whether they respond differently from younger subjects. 8.6 eptic Impirment Administrtion of ALAVEN t dose of 1.1 mg/m 2 to ptients with mild heptic impirment nd.7 mg/m 2 to ptients with moderte heptic impirment resulted in similr exposure to eribulin s dose of 1.4 mg/m 2 to ptients with norml heptic function. Therefore, lower strting dose of 1.1 mg/m 2 is recommended for ptients with mild heptic impirment (Child-Pugh A) nd of.7 mg/m 2 is recommended for ptients with moderte heptic
impirment (Child-Pugh B). ALAVEN ws not studied in ptients with severe heptic impirment (Child-Pugh C) [see Dosge nd Administrtion (2.1), Clinicl Phrmcology (12.3)]. 8.7 Renl Impirment For ptients with moderte or severe renl impirment (CLcr 15-49 ml/min), reduce the strting dose to 1.1 mg/m 2 [see Dosge nd Administrtion (2.1), Clinicl Phrmcology (12.3)]. 1 VERDSAGE verdosge of ALAVEN hs been reported t pproximtely 4 times the recommended dose, which resulted in Grde 3 neutropeni lsting seven dys nd Grde 3 hypersensitivity rection lsting one dy. There is no known ntidote for ALAVEN overdose. 11 DESCRIPTIN ALAVEN contins eribulin mesylte, microtubule dynmics inhibitor. Eribulin mesylte is synthetic nlogue of hlichondrin B, product isolted from the mrine sponge lichondri okdi. The chemicl nme for eribulin mesylte is 11,15:18,21:24,28-Triepoxy-7,9-ethno- 12,15-methno-9,15-furo[3,2-i]furo[2',3':5,6]pyrno[4,3-b][1,4]dioxcyclopentcosin-5(4)-one, 2-[(2S)-3-mino-2-hydroxypropyl]hexcoshydro-3-methoxy-26-methyl-2,27-bis(methylene)-, (2R,3R,3S,7R,8S,9S,1R,11S,12R,13R,13bS,15S,18S,21S,24S,26R,28R,29S)-, methnesulfonte (slt). It hs moleculr weight of 826. (729.9 for free bse). The empiricl formul is C 4 59 N 11 C 4 3 S. Eribulin mesylte hs the following structurl formul: 3 C 2 N C 2 3 C S 3 C 3 2 C ALAVEN is cler, colorless, sterile solution for intrvenous dministrtion. Ech vil contins 1 mg of eribulin mesylte s.5 mg/ml solution in ethnol: wter (5:95). 12 CLINICAL PARMACLGY 12.1 Mechnism of Action Eribulin inhibits the growth phse of microtubules without ffecting the shortening phse nd sequesters tubulin into nonproductive ggregtes. Eribulin exerts its effects vi tubulin-bsed ntimitotic mechnism leding to G 2 /M cell-cycle block, disruption of mitotic spindles, nd, ultimtely, poptotic cell deth fter prolonged mitotic blockge. In ddition, eribulin tretment of humn brest cncer cells cused chnges in morphology nd gene expression s well s decresed migrtion nd invsiveness in vitro. In mouse xenogrft models of humn brest cncer, eribulin tretment ws ssocited with incresed vsculr perfusion nd permebility in the tumor cores, resulting in reduced tumor hypoxi, nd chnges in the expression of genes in tumor specimens ssocited with chnge in phenotype. 12.2 Phrmcodynmics Crdic Electrophysiology The effect of ALAVEN on the QTc intervl ws ssessed in n open-lbel, uncontrolled, multicenter, single-rm dedicted QT tril. A totl of 26 ptients with solid tumors received 1.4 mg/m 2 of ALAVEN on Dys 1 nd 8 of 21-dy cycle. A delyed QTc prolongtion ws observed on Dy 8, with no prolongtion observed on Dy 1. The mximum men QTcF chnge from bseline (95% upper confidence intervl) ws 11.4 (19.5) ms. 12.3 Phrmcokinetics The phrmcokinetics (PK) of eribulin is liner with men elimintion hlf-life of pproximtely 4 hours, men volume of distribution of 43 L/m 2 to 114 L/m 2 nd men clernce of 1.16 L/hr/m 2 to 2.42 L/hr/m 2 over the dose rnge of.25 mg/m 2 to 4. mg/m 2. The humn plsm protein binding of eribulin t concentrtions of 1 ng/ml to 1, ng/ml rnges from 49% to 65%. Eribulin exposure fter multiple dosing is comprble to tht following single dose. No ccumultion of eribulin is observed with weekly dministrtion. Elimintion Metbolism Unchnged eribulin ws the mjor circulting species in plsm following dministrtion of 14 C-eribulin to ptients. Metbolite concentrtions represented <.6% of prent compound, confirming tht there re no mjor humn metbolites of eribulin. Cytochrome P45 3A4 (CYP3A4) negligibly metbolizes eribulin in vitro. Excretion Eribulin is eliminted primrily in feces unchnged. After dministrtion of 14 C-eribulin to ptients, pproximtely 82% of the dose ws eliminted in feces nd 9% in urine. Unchnged eribulin ccounted for pproximtely 88% nd 91% of totl eribulin in feces nd urine, respectively. Specific Popultions Age, Sex, nd Rce/Ethnicity: Bsed on popultion phrmcokinetic nlysis with dt collected from 34 ptients, sex, rce, nd ge do not hve cliniclly meningful effect on the exposure of eribulin. eptic Impirment In study evluting the effect of heptic impirment on the PK of eribulin, eribulin exposures incresed by 1.8-fold in ptients with mild heptic impirment (Child-Pugh A; n=7) nd by 2.5-fold in ptients with moderte (Child-Pugh B; n=5) heptic impirment s compred to ptients with norml heptic function (n=6). Administrtion of ALAVEN t dose of 1.1 mg/m 2 to ptients with mild heptic impirment nd.7 mg/m 2 to ptients with moderte heptic impirment resulted in similr exposure to eribulin t dose of 1.4 mg/m 2 to ptients with norml heptic function [see Dosge nd Administrtion (2.1), Use in Specific Popultions (8.6)]. Renl Impirment In study evluting the effect of renl impirment on the PK of eribulin, ptients with moderte (CLcr 3-49 ml/min; n=7) nd severe renl impirment (CLcr 15-29 ml/min; n=6) hd 1.5-fold higher eribulin dose-normlized exposures compred to tht in ptients with norml renl function (CLcr 8 ml/min; n=6). There were no cliniclly meningful chnges in ptients with mild renl impirment (CLcr 5-79 ml/min; n=27) [see Dosge nd Administrtion (2.1), Use in Specific Popultions (8.7)]. Drug Interction Studies Effect of Strong Inhibitors or Inducers of CYP3A4 on Eribulin: The effect of strong CYP3A4 inhibitor nd P-gp inhibitor, ketoconzole, on the PK of eribulin ws studied in crossover tril of 12 ptients with dvnced solid tumors. No cliniclly relevnt PK interction ws observed when ALAVEN ws dministered with or without ketoconzole (the geometric men rtio of the AUC:.97; 9% CI:.83, 1.12). The effect of CYP3A4 inducer, rifmpin, on the PK of eribulin ws studied in crossover tril of 14 ptients with dvnced solid tumors. No cliniclly relevnt PK interction ws observed when ALAVEN ws dministered with or without rifmpin (the geometric men rtio of the AUC: 1.1; 9 CI%:.91, 1.34). Effect of Eribulin on CYP Substrtes: Eribulin shows no induction potentil for CYP1A, CYP2B6, CYP2C9, CYP2C19, nd CYP3A in primry humn heptocytes. Eribulin inhibits CYP3A4 ctivity in humn liver microsomes, but it is unlikely tht eribulin will substntilly increse the plsm levels of CYP3A4 substrtes. No significnt inhibition of CYP1A2, CYP2C9, CYP2C19, CYP2D6, or CYP2E1 ws detected with eribulin concentrtions up to 5 μm in pooled humn liver microsomes. In vitro drug interction studies indicte tht eribulin does not inhibit drugs tht re substrtes of these enzymes nd it is unlikely tht eribulin will ffect plsm levels of drugs tht re substrtes of CYP enzymes. Effect of Trnsporters on Eribulin: In vitro dt suggest tht eribulin t cliniclly relevnt concentrtions is substrte of P-gp, but is not substrte of brest cncer resistnce protein (BCRP), multidrug resistnce proteins (MRP2, MRP4), bile slt extrusion pump (BSEP), orgnic nion trnsporting polypeptides (ATP1B1, ATP1B3), orgnic nion trnsporters (AT1, AT3), orgnic ction trnsporters (CT1, CT2), or multidrug nd toxin extrusion 1 (MATE1). Effect of Eribulin on Trnsporters: In vitro dt suggest tht eribulin t cliniclly relevnt concentrtions my inhibit P-gp, but does not inhibit BCRP, ATP1B1, CT1, AT1, AT3, or MATE1. 13 NNCLINICAL TXICLGY 13.1 Crcinogenesis, Mutgenesis, Impirment of Fertility Crcinogenicity studies hve not been conducted with eribulin mesylte. Eribulin mesylte ws not mutgenic in in vitro bcteril reverse muttion ssys (Ames test). Eribulin mesylte ws positive in mouse lymphom mutgenesis ssys, nd ws clstogenic in n in vivo rt bone mrrow micronucleus ssy. Fertility studies hve not been conducted with eribulin mesylte in humns or nimls; however, nonclinicl findings in repet-dose dog nd rt toxicology studies suggest tht mle fertility my be compromised by tretment with eribulin mesylte. Rts exhibited testiculr toxicity (hypocellulrity of seminiferous epithelium with hypospermi/spermi) following dosing with eribulin mesylte t or bove.43 times the recommended humn dose (bsed on body surfce re) given once weekly for 3 weeks, or t or bove.21 times the recommended humn dose (bsed on body surfce re) given once weekly for 3 out of 5 weeks, repeted for 6 cycles. Testiculr toxicity ws lso observed in dogs given.64 times the recommended humn dose (bsed on body surfce re) weekly for 3 out of 5 weeks, repeted for 6 cycles. 14 CLINICAL STUDIES 14.1 Metsttic Brest Cncer Study 1 ws n open-lbel, rndomized, multicenter tril of 762 ptients with metsttic brest cncer who received t lest two chemotherpeutic regimens for the tretment of metsttic disese nd experienced disese progression within 6 months of their lst chemotherpeutic regimen. Ptients were required to receive prior nthrcycline- nd txne-bsed chemotherpy for djuvnt or metsttic disese. Ptients were rndomized (2:1) to receive ALAVEN (n=58) or single gent therpy selected prior to rndomiztion (control rm, n=254). Rndomiztion ws strtified by geogrphic region, ER2/neu sttus, nd prior cpecitbine exposure. ALAVEN ws dministered t dose of 1.4 mg/m 2 on Dys 1 nd 8 of 21-dy cycle. ALAVEN-treted ptients received medin of 5 cycles (rnge: 1 to 23 cycles) of therpy. Control rm therpy consisted of 97% chemotherpy (26% vinorelbine, 18% gemcitbine, 18% cpecitbine, 16% txne, 9% nthrcycline, 1% other chemotherpy), nd 3% hormonl therpy. The min efficcy outcome ws overll survivl. Ptient demogrphic nd bseline chrcteristics were comprble between the tretment rms. The medin ge ws 55 (rnge: 27 to 85 yers) nd 92% were White. Sixty-four percent of ptients were enrolled in North Americ/Western Europe/Austrli, 25% in Estern Europe/ Russi, nd 11% in Ltin Americ/South Afric. Ninety-one percent of ptients hd bseline ECG performnce sttus of or 1. Tumor prognostic chrcteristics, including estrogen receptor sttus (positive: 67%, negtive: 28%), progesterone receptor sttus (positive: 49%, negtive: 39%), ER2/neu receptor sttus (positive: 16%, negtive: 74%), triple negtive sttus (ER -, PR -, ER2/neu - : 19%), presence of viscerl disese (82%, including 6% liver nd 38% lung) nd bone disese (61%), nd number of sites of metstses (greter thn two: 5%), were lso similr in the ALAVEN nd control rms. Ptients received medin of four prior chemotherpy regimens in both rms. In Study 1, sttisticlly significnt improvement in overll survivl ws observed in ptients rndomized to the ALAVEN rm compred to the control rm (see Tble 5). An updted, unplnned survivl nlysis, conducted when 77% of events hd been observed (see Figure 1), ws consistent with the primry nlysis. In ptients rndomized to ALAVEN, the objective response rte by the RECIST criteri ws 11% (95% CI: 8.6%, 14.3%) nd the medin response durtion ws 4.2 months (95% CI: 3.8, 5. months). Tble 5: Comprison of verll Survivl in ALAVEN nd Control Arm - Study 1 verll Survivl ALAVEN (n=58) Control Arm (n=254) Primry survivl nlysis Number of deths 274 148 Medin, months (95% CI) 13.1 (11.8, 14.3) 1.6 (9.3, 12.5) zrd Rtio (95% CI).81 (.66,.99) P vlue b.41 Updted survivl nlysis Number of deths 386 23 Medin, months (95% CI) 13.2 (12.1, 14.4) 1.6 (9.2, 12.) CI = confidence intervl Bsed on Cox proportionl hzrds model strtified by geogrphic region, ER2 sttus, nd prior cpecitbine therpy. b Bsed on log-rnk test strtified by geogrphic region, ER2 sttus, nd prior cpecitbine therpy.
Figure 1: Updted verll Survivl Anlysis for Study 1 Figure 2: Kpln-Meier Curves of verll Survivl in the Liposrcom Strtum in Study 2 1..9.8 1..8 ALAVEN Dcrbzine Proportion of Ptients Alive.7.6.5.4.3.2.1. ALAVEN (N=58) CNTRL (N=254) Survivl Probbility.6.4.2. 3 6 9 12 15 18 21 24 27 3 33 36 39 42 45 Subjects t Risk: ALAVEN 71 63 Dcrbzine 72 59 51 42 43 33 39 22 34 17 3 12 Survivl Time (months) 2 11 15 6 12 3 7 2 4 2 Number of 58 Ptients t Risk 254 6 12 18 24 3 36 Time (months) 46 178 274 16 14.2 Liposrcom The efficcy nd sfety of ALAVEN were evluted in Study 2, n open-lbel, rndomized (1:1), multicenter, ctive-controlled tril. Eligible ptients were required to hve unresectble, loclly dvnced or metsttic liposrcom or leiomyosrcom, t lest two prior systemic chemotherpies (one of which must hve included n nthrcycline), nd disese progression within 6 months of the most recent chemotherpy regimen. Ptients were rndomized to ALAVEN 1.4 mg/m 2 dministered intrvenously on Dys 1 nd 8 of 21-dy cycle or to dcrbzine t dose of 85 mg/m 2, 1 mg/m 2, or 12 mg/m 2 dministered intrvenously every 21 dys (dcrbzine dose ws selected by the investigtor prior to rndomiztion). Tretment continued until disese progression or uncceptble toxicity. Rndomiztion ws strtified by histology (liposrcom or leiomyosrcom), number of prior therpies (2 vs. > 2), nd geogrphic region (U.S. nd Cnd vs. Western Europe, Austrli, nd Isrel vs. Estern Europe, Ltin Americ, nd Asi). The mjor efficcy outcome mesure ws overll survivl (S). Additionl efficcy outcome mesures were progression-free survivl (PFS) nd confirmed objective response rte (RR) s ssessed by the investigtor ccording to Response Evlution Criteri in Solid Tumors (RECIST v1.1). Ptients in the dcrbzine rm were not offered ALAVEN t the time of disese progression. A totl of 446 ptients were rndomized, 225 to the ALAVEN rm nd 221 to the dcrbzine rm. The medin ge ws 56 yers (rnge: 24 to 83); 33% were mle; 73% were White; 44% hd ECG performnce sttus (PS) nd 53% hd ECG PS 1; 68% hd leiomyosrcom nd 32% hd liposrcom; 39% were enrolled in U.S. nd Cnd (Region 1) nd 46% were enrolled in Western Europe, Austrli, nd Isrel (Region 2); nd 47% received more thn two prior systemic chemotherpies. The most common (>4%) prior systemic chemotherpies were doxorubicin (9%), ifosfmide (62%), gemcitbine (59%), trbectedin (5%), nd docetxel (48%). f the 143 ptients with liposrcom, the medin ge ws 55 yers (rnge: 32 to 83); 62% were mle, 72% were White; 41% hd ECG PS of nd 53% hd ECG PS of 1; 35% were enrolled in Region 1 nd 51% were enrolled in Region 2; nd 44% received more thn two prior systemic chemotherpies. The distribution of subtypes of liposrcom, bsed on locl histologic ssessment, were 45% dedifferentited, 37% myxoid/round cell, nd 18% pleomorphic. Study 2 demonstrted sttisticlly significnt improvement in S in ptients rndomized to ALAVEN compred with dcrbzine (see Tble 6). There ws no significnt difference in progression-free survivl in the overll popultion. Tretment effects of ALAVEN were limited to ptients with liposrcom bsed on pre-plnned, explortory subgroup nlyses of S nd PFS (see Tbles 6 nd 7 nd Figure 2). There ws no evidence of efficcy of ALAVEN in ptients with dvnced or metsttic leiomyosrcom in Study 2 (see Tble 7). Tble 6: Efficcy Results for the Liposrcom Strtum nd All Ptients* in Study 2 Liposrcom All Ptients* lven (n=71) Strtum 142 61 Dcrbzine (n=72) 54 26 11 5 lven (n=225) Dcrbzine (n=221) verll Survivl Deths, n (%) 52 (73) 63 (88) 173 (77) 179 (81) Medin, months (95% CI) 15.6 8.4 13.5 11.3 (1.2, 18.6) (5.2, 1.1) (11.1, 16.5) (9.5, 12.6) zrd rtio (R) (95% CI).51 (.35,.75).75 (.61,.94) Strtified log-rnk p vlue N/A.11 Progression-free survivl Events, n (%) 57 (8) 59 (82) 194 (86) 185 (84) Disese progression 53 52 18 17 Deth 4 7 14 15 Medin, months (95% CI) 2.9 (2.6, 4.8) 1.7 (1.4, 2.6) 2.6 (2., 2.8) 2.6 (1.7, 2.7) R (95% CI).52 (.35,.78).86 (.69, 1.6) bjective response rte bjective response rte (%) (95% CI) 1.4 (, 7.6) (, 4.2) 4. (1.8, 7.5) 5. (2.5, 8.7) Efficcy dt from one study site enrolling six ptients were excluded. * All ptients = liposrcom nd leiomyosrcom. N/A = not pplicble Tble 7: Efficcy Results for the Leiomyosrcom Strtum in Study 2 Leiomyosrcom Strtum lven (n=154) Dcrbzine (n=149) verll survivl Deths, n (%) 121 (79) 116 (78) Medin, months (95% CI) 12.8 (1.3, 14.8) 12.3 (11., 15.1) R (95% CI).9 (.69, 1.18) Progression-free survivl Events, n (%) 137 (89) 126 (85) Disese progression 127 118 Deth 1 8 Medin, months (95% CI) 2.2 (1.5, 2.7) 2.6 (2.2, 2.9) R (95% CI) 1.5 (.81, 1.35) bjective response rte (%) (95% CI) 5.2 (2.3, 1) 7.4 (3.7, 12.8) Efficcy dt from one study site enrolling six ptients were excluded. 16 W SUPPLIED/STRAGE AND ANDLING NDC 62856-389-1 Injection: 1 mg/2 ml, in single-use vil. ne vil per crton. Store t 25 C (77 F); excursions permitted to 15 3 C (59 86 F). Do not freeze. Store the vils in their originl crtons. 17 PATIENT CUNSELING INFRMATIN Advise the ptient to red the FDA-pproved ptient lbeling (Ptient Informtion). Neutropeni Advise ptients to contct their helth cre provider for fever of 1.5 F or greter or other signs or symptoms of infection such s chills, cough, or burning or pin on urintion [see Wrnings nd Precutions (5.1)]. Peripherl Neuropthy Advise ptients to inform their helthcre providers of new or worsening numbness, tingling nd pin in their extremities [see Wrnings nd Precutions (5.2)]. Embryo-Fetl Toxicity Advise femles of reproductive potentil of the potentil risk to fetus nd to inform their helthcre provider of known or suspected pregnncy [see Wrnings nd Precutions (5.3), Use in Specific Popultions (8.1)]. Advise femles of reproductive potentil to use effective contrception during tretment with ALAVEN nd for t lest 2 weeks fter the finl dose [see Use in Specific Popultions (8.3)]. Advise mles with femle prtners of reproductive potentil to use effective contrception during tretment with ALAVEN nd for 3.5 months following the finl dose [see Use in Specific Popultions (8.3)]. Lcttion Advise women not to brestfeed during tretment with ALAVEN nd for 2 weeks fter the finl dose [see Use in Specific Popultions (8.2)]. Distributed by: Eisi Inc. Woodcliff Lke, NJ 7677 ALAVEN is registered trdemrk used by Eisi Inc. under license from Eisi R&D Mngement Co., Ltd. 216 Eisi Inc. All rights reserved. ALA-US277(1) Printed in USA / ctober 216