HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights d nt include all the infrmatin needed t use ISTODAX safely and effectively. See full prescribing infrmatin fr ISTODAX. ISTODAX (rmidepsin) fr injectin Fr intravenus infusin nly Initial US Apprval: 2009 --------------------------INDICATIONS AND USAGE---------------------------- ISTODAX is a histne deacetylase (HDAC) inhibitr indicated fr: Treatment f cutaneus T-cell lymphma (CTCL) in patients wh have received at least ne prir systemic therapy (1). Treatment f peripheral T-cell lymphma (PTCL) in patients wh have received at least ne prir therapy (1). These indicatins are based n respnse rate. Clinical benefit such as imprvement in verall survival has nt been demnstrated (1). Electrcardigraphic (ECG) changes have been bserved. Cnsider cardivascular mnitring precautins in patients with cngenital lng QT syndrme, a histry f significant cardivascular disease, and patients taking medicinal prducts that lead t significant QT prlngatin. Ensure that ptassium and magnesium are within the nrmal range befre administratin f ISTODAX (5.3). Tumr lysis syndrme has been reprted during treatment with ISTODAX. Patients with advanced stage disease and/r high tumr burden shuld be clsely mnitred and apprpriate precautins taken (5.4). ISTODAX may cause fetal harm when administered t a pregnant wman. Advise wmen f ptential hazard t the fetus and t avid pregnancy while receiving Istdax (5.5, 8.1). -------------------------------ADVERSE REACTIONS------------------------------ The mst cmmn adverse reactins were neutrpenia, lymphpenia, thrmbcytpenia, infectins, nausea, fatigue, vmiting, anrexia, anemia, and ECG T-wave changes (6). -----------------------DOSAGE AND ADMINISTRATION----------------------- 14 mg/m 2 administered intravenusly (IV) ver a 4-hur perid n days 1, 8, and 15 f a 28-day cycle. Repeat cycles every 28 days prvided that the patient cntinues t benefit frm and tlerates the drug (2.1). Treatment discntinuatin r interruptin with r withut dse reductin t 10 mg/m 2 may be needed t manage adverse drug reactins (2.2). ----------------------DOSAGE FORMS AND STRENGTHS--------------------- ISTODAX fr injectin, 10 mg, supplied with ne Diluent vial cntaining 2 ml (deliverable vlume) f slutin (3). -------------------------------CONTRAINDICATIONS------------------------------ Nne. -----------------------WARNINGS AND PRECAUTIONS----------------------- Treatment with ISTODAX has been assciated with thrmbcytpenia, leukpenia (neutrpenia and lymphpenia), and anemia; therefre, mnitr these hematlgical parameters during treatment with ISTODAX, mdify the dse as necessary (5.1). Serius and smetimes fatal infectins have been reprted during treatment and within 30 days after treatment with ISTODAX (5.2). T reprt SUSPECTED ADVERSE REACTIONS, cntact Celgene Crpratin at 1-888-423-5436 r the FDA at 1-800-FDA-1088 r www.fda.gv/medwatch. -------------------------------DRUG INTERACTIONS------------------------------ Carefully mnitr prthrmbin time (PT) and Internatinal Nrmalized Rati (INR) in patients cncurrently administered ISTODAX and Cumadin derivatives (7.1). Mnitr fr txicities related t increased rmidepsin expsure when cadministering rmidepsin with strng CYP3A4 inhibitrs (7.2). Avid use with rifampin and strng CYP3A4 inducers (7.3). See 17 fr PATIENT COUNSELING INFORMATION and FDAapprved patient labeling. Revised: June/2013 FULL PRESCRIBING INFORMATION CONTENTS* 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Dsing Infrmatin 2.2 Dse Mdificatin 2.3 Instructins fr Preparatin and Intravenus Administratin 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Hematlgic 5.2 Infectin 5.3 Electrcardigraphic Changes 5.4 Tumr Lysis Syndrme 5.5 Use in Pregnancy 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Pstmarketing Experience 7 DRUG INTERACTIONS 7.1 Cumadin r Cumadin Derivatives 7.2 Drugs that Inhibit Cytchrme P450 3A4 Enzymes 7.3 Drugs that Induce Cytchrme P450 3A4 Enzymes 7.4 Drugs that Inhibit Drug Transprt Systems 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.3 Nursing Mthers 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Hepatic Impairment 8.7 Renal Impairment 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism f Actin 12.2 Pharmacdynamics 12.3 Pharmackinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcingenesis, Mutagenesis, Impairment f Fertility 14 CLINICAL STUDIES 14.1 14.2 Cutaneus T-Cell Lymphma Peripheral T-Cell Lymphma 15 REFERENCES 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 16.2 Hw Supplied Strage 17 PATIENT COUNSELING INFORMATION 17.1 Instructins *Sectins r subsectins mitted frm the Full Prescribing Infrmatin are nt listed.
2 FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE ISTODAX is indicated fr: Treatment f cutaneus T-cell lymphma (CTCL) in patients wh have received at least ne prir systemic therapy. Treatment f peripheral T-cell lymphma (PTCL) in patients wh have received at least ne prir therapy. These indicatins are based n respnse rate. Clinical benefit such as imprvement in verall survival has nt been demnstrated. 2 DOSAGE AND ADMINISTRATION 2.1 Dsing Infrmatin The recmmended dse f rmidepsin is 14 mg/m 2 administered intravenusly ver a 4-hur perid n days 1, 8, and 15 f a 28-day cycle. Cycles shuld be repeated every 28 days prvided that the patient cntinues t benefit frm and tlerates the drug. 2.2 Dse Mdificatin Nnhematlgic txicities except alpecia Grade 2 r 3 txicity: Treatment with rmidepsin shuld be delayed until txicity returns t Grade 1 r baseline, then therapy may be restarted at 14 mg/m 2. If Grade 3 txicity recurs, treatment with rmidepsin shuld be delayed until txicity returns t Grade 1 r baseline and the dse shuld be permanently reduced t 10 mg/m 2. Grade 4 txicity: Treatment with rmidepsin shuld be delayed until txicity returns t Grade 1 r baseline, then the dse shuld be permanently reduced t 10 mg/m 2. Rmidepsin shuld be discntinued if Grade 3 r 4 txicities recur after dse reductin. Hematlgic txicities Grade 3 r 4 neutrpenia r thrmbcytpenia: Treatment with rmidepsin shuld be delayed until the specific cytpenia returns t ANC 1.5 10 9 /L and/r platelet cunt 75 10 9 /L r baseline, then therapy may be restarted at 14 mg/m 2. Grade 4 febrile ( 38.5ºC) neutrpenia r thrmbcytpenia that requires platelet transfusin: Treatment with rmidepsin shuld be delayed until the specific cytpenia returns t Grade 1 r baseline, and then the dse shuld be permanently reduced t 10 mg/m 2. 2.3 Instructins fr Preparatin and Intravenus Administratin ISTODAX shuld be handled in a manner cnsistent with recmmended safe prcedures fr handling cyttxic drugs. ISTODAX must be recnstituted with the supplied diluent and further diluted with 0.9% Sdium Chlride Injectin, USP befre intravenus infusin. Each 10 mg single-use vial f ISTODAX (rmidepsin) must be recnstituted with 2 ml f the supplied Diluent. With a suitable syringe, aseptically withdraw 2 ml frm the supplied Diluent vial, and slwly inject it int the ISTODAX (rmidepsin) fr injectin vial. Swirl the cntents f the vial until there are n visible particles in the resulting slutin. The recnstituted slutin will cntain ISTODAX 5 mg/ml. The recnstituted ISTODAX slutin is chemically stable fr at least 8 hurs at rm temperature. Extract the apprpriate amunt f ISTODAX frm the vials t deliver the desired dse, using prper aseptic technique. Befre intravenus infusin, further dilute ISTODAX in 500 ml 0.9% Sdium Chlride Injectin, USP. Infuse ver 4 hurs. The diluted slutin is cmpatible with plyvinyl chlride (PVC), ethylene vinyl acetate (EVA), plyethylene (PE) infusin bags as well as glass bttles, and is chemically stable fr at least 24 hurs when stred at rm temperature. Hwever, it shuld be administered as sn after dilutin as pssible. Parenteral drug prducts shuld be inspected visually fr particulate matter and disclratin befre administratin, whenever slutin and cntainer permit. 3 DOSAGE FORMS AND STRENGTHS ISTODAX is supplied as a kit which includes a sterile, lyphilized pwder in a single-use vial cntaining 10 mg f rmidepsin and 20 mg f the bulking agent, pvidne, USP. In additin, each kit includes 1 sterile vial cntaining 2 ml (deliverable vlume) f the Diluent cmpsed f 80% prpylene glycl, USP, and 20% dehydrated alchl, USP. 4 CONTRAINDICATIONS Nne. 5 WARNINGS AND PRECAUTIONS 5.1 Hematlgic Treatment with ISTODAX can cause thrmbcytpenia, leukpenia (neutrpenia and lymphpenia), and anemia; therefre, these hematlgical parameters shuld be mnitred during treatment with ISTODAX, and the dse shuld be mdified, as necessary [See Dsage and Administratin (2.2) and Adverse Reactins (6)]. 5.2 Infectin Serius and smetimes fatal infectins, including pneumnia and sepsis, have been reprted in clinical trials with ISTODAX. These can ccur during treatment and within 30 days after treatment, and the risk f life threatening infectins may be higher in patients with a histry f extensive r intensive chemtherapy [See Adverse Reactins (6)].
5.3 Electrcardigraphic Changes Several treatment-emergent mrphlgical changes in ECGs (including T-wave and ST-segment changes) have been reprted in clinical studies. The clinical significance f these changes is unknwn [See Adverse Reactins (6)]. In patients with cngenital lng QT syndrme, patients with a histry f significant cardivascular disease, and patients taking anti-arrhythmic medicines r medicinal prducts that lead t significant QT prlngatin, apprpriate cardivascular mnitring precautins shuld be cnsidered, such as the mnitring f electrlytes and ECGs at baseline and peridically during treatment. Ptassium and magnesium shuld be within the nrmal range befre administratin f ISTODAX [See Adverse Reactins (6)]. 3 5.4 Tumr Lysis Syndrme Tumr lysis syndrme (TLS) has been reprted t ccur in 1% f patients with tumr stage CTCL and 2% f patients with Stage III/IV PTCL. Patients with advanced stage disease and/r high tumr burden shuld be clsely mnitred, apprpriate precautins shuld be taken, and treatment shuld be instituted as apprpriate. 5.5 Use in Pregnancy There are n adequate and well-cntrlled studies f ISTODAX in pregnant wmen. Hwever, based n its mechanism f actin and findings in animals, ISTODAX may cause fetal harm when administered t a pregnant wman. In an animal reprductive study, rmidepsin was embrycidal and resulted in adverse effects n the develping fetus at expsures belw thse in patients at the recmmended dse f 14 mg/m 2 /week. If this drug is used during pregnancy, r if the patient becmes pregnant while taking ISTODAX, the patient shuld be apprised f the ptential hazard t the fetus [See Use in Specific Ppulatins (8.1)]. 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience Because clinical trials are cnducted under widely varying cnditins, adverse reactin rates bserved in the clinical trials f a drug cannt be directly cmpared t rates in the clinical trials f anther drug and may nt reflect the rates bserved in practice. Cutaneus T-Cell Lymphma The safety f ISTODAX was evaluated in 185 patients with CTCL in 2 single arm clinical studies in which patients received a starting dse f 14 mg/m 2. The mean duratin f treatment in these studies was 5.6 mnths (range: <1 t 83.4 mnths). Cmmn Adverse Reactins Table 1 summarizes the mst frequent adverse reactins (> 20%) regardless f causality using the Natinal Cancer Institute-Cmmn Terminlgy Criteria fr Adverse Events (NCI-CTCAE, Versin 3.0). Due t methdlgical differences between the studies, the AE data are presented separately fr Study 1 and Study 2. Adverse reactins are ranked by their incidence in Study 1. Labratry abnrmalities cmmnly reprted (> 20%) as adverse reactins are included in Table 1.
4 Table 1. Adverse Reactins Occurring in >20% f Patients in Either CTCL Study (N=185) Adverse Reactins n (%) All Grade 3 r 4 All Grade 3 r 4 Any adverse reactin 99 (97) 36 (35) 83 (100) 68 (82) Nausea 57 (56) 3 (3) 71 (86) 5 (6) Asthenia/Fatigue 54 (53) 8 (8) 64 (77) 12 (14) Infectins 47 (46) 11 (11) 45 (54) 27 (33) Vmiting 35 (34) 1 (<1) 43 (52) 8 (10) Anrexia 23 (23) 1 (<1) 45 (54) 3 (4) Hypmagnesemia 22 (22) 1 (<1) 23 (28) 0 Diarrhea 20 (20) 1 (<1) 22 (27) 1 (1) Pyrexia 20 (20) 4 (4) 19 (23) 1 (1) Anemia 19 (19) 3 (3) 60 (72) 13 (16) Thrmbcytpenia 17 (17) 0 54 (65) 12 (14) Dysgeusia 15 (15) 0 33 (40) 0 Cnstipatin 12 (12) 2 (2) 32 (39) 1 (1) Neutrpenia 11 (11) 4 (4) 47 (57) 22 (27) Hyptensin 7 (7) 3 (3) 19 (23) 3 (4) Pruritus 7 (7) 0 26 (31) 5 (6) Hypkalemia 6 (6) 0 17 (20) 2 (2) Dermatitis/Exfliative dermatitis 4 (4) 1 (<1) 22 (27) 7 (8) Hypcalcemia 4 (4) 0 43 (52) 5 (6) Leukpenia 4 (4) 0 38 (46) 18 (22) Lymphpenia 4 (4) 0 47 (57) 31 (37) Alanine amintransferase increased 3 (3) 0 18 (22) 2 (2) Aspartate amintransferase increased 3 (3) 0 23 (28) 3 (4) Hypalbuminemia 3 (3) 1 (<1) 40 (48) 3 (4) Electrcardigram ST-T wave changes 2 (2) 0 52 (63) 0 Hyperglycemia 2 (2) 2 (2) 42 (51) 1 (1) Hypnatremia 1 (<1) 1 (<1) 17 (20) 2 (2) Hypermagnesemia 0 0 22 (27) 7 (8) Hypphsphatemia 0 0 22 (27) 8 (10) Hyperuricemia 0 0 27 (33) 7 (8) Serius Adverse Reactins Infectins were the mst cmmn type f SAE reprted in bth studies with 8 patients (8%) in Study 1 and 26 patients (31%) in Study 2 experiencing a serius infectin. Serius adverse reactins reprted in > 2% f patients in Study 1 were sepsis and pyrexia (3%). In Study 2, serius adverse reactins in > 2% f patients were fatigue (7%), supraventricular arrhythmia, central line infectin, neutrpenia (6%), hyptensin, hyperuricemia, edema (5%), ventricular arrhythmia, thrmbcytpenia, nausea, leukpenia, dehydratin, pyrexia, aspartate amintransferase increased, sepsis, catheter related infectin, hypphsphatemia and dyspnea (4%). Mst deaths were due t disease prgressin. In Study 1, there were tw deaths due t cardipulmnary failure and acute renal failure. In Study 2, there were six deaths due t infectin (4), mycardial ischemia, and acute respiratry distress syndrme. Study 1 (n=102) Study 2 (n=83) Discntinuatins Discntinuatin due t an adverse event ccurred in 21% f patients in Study 1 and 11% in Study 2. Discntinuatins ccurring in at least 2% f patients in either study included infectin, fatigue, dyspnea, QT prlngatin, and hypmagnesemia. Peripheral T-Cell Lymphma The safety f ISTODAX was evaluated in 178 patients with PTCL in a spnsr-cnducted pivtal study (Study 3) and a secndary NCI-spnsred study (Study 4) in which patients received a starting dse f 14 mg/m 2. The mean duratin f treatment and number f cycles in these studies were 5.6 mnths and 6 cycles. Cmmn Adverse Reactins Table 2 summarizes the mst frequent adverse reactins ( 10%) regardless f causality, using the NCI-CTCAE, Versin 3.0. The AE data are presented separately fr Study 3 and Study 4. Labratry abnrmalities cmmnly reprted ( 10%) as adverse reactins are included in Table 2.
5 Table 2. Adverse Reactins Occurring in 10% f Patients with PTCL in Study 3 and Crrespnding Incidence in Study 4 (N=178) Adverse Reactins n (%) All Grade 3 r 4 All Grade 3 r 4 Study 3 (N=131) Any adverse reactins 127 (97) 86 (66) 47 (100) 40 (85) Gastrintestinal disrders Nausea 77 (59) 3 (2) 35 (75) 3 (6) Vmiting 51 (39) 6 (5) 19 (40) 4 (9) Diarrhea 47 (36) 3 (2) 17 (36) 1 (2) Cnstipatin 39 (30) 1 (<1) 19 (40) 1 (2) Abdminal pain 18 (14) 3 (2) 6 (13) 1 (2) Stmatitis 13 (10) 0 3 (6) 0 General disrders and administratin site cnditins Asthenia/Fatigue 72 (55) 11 (8) 36 (77) 9 (19) Pyrexia 46 (35) 7 (5) 22 (47) 8 (17) Chills 14 (11) 1 (<1) 8 (17) 0 Edema peripheral 13 (10) 1 (<1) 3 (6) 0 Bld and lymphatic system disrders Thrmbcytpenia 53 (41) 32 (24) 34 (72) 17 (36) Neutrpenia 39 (30) 26 (20) 31 (66) 22 (47) Anemia 32 (24) 14 (11) 29 (62) 13 (28) Leukpenia 16 (12) 8 (6) 26 (55) 21 (45) Metablism and nutritin disrders Anrexia 37 (28) 2 (2) 21 (45) 1 (2) Hypkalemia 14 (11) 3 (2) 8 (17) 1 (2) Nervus system disrders Dysgeusia 27 (21) 0 13 (28) 0 Headache 19 (15) 0 16 (34) 1 (2) Respiratry, thracic and mediastinal disrders Cugh 23 (18) 0 10 (21) 0 Dyspnea 17 (13) 3 (2) 10 (21) 2 (4) Investigatins Weight decreased 13 (10) 0 7 (15) 0 Cardiac disrders Tachycardia 13 (10) 0 0 0 Serius Adverse Reactins Infectins were the mst cmmn type f SAE reprted. In Study 3, 25 patients (19%) experienced a serius infectin, including 6 patients (5%) with serius treatment-related infectins. In Study 4, 11 patients (23%) experienced a serius infectin, including 8 patients (17%) with serius treatment-related infectins. Serius adverse reactins reprted in 2% f patients in Study 3 were pyrexia (7%), pneumnia, sepsis, vmiting (5%), cellulitis, deep vein thrmbsis, (4%), febrile neutrpenia, abdminal pain (3%), chest pain, neutrpenia, pulmnary emblism, dyspnea, and dehydratin (2%). In Study 4, serius adverse reactins in 2 patients were pyrexia (17%), aspartate amintransferase increased, hyptensin (13%), anemia, thrmbcytpenia, alanine amintransferase increased (11%), infectin, dehydratin, dyspnea (9%), lymphpenia, neutrpenia, hyperbilirubinemia, hypcalcemia, hypxia (6%), febrile neutrpenia, leukpenia, ventricular arrhythmia, vmiting, hypersensitivity, catheter related infectin, hyperuricemia, hypalbuminemia, syncpe, pneumnitis, packed red bld cell transfusin, and platelet transfusin (4%). Deaths due t all causes within 30 days f the last dse f ISTODAX ccurred in 7% f patients in Study 3 and 17% f patients in Study 4. In Study 3, there were 5 deaths unrelated t disease prgressin that were due t infectins, including multi-rgan failure/sepsis, pneumnia, septic shck, candida sepsis, and sepsis/cardigenic shck. In Study 4, there were 3 deaths unrelated t disease prgressin that were due t sepsis, aspartate amintransferase elevatin in the setting f Epstein Barr virus reactivatin, and death f unknwn cause. Discntinuatins Discntinuatin due t an adverse event ccurred in 19% f patients in Study 3 and in 28% f patients in Study 4. In Study 3, thrmbcytpenia and pneumnia were the nly events leading t treatment discntinuatin in at least 2% f patients. In Study 4, events leading t treatment discntinuatin in 2 patients were thrmbcytpenia (11%), anemia, infectin, and alanine amintransferase increased (4%). Study 4 (N=47) 6.2 Pstmarketing Experience N additinal safety signals have been bserved frm pstmarketing experience. 7 DRUG INTERACTIONS 7.1 Cumadin r Cumadin Derivatives Prlngatin f PT and elevatin f INR were bserved in a patient receiving ISTODAX cncmitantly with warfarin. Althugh the interactin ptential between ISTODAX and Cumadin r Cumadin derivatives has nt been frmally studied, physicians shuld carefully mnitr PT and INR in patients cncurrently administered ISTODAX and Cumadin r Cumadin derivatives [See Clinical Pharmaclgy (12.3)]. 7.2 Drugs that Inhibit Cytchrme P450 3A4 Enzymes Rmidepsin is metablized by CYP3A4. Strng CYP3A4 inhibitrs increase cncentratins f rmidepsin. In a pharmackinetic drug interactin trial the strng CYP3A4 inhibitr ketcnazle increased rmidepsin (AUC 0- ) by apprximately 25% [See Clinical Pharmaclgy (12.3)]. Mnitr fr txicity related t increased rmidepsin expsure and fllw the dse mdificatins fr txicity [see Dsage and Administratin (2.2)] when rmidepsin is initially c-administered with strng CYP3A4 inhibitrs (e.g., ketcnazle, itracnazle, clarithrmycin, atazanavir, indinavir, nefazdne, nelfinavir, ritnavir, saquinavir, telithrmycin, vricnazle).
6 7.3 Drugs that Induce Cytchrme P450 3A4 Enzymes Avid c-administratin f ISTODAX with rifampin. In a pharmackinetic drug interactin trial with c-administered rifampin (a strng CYP3A4 inducer), rmidepsin expsure was increased by apprximately 80% and 60% fr AUC 0- and C max, respectively [See Clinical Pharmaclgy (12.3)]. Typically, c-administratin f CYP3A4 inducers decrease cncentratins f drugs metablized by CYP3A4. The increase in expsure seen after c-administratin with rifampin is likely due t rifampin s inhibitin f an undetermined hepatic uptake prcess that is predminantly respnsible fr the dispsitin f ISTODAX. It is unknwn if ther ptent CYP3A4 inducers (e.g., dexamethasne, carbamazepine, phenytin, rifabutin, rifapentine, phenbarbital, St. Jhn s Wrt) wuld alter the expsure f ISTODAX. Therefre, the use f ther ptent CYP3A4 inducers shuld be avided when pssible. 7.4 Drugs that Inhibit Drug Transprt Systems Rmidepsin is a substrate f the efflux transprter P-glycprtein (P-gp, ABCB1). If ISTODAX is administered with drugs that inhibit P-gp, increased cncentratins f rmidepsin are likely, and cautin shuld be exercised. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Categry D [See Warnings and Precautins (5.5)]. There are n adequate and well-cntrlled studies f ISTODAX in pregnant wmen. Hwever, based n its mechanism f actin and findings in animals, ISTODAX may cause fetal harm when administered t a pregnant wman. In an animal reprductive study, rmidepsin was embrycidal and resulted in adverse effects n the develping fetus at expsures belw thse in patients at the recmmended dse. If this drug is used during pregnancy, r if the patient becmes pregnant while taking ISTODAX, the patient shuld be apprised f the ptential hazard t the fetus. Rmidepsin was administered intravenusly t rats during the perid f rgangenesis at dses f 0.1, 0.2, r 0.5 mg/kg/day. Substantial resrptin r pstimplantatin lss was bserved at the high-dse f 0.5 mg/kg/day, a maternally txic dse. Adverse embry-fetal effects were nted at rmidepsin dses f 0.1 mg/kg/day, with systemic expsures (AUC) 0.2% f the human expsure at the recmmended dse f 14 mg/m 2 /week. Drug-related fetal effects cnsisted f flded retina, rtated limbs, and incmplete sternal ssificatin. 8.3 Nursing Mthers It is nt knwn whether rmidepsin is excreted in human milk. Because many drugs are excreted in human milk and because f the ptential fr serius adverse reactins in nursing infants frm ISTODAX, a decisin shuld be made whether t discntinue nursing r discntinue the drug, taking int accunt the imprtance f the drug t the mther. 8.4 Pediatric Use The safety and effectiveness f ISTODAX in pediatric patients has nt been established. 8.5 Geriatric Use Of the apprximately 300 patients with CTCL r PTCL in trials, abut 25% were >65 years ld. N verall differences in safety r effectiveness were bserved between these subjects and yunger subjects; hwever, greater sensitivity f sme lder individuals cannt be ruled ut. 8.6 Hepatic Impairment N dedicated hepatic impairment study fr ISTODAX has been cnducted. Mild hepatic impairment des nt alter pharmackinetics f rmidepsin based n a ppulatin pharmackinetic analysis. Patients with mderate and severe hepatic impairment shuld be treated with cautin [See Clinical Pharmaclgy (12.3)]. 8.7 Renal Impairment N dedicated renal impairment study fr ISTODAX has been cnducted. Based upn the ppulatin pharmackinetic analysis, renal impairment is nt expected t significantly influence drug expsure. The effect f end-stage renal disease n rmidepsin pharmackinetics has nt been studied. Thus, patients with end-stage renal disease shuld be treated with cautin [See Clinical Pharmaclgy (12.3)]. 10 OVERDOSAGE N specific infrmatin is available n the treatment f verdsage f ISTODAX. Txicities in a single-dse study in rats r dgs, at intravenus rmidepsin dses up t 2.2 fld the recmmended human dse based n the bdy surface area, included irregular respiratin, irregular heart beat, staggering gait, tremr, and tnic cnvulsins. In the event f an verdse, it is reasnable t emply the usual supprtive measures, e.g., clinical mnitring and supprtive therapy, if required. There is n knwn antidte fr ISTODAX and it is nt knwn if ISTODAX is dialyzable. 11 DESCRIPTION Rmidepsin, a histne deacetylase (HDAC) inhibitr, is a bicyclic depsipeptide. At rm temperature, rmidepsin is a white pwder and is described chemically as (1S,4S,7Z,10S,16E,21R)-7-ethylidene-4,21-bis(1-methylethyl)-2-xa-12,13-dithia-5,8,20,23-tetraazabicycl[8.7.6]trics-16-ene-3,6,9,19,22-pentne. The empirical frmula is C 24 H 36 N 4 O 6 S 2.
The mlecular weight is 540.71 and the structural frmula is: H O CH 3 HN CH 3 S HN H 3 C O S H O NH HN O H O CH 3 7 H O CH 3 ISTODAX (rmidepsin) fr injectin is intended fr intravenus infusin nly after recnstitutin with the supplied Diluent and after further dilutin with 0.9% Sdium Chlride, USP. ISTODAX is supplied as a kit cntaining tw vials. ISTODAX (rmidepsin) fr injectin is a sterile lyphilized white pwder and is supplied in a single-use vial cntaining 10 mg rmidepsin and 20 mg pvidne, USP. Diluent fr ISTODAX is a sterile clear slutin and is supplied in a single-use vial cntaining a 2-mL deliverable vlume. Diluent fr ISTODAX cntains 80% (v/v) prpylene glycl, USP and 20% (v/v) dehydrated alchl, USP. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism f Actin Rmidepsin is a histne deacetylase (HDAC) inhibitr. HDACs catalyze the remval f acetyl grups frm acetylated lysine residues in histnes, resulting in the mdulatin f gene expressin. HDACs als deacetylate nn-histne prteins, such as transcriptin factrs. In vitr, rmidepsin causes the accumulatin f acetylated histnes, and induces cell cycle arrest and apptsis f sme cancer cell lines with IC 50 values in the nanmlar range. The mechanism f the antineplastic effect f rmidepsin bserved in nnclinical and clinical studies has nt been fully characterized. 12.2 Pharmacdynamics Cardiac Electrphysilgy The effect f rmidepsin n the heart-rate crrected QTc/QTcF was evaluated in 26 subjects with advanced malignancies given rmidepsin at dses f 14 mg/m 2 as a 4- hur intravenus infusin, and at dses f 8, 10 r 12 mg/m 2 as a 1 hur infusin. Patients received premedicatins with antiemetics. N large changes in the mean QTc interval (> 20 millisecnds) frm baseline based n Fridericia crrectin methd were detected in the trial. Small increase in mean QT interval (< 10 millisecnds) and mean QT interval increase between 10 t 20 millisecnds cannt be excluded because f the limitatins in the trial design. Rmidepsin was assciated with a delayed cncentratin-dependent increase in heart rate in patients with advanced cancer with a maximum mean increase in heart rate f 20 beats per minute ccurring at the 6 hur time pint after start f rmidepsin infusin fr patients receiving 14 mg/m 2 as a 4-hur infusin. 12.3 Pharmackinetics Absrptin Rmidepsin exhibited linear pharmackinetics acrss dses ranging frm 1.0 t 24.9 mg/m 2 when administered intravenusly ver 4 hurs in patients with advanced cancers. In patients with T-cell lymphmas wh received 14 mg/m 2 f rmidepsin intravenusly ver a 4-hur perid n days 1, 8, and 15 f a 28-day cycle, gemetric mean values f the maximum plasma cncentratin (C max ) and the area under the plasma cncentratin versus time curve (AUC 0-inf ) were 377 ng/ml and 1549 ng*hr/ml, respectively. Distributin Rmidepsin is highly prtein bund in plasma (92% t 94%) ver the cncentratin range f 50 ng/ml t 1000 ng/ml with α1-acid-glycprtein (AAG) being the principal binding prtein. Rmidepsin is a substrate f the efflux transprter P-glycprtein (P-gp, ABCB1). In vitr, rmidepsin accumulates int human hepatcytes via an unknwn active uptake prcess. Rmidepsin is nt a substrate f the fllwing uptake transprters: BCRP, BSEP, MRP2, OAT1, OAT3, OATP1B1, OATP1B3, r OCT2. In additin, rmidepsin is nt an inhibitr f BCRP, MRP2, MDR1 r OAT3. Althugh rmidepsin did nt inhibit OAT1, OCT2, and OATP1B3 at cncentratins seen clinically (1 μml/l), mdest inhibitin was bserved at 10 uml/l. Rmidepsin was fund t be an inhibitr f BSEP and OATP1B1. Metablism Rmidepsin underges extensive metablism in vitr primarily by CYP3A4 with minr cntributin frm CYP3A5, CYP1A1, CYP2B6, and CYP2C19. At therapeutic cncentratins, rmidepsin did nt cmpetitively inhibit CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, r CYP3A4 in vitr. At therapeutic cncentratins, rmidepsin did nt cause ntable inductin f CYP1A2, CYP2B6 and CYP3A4 in vitr. Therefre, pharmackinetic drug-drug interactins are unlikely t ccur due t CYP450 inductin r inhibitin by rmidepsin when c-administered with CYP450 substrates. Excretin Fllwing 4-hur intravenus administratin f rmidepsin at 14 mg/m 2 n days 1, 8, and 15 f a 28-day cycle in patients with T-cell lymphmas, the terminal half-life (t 1/2 ) was apprximately 3 hurs. N accumulatin f plasma cncentratin f rmidepsin was bserved after repeated dsing.
Drug Interactins Ketcnazle: A drug interactin clinical trial with the strng CYP3A4 inhibitr, ketcnazle, was cnducted in patients with advanced cancer. Fllwing cadministratin f 8 mg/m 2 ISTODAX (4-hur infusin) with ketcnazle, the verall rmidepsin expsure was increased by apprximately 25% and 10% fr AUC 0- and C max, respectively, cmpared t rmidepsin alne, and the difference between the tw treatments was statistically significant. C-administratin f ketcnazle slightly decreased the rmidepsin clearance and vlume f distributin, but did nt have a statistically significant effect n peak expsure (C max ). [See Drug Interactins (7.2)] Rifampin: A drug interactin clinical trial with the strng CYP3A4 inducer, rifampin, was cnducted in patients with advanced cancer. Fllwing c-administratin f 14 mg/m 2 ISTODAX (4-hur infusin) with rifampin, the verall rmidepsin expsure was unexpectedly increased by apprximately 80% and 60% fr AUC 0- and C max, respectively, cmpared t rmidepsin alne, and the difference between the tw treatments was statistically significant. C-administratin f rifampin decreased the rmidepsin clearance and vlume f distributin by 44% and 52%, respectively. The increase in expsure seen after c-administratin with rifampin is likely due t rifampin s inhibitin f a undetermined hepatic uptake prcess that is predminant fr the dispsitin f ISTODAX. [See Drug Interactins (7.3)] Use in Specific Ppulatins 8 Effect f Age, Gender r Race The ppulatin pharmackinetic analysis f rmidepsin shwed that age, gender, r race (white vs. black) did nt appear t influence the pharmackinetics f rmidepsin. Effect f Hepatic Impairment N dedicated hepatic impairment study has been cnducted fr ISTODAX. The ppulatin pharmackinetic analysis indicates that mild hepatic impairment [ttal bilirubin (TB) upper limit f nrmal (ULN) and aspartate amintransferase (AST) > ULN; r TB > 1.0x - 1.5x ULN and any AST] had n significant influence n rmidepsin pharmackinetics. As the effect f mderate (TB > 1.5x - 3x ULN and any AST) and severe (TB > 3x ULN and any AST) hepatic impairment n the pharmackinetics f rmidepsin is unknwn, patients with mderate and severe hepatic impairment shuld be treated with cautin [See Use in Specific Ppulatins (8.6)]. Effect f Renal Impairment N dedicated renal impairment study has been cnducted fr ISTODAX. The ppulatin pharmackinetic analysis shwed that rmidepsin pharmackinetics were nt affected by mild (estimated creatinine clearance 50-80 ml/min), mderate (estimated creatinine clearance 30-50 ml/min), r severe (estimated creatinine clearance < 30 ml/min) renal impairment. Nnetheless, the effect f end-stage renal disease n rmidepsin pharmackinetics has nt been studied. Thus, patients with end-stage renal disease shuld be treated with cautin [See Use in Specific Ppulatins (8.7)]. 13 NONCLINICAL TOXICOLOGY 13.1 Carcingenesis, Mutagenesis, Impairment f Fertility Carcingenicity studies have nt been perfrmed with rmidepsin. Rmidepsin was nt mutagenic in vitr in the bacterial reverse mutatin assay (Ames test) r the muse lymphma assay. Rmidepsin was nt clastgenic in an in viv rat bne marrw micrnucleus assay when tested t the maximum tlerated dse (MTD) f 1 mg/kg in males and 3 mg/kg in females (6 and 18 mg/m 2 in males and females, respectively). These dses were up t 1.3-fld the recmmended human dse, based n bdy surface area. Based n nn-clinical findings, male and female fertility may be cmprmised by treatment with ISTODAX. In a 26-week txiclgy study, rmidepsin administratin resulted in testicular degeneratin in rats at 0.33 mg/kg/dse (2 mg/m 2 /dse) fllwing the clinical dsing schedule. This dse resulted in AUC 0-inf. values that were apprximately 2% the expsure level in patients receiving the recmmended dse f 14 mg/m 2 /dse. A similar effect was seen in mice after 4 weeks f drug administratin at higher dses. Seminal vesicle and prstate rgan weights were decreased in a separate study in rats after 4 weeks f daily drug administratin at 0.1 mg/kg/day (0.6 mg/m 2 /day), apprximately 30% the estimated human daily dse based n bdy surface area. Rmidepsin shwed high affinity fr binding t estrgen receptrs in pharmaclgy studies. In a 26-week txiclgy study in rats, atrphy was seen in the vary, uterus, vagina and mammary gland f females administered dses as lw as 0.1 mg/kg/dse (0.6 mg/m 2 /dse) fllwing the clinical dsing schedule. This dse resulted in AUC 0-inf. values that were 0.3% f thse in patients receiving the recmmended dse f 14 mg/m 2 /dse. Maturatin arrest f varian fllicles and decreased weight f varies were bserved in a separate study in rats after fur weeks f daily drug administratin at 0.1 mg/kg/day (0.6 mg/m 2 /day). This dse is apprximately 30% the estimated human daily dse based n bdy surface area. 14 CLINICAL STUDIES 14.1 Cutaneus T-Cell Lymphma ISTODAX was evaluated in 2 multicenter, single-arm clinical studies in patients with CTCL. Overall, 167 patients with CTCL were treated in the US, Eurpe, and Australia. Study 1 included 96 patients with cnfirmed CTCL after failure f at least 1 prir systemic therapy. Study 2 included 71 patients with a primary diagnsis f CTCL wh received at least 2 prir skin directed therapies r ne r mre systemic therapies. Patients were treated with ISTODAX at a starting dse f 14 mg/m 2 infused ver 4 hurs n days 1, 8, and 15 every 28 days. In bth studies, patients culd be treated until disease prgressin at the discretin f the investigatr and lcal regulatrs. Objective disease respnse was evaluated accrding t a cmpsite endpint that included assessments f skin invlvement, lymph nde and visceral invlvement, and abnrmal circulating T-cells ( Sézary cells ). The primary efficacy endpint fr bth studies was verall bjective disease respnse rate (ORR) based n the investigatr assessments, and defined as the prprtin f patients with cnfirmed cmplete respnse (CR) r partial respnse (PR). CR was defined as n evidence f disease and PR as 50% imprvement in disease. Secndary endpints in bth studies included duratin f respnse and time t respnse.
9 Baseline Patient Characteristics Demgraphic and disease characteristics f the patients in Study 1 and Study 2 are prvided in Table 3. Clinical Results Table 3. Baseline Patient Characteristics (CTCL Ppulatin) Characteristic Study 1 (N=96) Study 2 (N=71) Age N 96 71 Mean (SD) 57 (12) 56 (13) Median (Range) 57 (21, 89) 57 (28, 84) Sex, n (%) Men 59 (61) 48 (68) Wmen 37 (39) 23 (32) Race, n (%) White 90 (94) 55 (77) Black 5 ( 5) 15 (21) Other/Nt Reprted 1 ( 1) 1 ( 1) Stage f Disease at Study Entry, n (%) IA 0 ( 0) 1 ( 1) IB 15 (16) 6 ( 9) IIA 13 (14) 2 ( 3) IIB 21 (22) 14 (20) III 23 (24) 9 (13) IVA 24 (25) 27 (38) IVB 0 ( 0) 12 (17) Number f Prir Skin-Directed Therapies Median (Range) 2 (0,6) 1 (0,3) Number f Prir Systemic Therapies Median (Range) 2 (1, 8) 2 (0, 7) Efficacy utcmes fr CTCL patients are prvided in Table 4. Median time t first respnse was 2 mnths (range 1 t 6) in bth studies. Median time t CR was 4 mnths in Study 1 and 6 mnths in Study 2 (range 2 t 9). Table 4. Clinical Results fr CTCL Patients Respnse Rate ORR (CR + PR), n (%) [95% Cnfidence Interval] CR, n (%) [95% Cnfidence Interval] PR, n (%) [95% Cnfidence Interval] Study 1 (N=96) 33 (34) [25, 45] 6 (6) [2, 13] 27 (28) [19, 38] Study 2 (N=71) 25 (35) [25, 49] 4 (6) [2, 14] 21 (30) [20, 43] Duratin f Respnse (mnths) N 33 25 Median (range) 15 (1, 20*) 11 (1, 66*) *dentes censred value 14.2 Peripheral T-Cell Lymphma ISTODAX was evaluated in a multicenter, single-arm, internatinal clinical study in patients with PTCL wh had failed at least 1 prir systemic therapy (Study 3). Patients in US, Eurpe and Australia were treated with ISTODAX at a dse f 14 mg/m 2 infused ver 4 hurs n days 1, 8, and 15 every 28 days. Of the 131 patients treated, 130 patients had histlgical cnfirmatin by independent central review and were evaluable fr efficacy (HC Ppulatin). Six cycles f treatment were planned; patients wh develped prgressive disease (PD), significant txicity, r wh met anther criterin fr study terminatin were t discntinue treatment. Respnding patients had the ptin f cntinuing treatment beynd 6 cycles at the discretin f the patient and Investigatr until study withdrawal criteria were met. Primary assessment f efficacy was based n rate f cmplete respnse (CR + CRu) as determined by an Independent Review Cmmittee (IRC) using the Internatinal Wrkshp Respnse Criteria (IWC). Secndary measures f efficacy included IRC assessment f duratin f respnse and bjective disease respnse (ORR, CR + CRu + PR). Baseline Patient Characteristics Demgraphic and disease characteristics f the PTCL patients are prvided in Table 5.
10 Table 5. Baseline Patient Characteristics (PTCL Ppulatin) Study 3 Study 4 Characteristic (N=130) (N=47) Age (years), n 130 47 Mean (SD) 59 (13) 59 (13) Median 61 59 Sex, n (%) Male 88 (68) 25 (53) Female 42 (32) 22 (47) Race, n (%) White 116 (89) 40 (85) Black 7 (5) 4 (9) Asian 3 (2) 3 (6) Other 4 (3) 0 PTCL Subtype Based n Central Diagnsis, n (%) PTCL Unspecified (NOS) 69 (53) 28 (60) Angiimmunblastic T-cell lymphma (AITL) 27 (21) 7 (15) ALK-1 negative anaplastic large cell lymphma (ALCL) 21 (16) 5 (11) Other 13 (10) 7 (16) Stage f Disease, n (%)* I/II 39 (30) 2 (4) III/IV 91 (70) 45 (96) ECOG Perfrmance Status, n (%) 0 46 (35) 20 (43) 1 67 (51) 22 (47) 2 17 (13) 4 (9) Number f Prir Systemic Therapies Median (Range) 2 (1, 8) 3 (1, 6) *Stage f disease was reprted at time f diagnsis fr Study 3 and at time f study entry fr Study 4. All patients in bth studies had received prir systemic therapy fr PTCL. In Study 4, a greater percentage f patients had extensive prir radiatin and chemtherapy. Twenty-ne patients (16%) in Study 3 and 18 patients (38%) in Study 4 had received prir autlgus stem cell transplant and 31 (24%) and 19 (40%) patients, respectively, had received prir radiatin therapy. Clinical Results Efficacy utcmes fr PTCL patients as determined by the IRC are prvided in Table 6 fr Study 3. The cmplete respnse rate was 15% and verall respnse rate was 25%. Similar cmplete respnse rates were bserved by the IRC acrss the 3 majr PTCL subtypes (NOS, AITL, and ALK-1 negative ALCL). Median time t bjective respnse was 1.8 mnths (~2 cycles) fr the 33 patients wh achieved CR, CRu r PR and was 3.7 mnths (~4 cycles) fr the 19 patients with cmplete respnse. The respnses in 11 f the 19 patients achieving CR and CRu were knwn t exceed 9.2 mnths; the fllw-up n the remaining 8 patients was discntinued prir t 9.2 mnths. Table 6. Clinical Results fr PTCL Patients Respnse Rate Study 3 (N=130) CR+CRu, n (%) 1 19 (14.6) [9.0, 21.9] 3 PR, n (%) 2 14 (10.8) [6.0, 17.4] 3 ORR (CR+CRu+PR), n (%) 2 33 (25.4) [18.2, 33.8] 3 1 Primary Endpint 2 Secndary Endpint 3 95% Cnfidence Interval In a secnd single-arm clinical study in patients with PTCL wh had failed prir therapy (Study 4), patients were treated with ISTODAX at a starting dse f 14 mg/m 2 infused ver 4 hurs n days 1, 8, and 15 every 28 days. Patients culd be treated until disease prgressin at the discretin f the patient and the Investigatr. The percentage f patients achieving CR + CRu in Study 4 was similar t that in Study 3. 15 REFERENCES 1. NIOSH Alert: Preventing ccupatinal expsures t antineplastic and ther hazardus drugs in healthcare settings. 2004. U.S. Department f Health and Human Services, Public Health Service, Centers fr Disease Cntrl and Preventin, Natinal Institute fr Occupatinal Safety and Health, DHHS (NIOSH) Publicatin N. 2004-165. 2. OSHA Technical Manual, TED 1-0.15A, Sectin VI: Chapter 2. Cntrlling Occupatinal Expsure t Hazardus Drugs. OSHA, 1999. http://www.sha.gv/dts/sta/tm/tm_vi/tm_vi_2.html 3. American Sciety f Health-System Pharmacists. ASHP Guidelines n Handling Hazardus Drugs: Am J Health-Syst Pharm. 2006; 63:1172-1193. 4. Plvich M, White JM, Kelleher LO (eds). Chemtherapy and bitherapy guidelines and recmmendatins fr practice (2 nd ed.) 2005. Pittsburgh, PA: Onclgy Nursing Sciety.
11 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 Hw Supplied ISTODAX is supplied as a kit including a sterile, lyphilized pwder in a single-use vial cntaining 10 mg f rmidepsin and 20 mg f the bulking agent, pvidne, USP. In additin, each kit includes ne sterile Diluent vial cntaining 2 ml (deliverable vlume) f 80% prpylene glycl, USP, and 20% dehydrated alchl, USP. NDC 59572-983-01: ISTODAX KIT cntaining 1 vial f rmidepsin, 10 mg and 1 vial f diluent fr rmidepsin, 2 ml per cartn 16.2 Strage ISTODAX (rmidepsin) fr injectin is supplied as a kit cntaining tw vials in a single cartn. The cartn must be stred at 20 t 25 C, excursins permitted between 15 t 30 C. (See USP Cntrlled Rm Temperature.) Keep ut f reach f children. Prcedures fr prper handling and dispsal f anticancer drugs shuld be cnsidered. Several guidelines n this subject have been published 1-4 [See References (15)]. 17 PATIENT COUNSELING INFORMATION See FDA-apprved patient labeling. 17.1 Instructins Nausea and Vmiting Nausea and vmiting are cmmn fllwing treatment with ISTODAX. Prphylactic antiemetics are recmmended t be used in all patients. Advise patients t reprt these symptms s that apprpriate treatment can be instituted [See Adverse Reactins (6)]. Lw Bld Cunts Patients shuld be infrmed that treatment with ISTODAX can cause lw bld cunts and that frequent mnitring f hematlgic parameters is required. Patients shuld be instructed t reprt fever r ther signs f infectin, significant fatigue, shrtness f breath, r bleeding [See Warnings and Precautins (5.1)]. Infectins Patients shuld be infrmed that infectins may ccur during treatment with ISTODAX. Patients shuld be instructed t reprt fever, cugh, shrtness f breath with r withut chest pain, burning n urinatin, flu-like symptms, muscle aches, r wrsening skin prblems [See Warnings and Precautins (5.2)]. Tumr Lysis Syndrme Patients at risk f tumr lysis syndrme (i.e., thse with advanced stage disease and/r high tumr burden) shuld be mnitred clsely fr TLS and apprpriate measures taken if symptms are bserved [See Warnings and Precautins (5.4)]. Use in Pregnancy If pregnancy ccurs during treatment with ISTODAX, female patients shuld be advised t seek immediate medical advice and cunseling. [See Warnings and Precautins (5.5)]. Patients shuld be instructed t read the patient insert carefully. Manufactured fr: Manufactured by: Celgene Crpratin Summit, NJ 07901 Ben Venue Labratries, Inc. Bedfrd, OH 44146 r Baxter Onclgy GmbH Halle/Westfalen, Germany ISTODAX is a registered trademark f Celgene Crpratin 2010-2013 Celgene Crpratin. All Rights Reserved. U.S. Patents: 4,977,138; 7,608,280; 7,611,724 ISTBAXPI.005/PPI.005 06/13
12 Patient Medicatin Infrmatin ISTODAX (ISS te dax) (rmidepsin) fr injectin Read the patient infrmatin that cmes with ISTODAX befre yu receive yur first treatment and each time befre yu are treated. There may be new infrmatin. This leaflet des nt take the place f talking with yur dctr abut yur medical cnditin r yur treatment. What is ISTODAX? ISTODAX is a prescriptin medicine used t treat peple with a type f cancer called cutaneus T-cell lymphma (CTCL) r peripheral T-cell lymphma (PTCL) after at least ne ther type f medicine by muth r injectin has been tried. It is nt knwn if ISTODAX is safe and effective in children under 18 years f age. What shuld I tell my dctr befre I receive ISTODAX? Befre receiving ISTODAX, tell yur dctr if yu: have any heart prblems, including an irregular r fast heartbeat, r a cnditin called QT prlngatin. have kidney prblems have liver prblems have prblems with the amunt f ptassium r magnesium in yur bld have nausea, vmiting, r diarrhea have any ther medical cnditins are pregnant r plan t becme pregnant. ISTODAX may harm yur unbrn baby. Talk t yur dctr abut the best way t prevent pregnancy while receiving ISTODAX. Tell yur dctr right away if yu becme pregnant while receiving ISTODAX. are breastfeeding r plan t breastfeed. It is nt knwn if ISTODAX passes int yur breast milk. Yu and yur dctr shuld decide if yu will receive ISTODAX r breast-feed. Talk t yur dctr abut the best way t feed yur baby while yu are being treated with ISTODAX. Tell yur dctr abut all f the medicines yu take, including prescriptin and nn-prescriptin medicines, vitamins, and herbal supplements and any recent changes in medicatins. Sme medicines may affect hw ISTODAX wrks, r ISTODAX may affect hw yur ther medicines wrk. Especially tell yur dctr if yu take r use: warfarin sdium (Cumadin, Jantven) r any ther bld thinner medicine. Ask yur dctr if yu are nt sure if yu are taking a bld thinner. Yur dctr may want t test yur bld mre ften. a medicine t treat abnrmal heart beats St. Jhn s Wrt (Hypericum perfratum) Dexamethasne (a sterid) Medicine fr: tuberculsis (TB) seizures (epilepsy) bacterial infectins (antibitics) fungal infectins (antifungals) HIV (AIDS) depressin Ask yur dctr if yu are nt sure if yur medicine is ne that is listed abve. Knw the medicines yu take. Keep a list f them and shw it t yur dctr and pharmacist when yu get a new medicine. Hw shuld I take ISTODAX? ISTODAX will be given t yu by yur dctr r nurse as an intravenus (IV) injectin int yur vein usually ver 4 hurs. ISTODAX is usually given n Day 1, Day 8, and Day 15 f a 28 day cycle f treatment. Yur dctr will decide hw lng yu will receive treatment with ISTODAX. Yur dctr will check yur bld cell cunts and ther bld tests regularly during yur treatment with ISTODAX t check fr side effects f ISTODAX. Yur dctr may decide t d ther tests t check yur health as needed. Yur dctr may stp yur treatment, change when yu get yur treatment, r change the dse f yur treatment if yu have certain side effects while taking ISTODAX. What are the pssible side effects f ISTODAX? ISTODAX may cause serius side effects, including: Lw bld cell cunts: Yur dctr will regularly d bld tests t check yur bld cunts. Lw platelets: can cause unusual bleeding, r bruising under the skin. Talk t yur dctr right away if this happens. Lw red bld cells: may make yu feel tired and yu may get tired easily. Yu may lk pale, and feel shrt f breath. Tell yur dctr if yu have these symptms. Lw white bld cells: can cause yu t get infectins, which may be serius.
13 Serius Infectins. Patients receiving ISTODAX can develp serius infectins that can smetimes lead t death. These infectins can happen during treatment and within 30 days after treatment with ISTODAX. Yur risk f infectin may be higher if yu have had chemtherapy in the past. Tell yur dctr right away if yu have any f these symptms f infectin: fever burning with urinatin cugh flu like symptms shrtness f breath with r withut chest pain muscle aches wrsening skin prblems Changes in yur heartbeat. Yur dctr may check yur heart by ding an ECG (electrcardigram) and yur ptassium and magnesium levels in yur bld befre yu start yur ISTODAX treatment. Tell yur dctr if yu feel an abnrmal heart beat, feel dizzy r faint, have chest pain r shrtness f breath. These may be symptms related t QT prlngatin and ST segment changes. Tumr Lysis Syndrme (TLS). TLS is a prblem f the rapid breakdwn f cancer cells that can happen during yur treatment with ISTODAX. Yur dctr may d bld tests t check fr TLS and may give yu medicine t prevent r treat TLS. Cmmn side effects f ISTODAX include: nausea, vmiting, diarrhea, and lss f appetite tiredness Tell yur dctr if yu have any side effect that bthers yu r des nt g away. These are nt all the pssible side effects f ISTODAX. Fr mre infrmatin, ask yur dctr r pharmacist. Ask yur dctr fr medical advice abut side effects. Yu may reprt side effects t FDA at 1-800-FDA-1088. General infrmatin abut ISTODAX Medicines are smetimes prescribed fr purpses ther than thse listed in patient infrmatin leaflets. This patient infrmatin leaflet summarizes the mst imprtant infrmatin abut ISTODAX. If yu wuld like mre infrmatin, talk with yur dctr. Yu can ask yur pharmacist r dctr fr infrmatin abut ISTODAX that is written fr health prfessinals. Fr mre infrmatin, g t www.istodax.cm r call 1-888- 423-5436. What are the ingredients in ISTODAX? Active ingredient: rmidepsin Inactive ingredients: pvidne. The diluent cntains 80% prpylene glycl and 20% dehydrated alchl. This Patient Infrmatin has been apprved by the U.S. Fd and Drug Administratin. Manufactured fr: Celgene Crpratin Summit, NJ 07901 ISTODAX is a registered trademark f Celgene Crpratin 2010-2013 Celgene Crpratin. All Rights Reserved. U.S. Patents: 4,977,138; 7,608,280; 7,611,724 ISTBAXPPI.005 06/13 Apprved June/2013