Billing for Xofigo (rdium R 223 dichloride) Injection nd Administrtion in Seprte Sites of Cre Providers re solely responsile for confirming pproprite coverge, coding nd reimursement nd ensuring tht ll clims re ccurte, complete nd dequtely supported y documenttion in the medicl record. Informtion provided in this resource is for informtionl purposes only nd does not gurntee tht codes re pproprite or tht reimursement will result. This resource is not intended s legl dvice or s sustitute for provider s independent professionl judgment. Billing y the Physicin for the Administrtion of Xofigo According to Medicre guidnce, if physicin who is not employed y the hospitl dministers Xofigo to ptient in the hospitl outptient deprtment, then the physicin my sumit seprte clim only for the dministrtion services of Xofigo. Smple CMS-1500 Clim Form (version 02-12 s of April 2014) DOE, JOHN X SAME 123 MAIN ST NY HOMETOWN 01234 201 555-0125 X 01 01 XX X X X Box 21 ICD Indictor: Identify the type of ICD dignosis code used; eg, enter 9 for ICD-9CM or 0 for ICD-10-CM Box 19 Additionl Informtion: Additionl informtion my not e required y pyers for A9606 Box 21 Dignosis: Enter the pproprite dignosis code; eg, ICD-10-CM: C61 Mlignnt neoplsm of prostte; C79.51 Secondry mlignnt neoplsm of one MM DD YY MM DD YY 11 MM DD YY MM DD YY 11 Box 24B The Plce of Service code identifies the loction where the service ws rendered Box 24D Procedures/Services/ Supplies: Enter the productspecific HCPCS code, A9606, rdium r-223 dichloride, therpeutic, per microcurie Box 24E Dignosis Pointer: Specify the dignosis, from Box 21, tht reltes to the product or procedure listed in Box 24D 0 C79.51 C61 A9606 79101 26 A,B XXX XX 100 A,B XXX XX 1 Box 24D Procedures/Services/Supplies: Enter the pproprite CPT code nd modifiers for Xofigo nd its dministrtion If Xofigo is dministered in the hospitl outptient setting, the physicin office JOHN SMITH MD should include modifier SAME 26 for the 2 DOCTORS BLVD HOMETOWN, PA 01234 professionl component PLEASE PRINT OR TYPE Box 24G Units: Indicte the numer of microcuries dministered; eg, if 100 μci dministered, put 100 in Box 24G APPROVED OMB-0938-1197 FORM 1500 (02-12) Other dignosis codes my e pplicle; code(s) nd sequencing order my vry y pyer. Indiction Xofigo is indicted for the tretment of ptients with cstrtion-resistnt prostte cncer, symptomtic one metstses nd no known viscerl metsttic disese. Importnt Sfety Informtion Contrindictions: Xofigo is contrindicted in women who re or my ecome pregnnt. Xofigo cn cuse fetl hrm when dministered to pregnnt womn Plese see dditionl Importnt Sfety Informtion on pge 3 nd ccompnying full Prescriing Informtion.
Billing y the Hospitl Outptient Deprtment for the product Xofigo According to Medicre guidnce, the hospitl outptient deprtment my sumit seprte clim for the product Xofigo purchsed on ehlf of the non-hospitl physicin nd the technicl component of its dministrtion. Smple UB-04 Clim Form (Medicre Ptient) 1 Doe, John 123 Min Street Hometown, US 01234 8 PATIENT NAME 4 6 5 FED. TAX NO. 9 PATIENT ADDRESS 11 SEX 31 OCCURRENCE Product-specific HCPCS code, A9606, rdium r-223 dichloride, 38 therpeutic, per microcurie 12 c ADMISSION 13 HR 14 TYPE 15 SRC 16 DHR 17 STAT 32 OCCURRENCE 33 OCCURRENCE 18 TYPE OF BILL 7 STATEMENT COVERS PERIOD FROM THROUGH 10 BIRTH 3 PAT. CNTL #. MED. REC. # 2 19 20 34 OCCURRENCE CONDITION S 24 22 23 21 35 25 26 27 36 OCCURRENCE SPAN FROM THROUGH d 28 e 29 ACDT 30 STATE 37 OCCURRENCE SPAN FROM THROUGH 39 40 VALUE S AMOUNT 41 VALUE S AMOUNT VALUE S AMOUNT c d 42 REV. CD. 44 HCPCS / RATE / HIPPS 43 DESCRIPTION 2 0510 Clinic visit (Rdiophrmceuticl therpy, y intrvenous dministrtion) 3 4 5 6 45 SERV. 46 SERV. UNITS A9606 100 79101 TC 1 0344 Therpeutic rdiophrmceuticls 1 Field 46 Service Units: Indicte the numer of microcuries dministered; eg, if 100 μci dministered, put 100 in Field 46 47 TOTAL CHARGES 48 NON-COVERED CHARGES 49 1 2 3 4 5 6 7 7 8 8 Field 42 Revenue Code Field 43 Description of Revenue (nd HCPCS/CPT) Codes Field 44 HCPCS/CPT Code Include modifier TC for the technicl component of the injection service if the physicin is illing for the dministrtion service seprtely 9 9 10 10 11 11 12 12 13 13 14 14 15 15 16 16 17 17 18 18 19 19 20 20 21 21 Field 67 Dignosis PAGE OF Codes: 50 PAYER NAME C61 Mlignnt neoplsm of prostte C79.51 Secondry 58 INSURED S NAME mlignnt neoplsm of one (Some pyers my 63lso TREATMENT AUTHORIZATION S require Z85.46) 22 22 TOTALS CREATION 23 52 REL. INFO 51 HEALTH PLAN ID 53 ASG. BEN. 23 55 EST. AMOUNT DUE 54 PRIOR PAYMENTS 56 NPI A 57 A B OTHER B PRV ID C C 59 P. REL 60 INSURED S UNIQUE ID 62 INSURANCE GROUP NO. 61 GROUP NAME A A B B C C 65 EMPLOYER NAME 64 DOCUMENT CONTROL NUMBER A A B B C C 66 DX C61 67 I C79.51 A J 69 ADMIT 70 PATIENT DX REASON DX PRINCIPAL PROCEDURE. 74 B K C L OTHER PROCEDURE. OTHER PROCEDURE e. c D M 71 PPS OTHER PROCEDURE E N 75 72 ECI F O 76 ATTENDING G P NPI LAST c. d. OTHER PROCEDURE OTHER PROCEDURE 77 OPERATING 80 REMARKS UB-04 CMS-1450 APPROVED OMB NO. 0938-0997 78 OTHER LAST c 79 OTHER d LAST NUBC Ntionl Uniform Billing Committee 68 73 QUAL FIRST NPI LAST 81CC H Q c QUAL FIRST NPI QUAL FIRST NPI QUAL FIRST Field 80 Remrks: Informtion in the remrks field my not e required y pyers for A9606 THE CERTIFICATIONS ON THE REVERSE APPLY TO THIS BILL AND ARE MADE A PART HEREOF. T he technicl component includes non-physicin work, including dministrtive, personnel, equipment, nd fcility costs nd relted mlprctice expenses. Other dignosis codes my e pplicle; code(s) nd sequencing order my vry y pyer. Plese see dditionl Importnt Sfety Informtion on pges 1 nd 3 nd ccompnying full Prescriing Informtion. Plese see disclimer on pge 1.
Importnt Sfety Informtion (continued) Bone Mrrow Suppression: In the rndomized tril, 2% of ptients in the Xofigo rm experienced one mrrow filure or ongoing pncytopeni, compred to no ptients treted with plceo. There were two deths due to one mrrow filure. For 7 of 13 ptients treted with Xofigo one mrrow filure ws ongoing t the time of deth. Among the 13 ptients who experienced one mrrow filure, 54% required lood trnsfusions. Four percent (4%) of ptients in the Xofigo rm nd 2% in the plceo rm permnently discontinued therpy due to one mrrow suppression. In the rndomized tril, deths relted to vsculr hemorrhge in ssocition with myelosuppression were oserved in 1% of Xofigo-treted ptients compred to 0.3% of ptients treted with plceo. The incidence of infection-relted deths (2%), serious infections (10%), nd ferile neutropeni (<1%) ws similr for ptients treted with Xofigo nd plceo. Myelosuppression notly thromocytopeni, neutropeni, pncytopeni, nd leukopeni hs een reported in ptients treted with Xofigo. Monitor ptients with evidence of compromised one mrrow reserve closely nd provide supportive cre mesures when cliniclly indicted. Discontinue Xofigo in ptients who experience life-thretening complictions despite supportive cre for one mrrow filure Hemtologicl Evlution: Monitor lood counts t seline nd prior to every dose of Xofigo. Prior to first dministering Xofigo, the solute neutrophil count (ANC) should e 1.5 109/L, the pltelet count 100 109/L, nd hemogloin 10 g/ dl. Prior to susequent dministrtions, the ANC should e 1 109/L nd the pltelet count 50 109/L. Discontinue Xofigo if hemtologic vlues do not recover within 6 to 8 weeks fter the lst dministrtion despite receiving supportive cre Concomitnt Use With Chemotherpy: Sfety nd efficcy of concomitnt chemotherpy with Xofigo hve not een estlished. Outside of clinicl tril, concomitnt use of Xofigo in ptients on chemotherpy is not recommended due to the potentil for dditive myelosuppression. If chemotherpy, other systemic rdioisotopes, or hemiody externl rdiotherpy re dministered during the tretment period, Xofigo should e discontinued Administrtion nd Rdition Protection: Xofigo should e received, used, nd dministered only y uthorized persons in designted clinicl settings. The dministrtion of Xofigo is ssocited with potentil risks to other persons from rdition or contmintion from spills of odily fluids such s urine, feces, or vomit. Therefore, rdition protection precutions must e tken in ccordnce with ntionl nd locl regultions Adverse Rections: The most common dverse rections ( 10%) in the Xofigo rm vs the plceo rm, respectively, were nuse (36% vs 35%), dirrhe (25% vs 15%), vomiting (19% vs 14%), nd peripherl edem (13% vs 10%). Grde 3 nd 4 dverse events were reported in 57% of Xofigo-treted ptients nd 63% of plceo-treted ptients. The most common hemtologic lortory normlities in the Xofigo rm ( 10%) vs the plceo rm, respectively, were nemi (93% vs 88%), lymphocytopeni (72% vs 53%), leukopeni (35% vs 10%), thromocytopeni (31% vs 22%), nd neutropeni (18% vs 5%) Plese see ccompnying full Prescriing Informtion. 2016 Byer. All rights reserved. BAYER, the Byer Cross, Xofigo nd the Xofigo Access Services logo re registered trdemrks of Byer. PP-600-US-2045 04/16
HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include ll the informtion needed to use XOFIGO sfely nd effectively. See full prescriing informtion for XOFIGO. XOFIGO (rdium R 223 dichloride) Injection, for intrvenous use Initil U.S. Approvl: 2013 --------------------------- RECENT MAJOR CHANGES --------------------------- Dosge nd Administrtion (2.1) 3/2016 Dosge Forms nd Strengths (3) 3/2016 --------------------------- INDICATIONS AND USAGE -------------------------- Xofigo is n lph prticle-emitting rdioctive therpeutic gent indicted for the tretment of ptients with cstrtion-resistnt prostte cncer, symptomtic one metstses nd no known viscerl metsttic disese. (1) ---------------------- DOSAGE AND ADMINISTRATION ---------------------- The dose regimen of Xofigo is 55 kbq (1.49 microcurie) per kg ody weight, given t 4 week intervls for 6 injections. (2.1) --------------------- DOSAGE FORMS AND STRENGTHS -------------------- Single-use vil t concentrtion of 1,100 kbq/ml (30 microcurie/ml) t the reference dte with totl rdioctivity of 6,600 kbq/vil (178 microcurie/vil) t the reference dte (3) ------------------------------ CONTRAINDICATIONS ----------------------------- Pregnncy (4, 8.1) ----------------------- WARNINGS AND PRECAUTIONS ---------------------- Bone Mrrow Suppression: Mesure lood counts prior to tretment initition nd efore every dose of Xofigo. Discontinue Xofigo if hemtologic vlues do not recover within 6 to 8 weeks fter tretment. Monitor ptients with compromised one mrrow reserve closely. Discontinue Xofigo in ptients who experience life-thretening complictions despite supportive cre mesures. (5.1) ------------------------------ ADVERSE REACTIONS ----------------------------- The most common dverse drug rections ( 10%) in ptients receiving Xofigo were nuse, dirrhe, vomiting, nd peripherl edem. The most common hemtologic lortory normlities ( 10%) were nemi, lymphocytopeni, leukopeni, thromocytopeni, nd neutropeni (6.1). To report SUSPECTED ADVERSE REACTIONS, contct Byer HelthCre Phrmceuticls Inc. t 1-888-842-2937 or FDA t 1-800- FDA-1088 or www.fd.gov/medwtch SEE 17 FOR PATIENT COUNSELING INFORMATION Revised: 3/2016 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosge 2.2 Administrtion 2.3 Instructions for Use / Hndling 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Bone Mrrow Suppression 6 ADVERSE REACTIONS 6.1 Clinicl Trils Experience 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnncy 8.3 Nursing Mothers 8.4 Peditric Use 8.5 Geritric Use 8.6 Ptients with Heptic Impirment 8.7 Ptients with Renl Impirment 8.8 Mles of Reproductive Potentil 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechnism of Action 12.2 Phrmcodynmics 12.3 Phrmcokinetics 12.6 Crdic Electrophysiology 13 NONCLINICAL TOXICOLOGY 13.1 Crcinogenesis, Mutgenesis, Impirment of Fertility 14 CLINICAL STUDIES 15 REFERENCES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION *Sections or susections omitted from the full prescriing informtion re not listed. FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE Xofigo is indicted for the tretment of ptients with cstrtion-resistnt prostte cncer, symptomtic one metstses nd no known viscerl metsttic disese. 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosge The dose regimen of Xofigo is 55 kbq (1.49 microcurie) per kg ody weight, given t 4 week intervls for 6 injections. Sfety nd efficcy eyond 6 injections with Xofigo hve not een studied. The volume to e dministered to given ptient should e clculted using the: Ptient s ody weight (kg) Dosge level 55 kbq/kg ody weight or 1.49 microcurie/kg ody weight Rdioctivity concentrtion of the product (1,100 kbq/ml; 30 microcurie/ml) t the reference dte 1
Decy correction fctor to correct for physicl decy of rdium-223. The totl volume to e dministered to ptient is clculted s follows: Volume to e dministered (ml) = or Volume to e dministered (ml) = Body weight in kg 55 kbq/kg ody weight Decy fctor 1,100 kbq/ml Body weight in kg 1.49 microcurie/kg ody weight Decy fctor 30 microcurie/ml Tle 1: Decy Correction Fctor Tle Dys from Reference Dte Decy Fctor Dys from Reference Dte Decy Fctor -14 2.296 0 0.982-13 2.161 1 0.925-12 2.034 2 0.870-11 1.914 3 0.819-10 1.802 4 0.771-9 1.696 5 0.725-8 1.596 6 0.683-7 1.502 7 0.643-6 1.414 8 0.605-5 1.330 9 0.569-4 1.252 10 0.536-3 1.178 11 0.504-2 1.109 12 0.475-1 1.044 13 0.447 14 0.420 The Decy Correction Fctor Tle is corrected to 12 noon Centrl Stndrd Time (CST). To determine the decy correction fctor, count the numer of dys efore or fter the reference dte. The Decy Correction Fctor Tle includes correction to ccount for the 7 hour time difference etween 12 noon Centrl Europen Time (CET) t the site of mnufcture nd 12 noon US CST, which is 7 hours erlier thn CET. Immeditely efore nd fter dministrtion, the net ptient dose of dministered Xofigo should e determined y mesurement in n pproprite rdioisotope dose clirtor tht hs een clirted with Ntionl Institute of Stndrds nd Technology (NIST) trcele rdium-223 stndrd (ville upon request from Byer) nd corrected for decy using the dte nd time of clirtion. The dose clirtor must e clirted with ntionlly recognized stndrds, crried out t the time of commissioning, fter ny mintennce procedure tht could ffect the dosimetry nd t intervls not to exceed one yer. 2.2 Administrtion Administer Xofigo y slow intrvenous injection over 1 minute. Flush the intrvenous ccess line or cnnul with isotonic sline efore nd fter injection of Xofigo. 2.3 Instructions for Use/Hndling Generl wrning Xofigo (n lph prticle-emitting phrmceuticl) should e received, used nd dministered only y uthorized persons in designted clinicl settings. The receipt, storge, use, trnsfer nd disposl Xofigo re suject to the regultions nd/or pproprite licenses of the competent officil orgniztion. 2
Xofigo should e hndled y the user in mnner which stisfies oth rdition sfety nd phrmceuticl qulity requirements. Approprite septic precutions should e tken. Rdition protection The dministrtion of Xofigo is ssocited with potentil risks to other persons (e.g., medicl stff, cregivers nd ptient s household memers) from rdition or contmintion from spills of odily fluids such s urine, feces, or vomit. Therefore, rdition protection precutions must e tken in ccordnce with ntionl nd locl regultions. For drug hndling Follow the norml working procedures for the hndling of rdiophrmceuticls nd use universl precutions for hndling nd dministrtion such s gloves nd rrier gowns when hndling lood nd odily fluids to void contmintion. In cse of contct with skin or eyes, the ffected re should e flushed immeditely with wter. In the event of spillge of Xofigo, the locl rdition sfety officer should e contcted immeditely to initite the necessry mesurements nd required procedures to decontminte the re. A complexing gent such s 0.01 M ethylene-diminetetrcetic cid (EDTA) solution is recommended to remove contmintion. For ptient cre Whenever possile, ptients should use toilet nd the toilet should e flushed severl times fter ech use. When hndling odily fluids, simply wering gloves nd hnd wshing will protect cregivers. Clothing soiled with Xofigo or ptient fecl mtter or urine should e wshed promptly nd seprtely from other clothing. Rdium-223 is primrily n lph emitter, with 95.3% frction of energy emitted s lph-prticles. The frction emitted s et-prticles is 3.6%, nd the frction emitted s gmm-rdition is 1.1%. The externl rdition exposure ssocited with hndling of ptient doses is expected to e low, ecuse the typicl tretment ctivity will e elow 8,000 kbq (216 microcurie). In keeping with the As Low As Resonly Achievle (ALARA) principle for minimiztion of rdition exposure, it is recommended to minimize the time spent in rdition res, to mximize the distnce to rdition sources, nd to use dequte shielding. Any unused product or mterils used in connection with the preprtion or dministrtion re to e treted s rdioctive wste nd should e disposed of in ccordnce with locl regultions. The gmm rdition ssocited with the decy of rdium-223 nd its dughters llows for the rdioctivity mesurement of Xofigo nd the detection of contmintion with stndrd instruments. Instructions for preprtion Prenterl drug products should e inspected visully for prticulte mtter nd discolortion prior to dministrtion, whenever solution nd continer permit. Xofigo is redy-to-use solution nd should not e diluted or mixed with ny solutions. Ech vil is for single use only. Dosimetry The sored rdition doses in mjor orgns were clculted sed on clinicl iodistriution dt in five ptients with cstrtion-resistnt prostte cncer. Clcultions of sored rdition doses were performed using OLINDA/EXM (Orgn Level INternl Dose Assessment/EXponentil Modeling), softwre progrm sed on the Medicl Internl Rdition Dose (MIRD) lgorithm, which is widely used for estlished et nd gmm emitting rdionuclides. For rdium-223, which is primrily n lph prticle-emitter, ssumptions were mde for intestine, red mrrow nd one/osteogenic cells to provide the est possile sored rdition dose clcultions for Xofigo, considering its oserved iodistriution nd specific chrcteristics. The clculted sored rdition doses to different orgns re listed in Tle 2. The orgns with highest sored rdition doses were one (osteogenic cells), red mrrow, upper lrge intestine wll, nd lower lrge intestine wll. The clculted sored doses to other orgns re lower. 3
Tle 2: Clculted Asored Rdition Doses to Orgns Trget Orgn Men (Gy/MBq) Men (rd/mci) Coefficient of Vrition (%) Adrenls 0.00012 0.44 56 Brin 0.00010 0.37 80 Brests 0.00005 0.18 120 Gllldder wll 0.00023 0.85 14 LLI 1 wll 0.04645 171.88 83 Smll intestine wll 0.00726 26.87 45 Stomch wll 0.00014 0.51 22 ULI 2 wll 0.03232 119.58 50 Hert wll 0.00173 6.40 42 Kidneys 0.00320 11.86 36 Liver 0.00298 11.01 36 Lungs 0.00007 0.27 90 Muscle 0.00012 0.44 41 Ovries 0.00049 1.80 40 Pncres 0.00011 0.41 43 Red mrrow 0.13879 513.51 41 Osteogenic cells 1.15206 4262.60 41 Skin 0.00007 0.27 79 Spleen 0.00009 0.33 54 Testes 0.00008 0.31 59 Thymus 0.00006 0.21 109 Thyroid 0.00007 0.26 96 Urinry ldder wll 0.00403 14.90 63 Uterus 0.00026 0.94 28 Whole ody 0.02311 85.50 16 1 LLI: lower lrge intestine 2 ULI: upper lrge intestine 3 DOSAGE FORMS AND STRENGTHS Xofigo (rdium R 223 dichloride injection) is ville in single-use vils contining 6 ml of solution t concentrtion of 1,100 kbq/ml (30 microcurie/ml) t the reference dte with totl rdioctivity of 6,600 kbq/vil (178 microcurie/vil) t the reference dte. 4 CONTRAINDICATIONS Xofigo is contrindicted in pregnncy. Xofigo cn cuse fetl hrm when dministered to pregnnt womn sed on its mechnism of ction. Xofigo is not indicted for use in women. Xofigo is contrindicted in women who re or my ecome pregnnt. If this drug is used during pregnncy, or if the ptient ecomes pregnnt while tking this drug, pprise the ptient of the potentil hzrd to the fetus [see Use in Specific Popultions (8.1)]. 4
5 WARNINGS AND PRECAUTIONS 5.1 Bone Mrrow Suppression In the rndomized tril, 2% of ptients on the Xofigo rm experienced one mrrow filure or ongoing pncytopeni compred to no ptients treted with plceo. There were two deths due to one mrrow filure nd for 7 of 13 ptients treted with Xofigo, one mrrow filure ws ongoing t the time of deth. Among the 13 ptients who experienced one mrrow filure, 54% required lood trnsfusions. Four percent (4%) of ptients on the Xofigo rm nd 2% on the plceo rm permnently discontinued therpy due to one mrrow suppression. In the rndomized tril, deths relted to vsculr hemorrhge in ssocition with myelosuppression were oserved in 1% of Xofigo-treted ptients compred to 0.3% of ptients treted with plceo. The incidence of infection-relted deths (2%), serious infections (10%), nd ferile neutropeni (<1%) were similr for ptients treted with Xofigo nd plceo. Myelosuppression; notly thromocytopeni, neutropeni, pncytopeni, nd leukopeni; hs een reported in ptients treted with Xofigo. In the rndomized tril, complete lood counts (CBCs) were otined every 4 weeks prior to ech dose nd the ndir CBCs nd times of recovery were not well chrcterized. In seprte single-dose phse 1 study of Xofigo, neutrophil nd pltelet count ndirs occurred 2 to 3 weeks fter Xofigo dministrtion t doses tht were up to 1 to 5 times the recommended dose, nd most ptients recovered pproximtely 6 to 8 weeks fter dministrtion [see Adverse Rections (6)]. Hemtologic evlution of ptients must e performed t seline nd prior to every dose of Xofigo. Before the first dministrtion of Xofigo, the solute neutrophil count (ANC) should e 1.5 x 10 9 /L, the pltelet count 100 x 10 9 /L nd hemogloin 10 g/dl. Before susequent dministrtions of Xofigo, the ANC should e 1 x 10 9 /L nd the pltelet count 50 x 10 9 /L. If there is no recovery to these vlues within 6 to 8 weeks fter the lst dministrtion of Xofigo, despite receiving supportive cre, further tretment with Xofigo should e discontinued. Ptients with evidence of compromised one mrrow reserve should e monitored closely nd provided with supportive cre mesures when cliniclly indicted. Discontinue Xofigo in ptients who experience life-thretening complictions despite supportive cre for one mrrow filure. The sfety nd efficcy of concomitnt chemotherpy with Xofigo hve not een estlished. Outside of clinicl tril, concomitnt use with chemotherpy is not recommended due to the potentil for dditive myelosuppression. If chemotherpy, other systemic rdioisotopes or hemiody externl rdiotherpy re dministered during the tretment period, Xofigo should e discontinued. 6 ADVERSE REACTIONS The following serious dverse rections re discussed in greter detil in nother section of the lel: Bone Mrrow Suppression [see Wrnings nd Precutions (5.1)] 6.1 Clinicl Trils Experience Becuse clinicl trils re conducted under widely vrying conditions, dverse rection rtes oserved in the clinicl trils of drug cnnot e directly compred to rtes in the clinicl trils of nother drug nd my not reflect the rtes oserved in prctice. In the rndomized clinicl tril in ptients with metsttic cstrtion-resistnt prostte cncer with one metstses, 600 ptients received intrvenous injections of 55 kbq/kg (1.49 microcurie/kg) of Xofigo nd est stndrd of cre nd 301 ptients received plceo nd est stndrd of cre once every 4 weeks for up to 6 injections. Prior to rndomiztion, 58% nd 57% of ptients hd received docetxel in the Xofigo nd plceo rms, respectively. The medin durtion of tretment ws 20 weeks (6 cycles) for Xofigo nd 18 weeks (5 cycles) for plceo. 5
The most common dverse rections ( 10%) in ptients receiving Xofigo were nuse, dirrhe, vomiting, nd peripherl edem (Tle 3). Grde 3 nd 4 dverse events were reported mong 57% of Xofigo-treted ptients nd 63% of plceotreted ptients. The most common hemtologic lortory normlities in Xofigo-treted ptients ( 10%) were nemi, lymphocytopeni, leukopeni, thromocytopeni, nd neutropeni (Tle 4). Tretment discontinutions due to dverse events occurred in 17% of ptients who received Xofigo nd 21% of ptients who received plceo. The most common hemtologic lortory normlities leding to discontinution for Xofigo were nemi (2%) nd thromocytopeni (2%). Tle 3 shows dverse rections occurring in 2% of ptients nd for which the incidence for Xofigo exceeds the incidence for plceo. Tle 3: Adverse Rections in the Rndomized Tril System/Orgn Clss Xofigo (n=600) Preferred Term Grdes 1-4 Grdes 3-4 % % Blood nd lymphtic system disorders Grdes 1-4 % Plceo (n=301) Grdes 3-4 % Pncytopeni 2 1 0 0 Gstrointestinl disorders Nuse 36 2 35 2 Dirrhe 25 2 15 2 Vomiting 19 2 14 2 Generl disorders nd dministrtion site conditions Peripherl edem 13 2 10 1 Renl nd urinry disorders Renl filure nd impirment 3 1 1 1 Lortory Anormlities Tle 4 shows hemtologic lortory normlities occurring in > 10% of ptients nd for which the incidence for Xofigo exceeds the incidence for plceo. Tle 4: Hemtologic Lortory Anormlities Hemtologic Xofigo (n=600) Plceo (n=301) Lortory Anormlities Grdes 1-4 % Grdes 3-4 % Grdes 1-4 % Grdes 3-4 % Anemi 93 6 88 6 Lymphocytopeni 72 20 53 7 Leukopeni 35 3 10 <1 Thromocytopeni 31 3 22 <1 Neutropeni 18 2 5 <1 Lortory vlues were otined t seline nd prior to ech 4-week cycle. As n dverse rection, grde 3-4 thromocytopeni ws reported in 6% of ptients on Xofigo nd in 2% of ptients on plceo. Among ptients who received Xofigo, the lortory normlity grde 3-4 thromocytopeni occurred in 1% of docetxel nïve ptients nd in 4% of ptients who hd received prior docetxel. Grde 3-4 neutropeni occurred in 1% of docetxel nïve ptients nd in 3% of ptients who hve received prior docetxel. 6
Fluid Sttus Dehydrtion occurred in 3% of ptients on Xofigo nd 1% of ptients on plceo. Xofigo increses dverse rections such s dirrhe, nuse, nd vomiting which my result in dehydrtion. Monitor ptients orl intke nd fluid sttus crefully nd promptly tret ptients who disply signs or symptoms of dehydrtion or hypovolemi. Injection Site Rections Erythem, pin, nd edem t the injection site were reported in 1% of ptients on Xofigo. Secondry Mlignnt Neoplsms Xofigo contriutes to ptient s overll long-term cumultive rdition exposure. Long-term cumultive rdition exposure my e ssocited with n incresed risk of cncer nd hereditry defects. Due to its mechnism of ction nd neoplstic chnges, including osteosrcoms, in rts following dministrtion of rdium-223 dichloride, Xofigo my increse the risk of osteosrcom or other secondry mlignnt neoplsms [see Nonclinicl Toxicology (13.1)]. However, the overll incidence of new mlignncies in the rndomized tril ws lower on the Xofigo rm compred to plceo (<1% vs. 2%; respectively), ut the expected ltency period for the development of secondry mlignncies exceeds the durtion of follow up for ptients on the tril. Susequent Tretment with Cytotoxic Chemotherpy In the rndomized clinicl tril, 16% ptients in the Xofigo group nd 18% ptients in the plceo group received cytotoxic chemotherpy fter completion of study tretments. Adequte sfety monitoring nd lortory testing ws not performed to ssess how ptients treted with Xofigo will tolerte susequent cytotoxic chemotherpy. 7 DRUG INTERACTIONS No forml clinicl drug interction studies hve een performed. Sugroup nlyses indicted tht the concurrent use of isphosphontes or clcium chnnel lockers did not ffect the sfety nd efficcy of Xofigo in the rndomized clinicl tril. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnncy Ctegory X [see Contrindictions (4)] Xofigo cn cuse fetl hrm when dministered to pregnnt womn sed on its mechnism of ction. While there re no humn or niml dt on the use of Xofigo in pregnncy nd Xofigo is not indicted for use in women, mternl use of rdioctive therpeutic gent could ffect development of fetus. Xofigo is contrindicted in women who re or my ecome pregnnt while receiving the drug. If this drug is used during pregnncy, or if the ptient ecomes pregnnt while tking this drug, pprise the ptient of the potentil hzrd to the fetus nd the potentil risk for pregnncy loss. Advise femles of reproductive potentil to void ecoming pregnnt during tretment with Xofigo. 8.3 Nursing Mothers Xofigo is not indicted for use in women. It is not known whether rdium-223 dichloride is excreted in humn milk. Becuse mny drugs re excreted in humn milk, nd ecuse of potentil for serious dverse rections in nursing infnts from Xofigo, decision should e mde whether to discontinue nursing, or discontinue the drug tking into ccount the importnce of the drug to the mother. 8.4 Peditric Use The sfety nd efficcy of Xofigo in peditric ptients hve not een estlished. 7
In single- nd repet-dose toxicity studies in rts, findings in the ones (depletion of osteocytes, osteolsts, osteoclsts, firo-osseous lesions, disruption/disorgniztion of the physis/growth line) nd teeth (missing, irregulr growth, firoosseous lesions in one socket) correlted with reduction of osteogenesis tht occurred t cliniclly relevnt doses eginning in the rnge of 22 88 kbq (0.59-2.38 microcurie) per kg ody weight. 8.5 Geritric Use Of the 600 ptients treted with Xofigo in the rndomized tril, 75% were 65 yers of ge nd over nd while 33% were 75 yers of ge nd over. No dosge djustment is considered necessry in elderly ptients. No overll differences in sfety or effectiveness were oserved etween these sujects nd younger sujects, nd other reported clinicl experience hs not identified differences in responses etween the elderly nd younger ptients, ut greter sensitivity of some older individuls cnnot e ruled out. 8.6 Ptients with Heptic Impirment No dedicted heptic impirment tril for Xofigo hs een conducted. Since rdium-223 is neither metolized y the liver nor eliminted vi the ile, heptic impirment is unlikely to ffect the phrmcokinetics of rdium-223 dichloride [see Clinicl Phrmcology (12.3)]. Bsed on sugroup nlyses in the rndomized clinicl tril, dose djustment is not needed in ptients with mild heptic impirment. No dose djustments cn e recommended for ptients with moderte or severe heptic impirment due to lck of clinicl dt. 8.7 Ptients with Renl Impirment No dedicted renl impirment tril for Xofigo hs een conducted. Bsed on sugroup nlyses in the rndomized clinicl tril, dose djustment is not needed in ptients with existing mild (cretinine clernce [CrCl] 60 to 89 ml/min) or moderte (CrCl 30 to 59 ml/min) renl impirment. No dose djustment cn e recommended for ptients with severe renl impirment (CrCl less thn 30 ml/min) due to limited dt ville (n = 2) [see Clinicl Phrmcology (12.3)]. 8.8 Mles of Reproductive Potentil Contrception Becuse of potentil effects on spermtogenesis ssocited with rdition, dvise men who re sexully ctive to use condoms nd their femle prtners of reproductive potentil to use highly effective contrceptive method during nd for 6 months fter completing tretment with Xofigo. Infertility There re no dt on the effects of Xofigo on humn fertility. There is potentil risk tht rdition y Xofigo could impir humn fertility [see Nonclinicl Toxicology (13.1)]. 10 OVERDOSAGE There hve een no reports of indvertent overdosing of Xofigo during clinicl studies. There is no specific ntidote. In the event of n indvertent overdose of Xofigo, utilize generl supportive mesures, including monitoring for potentil hemtologicl nd gstrointestinl toxicity, nd consider using medicl countermesures such s luminum hydroxide, rium sulfte, clcium cronte, clcium gluconte, clcium phosphte, or sodium lginte. 1 Single Xofigo doses up to 274 kbq (7.41 microcurie) per kg ody weight were evluted in phse 1 clinicl tril nd no dose-limiting toxicities were oserved. 8
11 DESCRIPTION Rdium R 223 dichloride, n lph prticle-emitting phrmceuticl, is rdiotherpeutic drug. Xofigo is supplied s cler, colorless, isotonic, nd sterile solution to e dministered intrvenously with ph etween 6 nd 8. Ech milliliter of solution contins 1,100 kbq rdium-223 dichloride (30 microcurie), corresponding to 0.58 ng rdium- 223, t the reference dte. Rdium is present in the solution s free divlent ction. Ech vil contins 6 ml of solution (6,600 kbq (178 microcurie) rdium-223 dichloride t the reference dte). The inctive ingredients re 6.3 mg/ml sodium chloride USP (tonicity gent), 7.2 mg/ml sodium citrte USP (for ph djustment), 0.2 mg/ml hydrochloric cid USP (for ph djustment), nd wter for injection USP. The moleculr weight of rdium-223 dichloride, 223 RCl 2, is 293.9 g/mol. Rdium-223 hs hlf-life of 11.4 dys. The specific ctivity of rdium-223 is 1.9 MBq (51.4 microcurie)/ng. The six-stge-decy of rdium-223 to stle led-207 occurs vi short-lived dughters, nd is ccompnied predominntly y lph emissions. There re lso et nd gmm emissions with different energies nd emission proilities. The frction of energy emitted from rdium-223 nd its dughters s lph-prticles is 95.3% (energy rnge of 5-7.5 MeV). The frction emitted s et-prticles is 3.6% (verge energies re 0.445 MeV nd 0.492 MeV), nd the frction emitted s gmm-rdition is 1.1% (energy rnge of 0.01-1.27 MeV). 12 CLINICAL PHARMACOLOGY 12.1 Mechnism of Action The ctive moiety of Xofigo is the lph prticle-emitting isotope rdium-223 (s rdium R 223 dichloride), which mimics clcium nd forms complexes with the one minerl hydroxyptite t res of incresed one turnover, such s one metstses (see Tle 2). The high liner energy trnsfer of lph emitters (80 kev/micrometer) leds to high frequency of doule-strnd DNA reks in djcent cells, resulting in n nti-tumor effect on one metstses. The lph prticle rnge from rdium-223 dichloride is less thn 100 micrometers (less thn 10 cell dimeters) which limits dmge to the surrounding norml tissue. 12.2 Phrmcodynmics Compred with plceo, there ws significnt difference in fvor of Xofigo for ll five serum iomrkers for one turnover studied in phse 2 rndomized study (one formtion mrkers: one lkline phosphtse [ALP], totl ALP nd procollgen I N propeptide [PINP], one resorption mrkers: C-terminl crosslinking telopeptide of type I collgen [S-CTX-I] nd type I collgen crosslinked C-telopeptide [ICTP]). 12.3 Phrmcokinetics The phrmcokinetics of rdium-223 dichloride in lood ws liner in terms of dose proportionlity nd time independence in the dose rnge investigted (50 to 274 kbq [1.35 to 7.41 microcurie] per kg ody weight). Distriution After intrvenous injection, rdium-223 is rpidly clered from the lood nd is distriuted primrily into one or is excreted into intestine. Fifteen minutes post-injection, out 20% of the injected rdioctivity remined in lood. At 4 hours, out 4% of the injected rdioctivity remined in lood, decresing to less thn 1% t 24 hours fter the injection. At 10 minutes post-injection, rdioctivity ws oserved in one nd in intestine. At 4 hours post-injection, the percentge of the rdioctive dose present in one nd intestine ws pproximtely 61% nd 49%, respectively. No significnt uptke 9
ws seen in other orgns such s hert, liver, kidneys, urinry ldder, nd spleen t 4 hours post-injection [see Dosge nd Administrtion (2.3)]. Metolism Rdium-223 is n isotope tht decys nd is not metolized. Elimintion The whole ody mesurements indicted tht pproximtely 63% of the dministered rdioctivity ws excreted from the ody within 7 dys fter injection (fter correcting for decy). Fecl excretion is the mjor route of elimintion from the ody. At 48 hours fter injection, the cumultive fecl excretion ws 13% (rnge 0-34%), nd the cumultive urine excretion ws 2% (rnge 1-5%). There ws no evidence of hepto-iliry excretion sed on imging dt. The rte of elimintion of rdium-223 dichloride from the gstrointestinl trct is influenced y the high vriility in intestinl trnsit rtes cross the popultion. Ptients with slower intestinl trnsit rte could potentilly receive higher intestinl rdition exposure. It is not known whether this will result in incresed gstrointestinl toxicity. Specil Popultions Peditric ptients Sfety nd effectiveness of Xofigo hve not een estlished in children nd dolescents elow 18 yers of ge. Ptients with heptic impirment No dedicted phrmcokinetic study in ptients with heptic impirment hs een conducted. However, since rdium-223 is not metolized nd there is no evidence of hepto-iliry excretion sed on imging dt, heptic impirment is not expected to ffect the phrmcokinetics of rdium-223 dichloride. Ptients with renl impirment No dedicted phrmcokinetic study in ptients with renl impirment hs een conducted. However, since excretion in urine is miniml nd the mjor route of elimintion is vi the feces, renl impirment is not expected to ffect the phrmcokinetics of rdium-223 dichloride. 12.6 Crdic Electrophysiology The effect of single dose of 55 kbq/kg of rdium-223 dichloride on the QTc intervl ws evluted in sugroup of 29 ptients (21 received Xofigo nd 8 received plceo) in the rndomized clinicl tril. No lrge chnges in the men QTc intervl (i.e., greter thn 20 ms) were detected up to 6 hours post-dose. The potentil for delyed effects on the QT intervl fter 6 hours ws not evluted. 13 NONCLINICAL TOXICOLOGY 13.1 Crcinogenesis, Mutgenesis, Impirment of Fertility Animl studies hve not een conducted to evlute the crcinogenic potentil of rdium-223 dichloride. However, in repet-dose toxicity studies in rts, osteosrcoms, known effect of one-seeking rdionuclides, were oserved t cliniclly relevnt doses 7 to 12 months fter the strt of tretment. The presence of other neoplstic chnges, including lymphom nd mmmry glnd crcinom, ws lso reported in 12- to 15-month repet-dose toxicity studies in rts. Genetic toxicology studies hve not een conducted with rdium-223 dichloride. However, the mechnism of ction of rdium-223 dichloride involves induction of doule-strnd DNA reks, which is known effect of rdition. Animl studies hve not een conducted to evlute the effects of rdium-223 dichloride on mle or femle fertility or reproductive function. Xofigo my impir fertility nd reproductive function in humns sed on its mechnism of ction. 10
14 CLINICAL STUDIES The efficcy nd sfety of Xofigo were evluted in doule-lind, rndomized, plceo-controlled phse 3 clinicl tril of ptients with cstrtion-resistnt prostte cncer with symptomtic one metstses. Ptients with viscerl metstses nd mlignnt lymphdenopthy exceeding 3 cm were excluded. The primry efficcy endpoint ws overll survivl. A key secondry efficcy endpoint ws time to first symptomtic skeletl event (SSE) defined s externl em rdition therpy (EBRT) to relieve skeletl symptoms, new symptomtic pthologic one frcture, occurrence of spinl cord compression, or tumor-relted orthopedic surgicl intervention. There were no scheduled rdiogrphic ssessments performed on study. All ptients were to continue ndrogen deprivtion therpy. At the cut-off dte of the pre-plnned interim nlysis, totl of 809 ptients hd een rndomized 2:1 to receive Xofigo 55 kbq (1.49 microcurie)/kg intrvenously every 4 weeks for 6 cycles (n = 541) plus est stndrd of cre or mtching plceo plus est stndrd of cre (n = 268). Best stndrd of cre included locl EBRT, corticosteroids, ntindrogens, estrogens, estrmustine or ketoconzole. Therpy ws continued until uncceptle toxicity or initition of cytotoxic chemotherpy, other systemic rdioisotope, hemi-ody EBRT or other investigtionl drug. Ptients with Crohn s disese, ulcertive colitis, prior hemiody rdition or untreted imminent spinl cord compression were excluded from the study. In ptients with one frctures, orthopedic stiliztion ws performed efore strting or resuming tretment with Xofigo. The following ptient demogrphics nd seline disese chrcteristics were lnced etween the rms. The medin ge ws 71 (rnge 44-94) with rcil distriution of 94% Cucsin, 4% Asin, 2% Blck nd <1% Other. Ptients were enrolled predominntly from Europe (85%) with 4% of ptients enrolled from North Americ. ECOG performnce sttus ws 0-1 in 86% of ptients. Eighty-five percent of ptients hd 6 or more one scn lesions nd of those 40% hd > 20 lesions or superscn. Opite pin medictions were used for cncer-relted pin in 54% of ptients, non-opite pin medictions in 44% of ptients nd no pin medictions in 2% of ptients. Ptients were strtified y seline ALP, isphosphonte use, nd prior docetxel exposure. Prior isphosphontes were used y 41% of ptients nd 58% hd received prior docetxel. During the tretment period, 83% of Xofigo ptients nd 82% of plceo ptients received gondotropin-relesing hormone gonists nd 21% of Xofigo ptients nd 34% of plceo ptients received concomitnt ntindrogens. Use of systemic steroids (41%) nd isphosphontes (40%) ws lnced etween the rms. The pre-specified interim nlysis of overll survivl reveled sttisticlly significnt improvement in ptients receiving XOFIGO plus est stndrd of cre compred with ptients receiving plceo plus est stndrd of cre. An explortory updted overll survivl nlysis performed efore ptient crossover with n dditionl 214 events resulted in findings consistent with the interim nlysis (Tle 5). 11
Tle 5: Overll Survivl Results from the Phse 3 Clinicl Tril Xofigo Plceo Interim Anlysis Sujects rndomized 541 268 Numer of deths 191 (35.3%) 123 (45.9%) Censored 350 (64.7%) 145 (54.1%) Medin survivl (months) (95% CI) 14.0 (12.1, 15.8) p-vlue 0.00185 Hzrd rtio (95% CI) c 0.695 (0.552, 0.875) 11.2 ( 9.0, 13.2) Updted Anlysis Sujects rndomized 614 307 Numer of deths 333 (54.2%) 195 (63.5%) Censored 281 (45.8%) 112 (36.5%) Medin survivl (months) (95% CI) 14.9 (13.9, 16.1) Hzrd rtio (95% CI) c 0.695 (0.581, 0.832) 11.3 (10.4, 12.8) Survivl time is clculted s months from dte of rndomiztion to dte of deth from ny cuse. Sujects who re not decesed t time of nlysis re censored on the lst dte suject ws known to e live or lost to follow-up. p-vlue is from log-rnk test strtified y totl ALP, current use of isphosphontes, nd prior use of docetxel. c Hzrd rtio is from Cox proportionl hzrds model djusted for totl ALP, current use of isphosphontes, nd prior use of docetxel. Hzrd rtio < 1 fvors rdium-223 dichloride. 12
The Kpln-Meier curves for overll survivl sed on the updted survivl results re shown in Figure 1. Figure 1: Kpln-Meier Overll Survivl Curves from the Phse 3 Clinicl Tril The survivl results were supported y dely in the time to first SSE fvoring the Xofigo rm. The mjority of events consisted of externl em rdiotherpy to one metstses. 15 REFERENCES 1. Rdition Emergency Medicl Mngement. [REMM/Ntionl Lirry of Medicine Wesite.] http://www.remm.nlm.gov/int_contmintion.htm#lockinggents 16 HOW SUPPLIED/STORAGE AND HANDLING Xofigo (rdium R 223 dichloride injection) is supplied in single-use vils contining 6 ml of solution t concentrtion of 1,100 kbq/ml (30 microcurie/ml) with totl rdioctivity of 6,600 kbq/vil (178 microcurie/vil) t the reference dte (NDC 50419-208-01). Store t room temperture, elow 40 C (104 F). Store Xofigo in the originl continer or equivlent rdition shielding. This preprtion is pproved for use y persons under license y the Nucler Regultory Commission or the relevnt regultory uthority of n Agreement Stte. Follow procedures for proper hndling nd disposl of rdioctive phrmceuticls [see Dosge nd Administrtion (2.3)]. 13
17 PATIENT COUNSELING INFORMATION Advise ptients: To e complint with lood cell count monitoring ppointments while receiving Xofigo. Explin the importnce of routine lood cell counts. Instruct ptients to report signs of leeding or infections. To sty well hydrted nd to monitor orl intke, fluid sttus, nd urine output while eing treted with Xofigo. Instruct ptients to report signs of dehydrtion, hypovolemi, urinry retention, or renl filure / insufficiency. There re no restrictions regrding contct with other people fter receiving Xofigo. Follow good hygiene prctices while receiving Xofigo nd for t lest 1 week fter the lst injection in order to minimize rdition exposure from odily fluids to household memers nd cregivers. Whenever possile, ptients should use toilet nd the toilet should e flushed severl times fter ech use. Clothing soiled with ptient fecl mtter or urine should e wshed promptly nd seprtely from other clothing. Cregivers should use universl precutions for ptient cre such s gloves nd rrier gowns when hndling odily fluids to void contmintion. When hndling odily fluids, wering gloves nd hnd wshing will protect cregivers. Who re sexully ctive to use condoms nd their femle prtners of reproductive potentil to use highly effective method of irth control during tretment nd for 6 months following completion of Xofigo tretment. Mnufctured for: Byer HelthCre Phrmceuticls Inc. Whippny, NJ 07981 Mnufctured in Norwy Xofigo is trdemrk of Byer Aktiengesellschft. 2013, Byer HelthCre Phrmceuticls Inc. All rights reserved. Revised: Mrch 2016 14