Ptient Monitoring Checklist Ptient nme Dte This checklist is intended for nurses or other helthcre professionls (HCPs) to use prior to dosing ech ptient nd t ny follow-up visits or clls with the ptient to identify some of the signs nd symptoms ssocited with dverse rections relted to tretment with. Erly identifiction of dverse rections nd intervention re importnt prts of the sfe use of. Plese note: this checklist is not ment to e ll inclusive. If the ptient responds Yes to ny of these questions, consult with the ptient s HCP efore dministering. QUESTION RESPONSE NOTES GENERAL Are you hving difficulty performing your norml ctivities? Yes No Hve you hd constnt or unusul hedches? Yes No Hve you felt drowsy or extremely tired? Yes No Hve you felt dizzy or finted? Yes No Hve you hd chnges in mood or ehvior, such s decresed sex drive, irritility, or forgetfulness? Yes No Hve you felt cold? Yes No Hve you gined or lost weight? Yes No Hve you hd hir loss? Yes No Hs your voice gotten deeper? Yes No Hve you noticed your skin or eyes turning yellow? Yes No Are you experiencing incresed thirst? Yes No Are you urinting more or less often thn usul? Yes No Is your urine loody, drk, or te-colored? Yes No Do you leed or ruise more esily thn norml? Yes No Do you hve swelling in your nkles? Yes No Hve you hd severe or constnt muscle or joint pin? Yes No Hve you hd severe muscle wekness? Yes No Hve you een running fever? Yes No Hve you hd chnges in your eyesight? Yes No Hve you strted tking ny new medictions (prescription, nonprescription, or herl)? If yes, which nd how often? Yes No Hve you experienced ny wekness? Yes No PULMONARY Do you hve new cough or one tht hs worsened? Yes No Are you hving chest pin? Yes No Are you hving troule rething or shortness of reth? Yes No GASTROINTESTINAL Are you severely nuseous nd/or vomiting? Yes No Do you hve loss of ppetite or hve you felt less hungry thn usul? Yes No How mny owel movements re you hving ech dy? Is this different thn norml? If yes, how? Yes No Are your stools loose or wtery, or do they hve foul smell? Yes No Hve you seen lood or mucous in your stools? Yes No Are your stools drk, trry, or sticky? Yes No Are you hving pinful owel movements? Yes No Are you hving pin or tenderness round your elly? If yes, where? Yes No Questions pertining to s single gent continue on the next pge. Plese see Importnt Sfety Informtion on pges 2 3 nd ccompnying U.S. Full Prescriing Informtion for. Plese refer to the end of the Importnt Sfety Informtion for rief description of the ptient popultions studied in the Checkmte trils. 1
QUESTION RESPONSE NOTES NEUROLOGIC Hve you experienced ny periods of confusion? Yes No Hve you lost consciousness t ny point? Yes No Hve you hd ny stiffness in your neck? Yes No Hve you hd ny seizures? Yes No Hve you hd ny sudden chnges in your mood, perception, judgment, or memory? Yes No SKIN Hve you hd rsh or itching? Yes No Hve you hd ny skin listers or ulcers in your mouth or other mucous memrnes? Yes No In ddition, if the ptient responds Yes to ny of these questions, consult with the ptient s HCP efore dministering. cn cuse severe infusion rections, which hve een reported in less thn 1.0% of ptients in clinicl trils. Ptients should tell their doctor or nurse immeditely if they experience ny of the following symptoms during n infusion with : chills or shking, itching or rsh, flushing, difficulty rething, dizziness, fever, or feeling like pssing out. QUESTION RESPONSE NOTES INFUSION REACTIONS Hve you experienced chills or shking fter receiving dose of? Yes No Hve you experienced itching or rsh fter receiving dose of? Yes No Hve you experienced flushing fter receiving dose of? Yes No Hve you hd difficulty rething fter receiving dose of? Yes No Hve you experienced dizziness fter receiving dose of? Yes No Hve you hd fever fter receiving dose of? Yes No Hve you felt like pssing out fter receiving dose of? Yes No INDICATIONS is indicted for the tretment of ptients with metsttic non-smll cell lung cncer (NSCLC) with progression on or fter pltinum-sed chemotherpy. Ptients with EGFR or ALK genomic tumor errtions should hve disese progression on FDA-pproved therpy for these errtions prior to receiving. is indicted for the tretment of ptients with dvnced renl cell crcinom (RCC) who hve received prior nti-ngiogenic therpy. is indicted for the tretment of ptients with recurrent or metsttic squmous cell crcinom of the hed nd neck (SCCHN) with disese progression on or fter pltinum-sed therpy. IMPORTANT SAFETY INFORMATION Immune-Medited Pneumonitis cn cuse immune-medited pneumonitis. Ftl cses hve een reported. Monitor ptients for signs with rdiogrphic imging nd for symptoms of pneumonitis. Administer corticosteroids for Grde 2 or more severe pneumonitis. Permnently discontinue for Grde 3 or 4 nd withhold until resolution for Grde 2. In ptients receiving monotherpy, ftl cses of immune-medited pneumonitis hve occurred. Immune-medited pneumonitis occurred in 3.1% (61/1994) of ptients. Immune-Medited Colitis cn cuse immune-medited colitis. Monitor ptients for signs nd symptoms of colitis. Administer corticosteroids for Grde 2 (of more thn 5 dys durtion), 3, or 4 colitis. Withhold monotherpy for Grde 2 or 3 nd permnently discontinue for Grde 4 or recurrent colitis upon re-initition of. In ptients receiving monotherpy, immune-medited colitis occurred in 2.9% (58/1994) of ptients. Plese see Importnt Sfety Informtion continued on the next pge nd ccompnying U.S. Full Prescriing Informtion for. Plese refer to the end of the Importnt Sfety Informtion for rief description of the ptient popultions studied in the Checkmte trils. 2
Immune-Medited Heptitis cn cuse immune-medited heptitis. Monitor ptients for norml liver tests prior to nd periodiclly during tretment. Administer corticosteroids for Grde 2 or greter trnsminse elevtions. Withhold for Grde 2 nd permnently discontinue for Grde 3 or 4 immune-medited heptitis. In ptients receiving monotherpy, immune-medited heptitis occurred in 1.8% (35/1994) of ptients. Immune-Medited Endocrinopthies cn cuse immune-medited hypophysitis, immune-medited drenl insufficiency, utoimmune thyroid disorders, nd Type 1 dietes mellitus. Monitor ptients for signs nd symptoms of hypophysitis, signs nd symptoms of drenl insufficiency, thyroid function prior to nd periodiclly during tretment, nd hyperglycemi. Administer hormone replcement s cliniclly indicted nd corticosteroids for Grde 2 or greter hypophysitis. Withhold for Grde 2 or 3 nd permnently discontinue for Grde 4 hypophysitis. Administer corticosteroids for Grde 3 or 4 drenl insufficiency. Withhold for Grde 2 nd permnently discontinue for Grde 3 or 4 drenl insufficiency. Administer hormone-replcement therpy for hypothyroidism. Initite medicl mngement for control of hyperthyroidism. Withhold for Grde 3 nd permnently discontinue for Grde 4 hyperglycemi. In ptients receiving monotherpy, hypophysitis occurred in 0.6% (12/1994) of ptients. In ptients receiving monotherpy, drenl insufficiency occurred in 1% (20/1994) of ptients. In ptients receiving monotherpy, hypothyroidism or thyroiditis resulting in hypothyroidism occurred in 9% (171/1994) of ptients. Hyperthyroidism occurred in 2.7% (54/1994) of ptients receiving monotherpy. In ptients receiving monotherpy, dietes occurred in 0.9% (17/1994) of ptients. Immune-Medited Nephritis nd Renl Dysfunction cn cuse immune-medited nephritis. Monitor ptients for elevted serum cretinine prior to nd periodiclly during tretment. Administer corticosteroids for 2-4 incresed serum cretinine. Withhold for Grde 2 or 3 nd permnently discontinue for Grde 4 incresed serum cretinine. In ptients receiving monotherpy, immune-medited nephritis nd renl dysfunction occurred in 1.2% (23/1994) of ptients. Immune-Medited Skin Adverse Rections cn cuse immune-medited rsh, including Stevens-Johnson syndrome (SJS) nd toxic epiderml necrolysis (TEN), some cses with ftl outcome. Administer corticosteroids for Grde 3 or 4 rsh. Withhold for Grde 3 nd permnently discontinue for Grde 4 rsh. For symptoms or signs of SJS or TEN, withhold nd refer the ptient for specilized cre for ssessment nd tretment; if confirmed, permnently discontinue. In ptients receiving monotherpy, immune-medited rsh occurred in 9% (171/1994) of ptients. Immune-Medited Encephlitis cn cuse immune-medited encephlitis. Evlution of ptients with neurologic symptoms my include, ut not e limited to, consulttion with neurologist, rin MRI, nd lumr puncture. Withhold in ptients with new-onset moderte to severe neurologic signs or symptoms nd evlute to rule out other cuses. If other etiologies re ruled out, dminister corticosteroids nd permnently discontinue for immune-medited encephlitis. In ptients receiving monotherpy, encephlitis occurred in 0.2% (3/1994) of ptients. Ftl limic encephlitis occurred in one ptient fter 7.2 months of exposure despite discontinution of nd dministrtion of corticosteroids. Other Immune-Medited Adverse Rections Bsed on the severity of dverse rection, permnently discontinue or withhold tretment, dminister high-dose corticosteroids, nd, if pproprite, initite hormonereplcement therpy. Across clinicl trils of the following cliniclly significnt immune-medited dverse rections occurred in <1.0% of ptients receiving : uveitis, iritis, pncretitis, fcil nd ducens nerve presis, demyelintion, polymylgi rheumtic, utoimmune neuropthy, Guillin Brré syndrome, hypopituitrism, systemic inflmmtory response syndrome, gstritis, duodenitis, srcoidosis, histiocytic necrotizing lymphdenitis (Kikuchi lymphdenitis), myositis, myocrditis, rhdomyolysis, motor dysfunction, vsculitis, nd mysthenic syndrome. Infusion Rections cn cuse severe infusion rections, which hve een reported in <1.0% of ptients in clinicl trils. Discontinue in ptients with Grde 3 or 4 infusion rections. Interrupt or slow the rte of infusion in ptients with Grde 1 or 2. In ptients receiving monotherpy, infusion-relted rections occurred in 6.4% (127/1994) of ptients. Emryo-Fetl Toxicity Bsed on its mechnism of ction, cn cuse fetl hrm when dministered to pregnnt womn. Advise pregnnt women of the potentil risk to fetus. Advise femles of reproductive potentil to use effective contrception during tretment with n -contining regimen nd for t lest 5 months fter the lst dose of. Lcttion It is not known whether is present in humn milk. Becuse mny drugs, including ntiodies, re excreted in humn milk nd ecuse of the potentil for serious dverse rections in nursing infnts from n -contining regimen, dvise women to discontinue restfeeding during tretment. Serious Adverse Rections In Checkmte 017 nd 057, serious dverse rections occurred in 46% of ptients receiving (n=418). The most frequent serious dverse rections reported in t lest 2% of ptients receiving were pneumoni, pulmonry emolism, dyspne, pyrexi, pleurl effusion, pneumonitis, nd respirtory filure. In Checkmte 025, serious dverse rections occurred in 47% of ptients receiving (n=406). The most frequent serious dverse rections reported in 2% of ptients were cute kidney injury, pleurl effusion, pneumoni, dirrhe, nd hyperclcemi. In Checkmte 141, serious dverse rections occurred in 49% of ptients receiving. The most frequent serious dverse rections reported in t lest 2% of ptients receiving were pneumoni, dyspne, respirtory filure, respirtory trct infections, nd sepsis. Common Adverse Rections In Checkmte 017 nd 057, the most common dverse rections ( 20%) in ptients receiving (n=418) were ftigue, musculoskeletl pin, cough, dyspne, nd decresed ppetite. In Checkmte 025, the most common dverse rections ( 20%) reported in ptients receiving (n=406) vs everolimus (n=397) were sthenic conditions (56% vs 57%), cough (34% vs 38%), nuse (28% vs 29%), rsh (28% vs 36%), dyspne (27% vs 31%), dirrhe (25% vs 32%), constiption (23% vs 18%), decresed ppetite (23% vs 30%), ck pin (21% vs 16%), nd rthrlgi (20% vs 14%). In Checkmte 141, the most common dverse rections ( 10%) in ptients receiving were cough nd dyspne t higher incidence thn investigtor s choice. Checkmte Trils nd Ptient Popultions Checkmte 017 - squmous non-smll cell lung cncer (NSCLC); Checkmte 057 - non-squmous NSCLC; Checkmte 025 - renl cell crcinom; Checkmte 141 - squmous cell crcinom of the hed nd neck. nd the relted logo re trdemrks of Bristol-Myers Squi Compny. 2016 Bristol-Myers Squi Compny. rights reserved. 1506US1604551-01-01 11/16 3
HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include ll the informtion needed to use sfely nd effectively. See full prescriing informtion for. (nivolum) injection, for intrvenous use Initil U.S. Approvl: 2014 -----------------------------RECENT MAJOR CHANGES ---------------------------- Indictions nd Usge (1) 11/2016 Dosge nd Administrtion (2) 11/2016 Wrnings nd Precutions (5) 10/2016 ----------------------------- INDICATIONS AND USAGE ----------------------------- is progrmmed deth receptor-1 (PD-1) locking ntiody indicted for the tretment of ptients with: BRAF V600 wild-type unresectle or metsttic melnom, s single gent. (1.1) BRAF V600 muttion-positive unresectle or metsttic melnom, s single gent. This indiction is pproved under ccelerted pprovl sed on progressionfree survivl. Continued pprovl for this indiction my e contingent upon verifiction nd description of clinicl enefit in the confirmtory trils. (1.1) Unresectle or metsttic melnom, in comintion with ipilimum. This indiction is pproved under ccelerted pprovl sed on progression-free survivl. Continued pprovl for this indiction my e contingent upon verifiction nd description of clinicl enefit in the confirmtory trils. (1.1) Metsttic non-smll cell lung cncer nd progression on or fter pltinum-sed chemotherpy. Ptients with EGFR or ALK genomic tumor errtions should hve disese progression on FDA-pproved therpy for these errtions prior to receiving. (1.2) Advnced renl cell crcinom who hve received prior nti-ngiogenic therpy. (1.3) Clssicl Hodgkin lymphom tht hs relpsed or progressed fter utologous hemtopoietic stem cell trnsplnttion (HSCT) nd post-trnsplnttion rentuxim vedotin. This indiction is pproved under ccelerted pprovl sed on overll response rte. Continued pprovl for this indiction my e contingent upon verifiction nd description of clinicl enefit in confirmtory trils. (1.4) Recurrent or metsttic squmous cell crcinom of the hed nd neck with disese progression on or fter pltinum-sed therpy. (1.5) -------------------------- DOSAGE AND ADMINISTRATION -------------------------- Administer s n intrvenous infusion over 60 minutes. Unresectle or metsttic melnom 240 mg every 2 weeks. (2.1) with ipilimum: 1 mg/kg, followed y ipilimum on the sme dy, every 3 weeks for 4 doses, then 240 mg every 2 weeks. (2.1) Metsttic non-smll cell lung cncer 240 mg every 2 weeks. (2.2) Advnced renl cell crcinom 240 mg every 2 weeks. (2.3) Clssicl Hodgkin lymphom 3 mg/kg every 2 weeks. (2.4) Recurrent or metsttic squmous cell crcinom of the hed nd neck 3 mg/kg every 2 weeks. (2.5) FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 1.1 Unresectle or Metsttic Melnom 1.2 Metsttic Non-Smll Cell Lung Cncer 1.3 Renl Cell Crcinom 1.4 Clssicl Hodgkin Lymphom 1.5 Squmous Cell Crcinom of the Hed nd Neck 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosge for Melnom 2.2 Recommended Dosge for NSCLC 2.3 Recommended Dosge for RCC 2.4 Recommended Dosge for chl 2.5 Recommended Dosge for SCCHN 2.6 Dose Modifictions 2.7 Preprtion nd Administrtion 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Immune-Medited Pneumonitis 5.2 Immune-Medited Colitis 5.3 Immune-Medited Heptitis 5.4 Immune-Medited Endocrinopthies 5.5 Immune-Medited Nephritis nd Renl Dysfunction 5.6 Immune-Medited Skin Adverse Rections 5.7 Immune-Medited Encephlitis 5.8 Other Immune-Medited Adverse Rections 5.9 Infusion Rections 5.10 Complictions of ogeneic HSCT fter 5.11 Emryo-Fetl Toxicity -------------------------DOSAGE FORMS AND STRENGTHS ------------------------ Injection: 40 mg/4 ml nd 100 mg/10 ml solution in single-dose vil. (3) ------------------------------- CONTRAINDICATIONS ------------------------------- None. (4) -------------------------- WARNINGS AND PRECAUTIONS -------------------------- Immune-medited pneumonitis: Withhold for moderte nd permnently discontinue for severe or life-thretening pneumonitis. (5.1) Immune-medited colitis: Withhold (nivolum) when given s single gent for moderte or severe nd permnently discontinue for life-thretening colitis. Withhold when given with ipilimum for moderte nd permnently discontinue for severe or life-thretening colitis. (5.2) Immune-medited heptitis: Monitor for chnges in liver function. Withhold for moderte nd permnently discontinue for severe or life-thretening trnsminse or totl iliruin elevtion. (5.3) Immune-medited endocrinopthies: Withhold for moderte or severe nd permnently discontinue for life-thretening hypophysitis. Withhold for moderte nd permnently discontinue for severe or life-thretening drenl insufficiency. Monitor for chnges in thyroid function. Initite thyroid hormone replcement s needed. Monitor for hyperglycemi. Withhold for severe nd permnently discontinue for life-thretening hyperglycemi. (5.4) Immune-medited nephritis nd renl dysfunction: Monitor for chnges in renl function. Withhold for moderte or severe nd permnently discontinue for life-thretening serum cretinine elevtion. (5.5) Immune-medited skin dverse rections: Withhold for severe nd permnently discontinue for life-thretening rsh. (5.6) Immune-medited encephlitis: Monitor for chnges in neurologic function. Withhold for new-onset moderte to severe neurologicl signs or symptoms nd permnently discontinue for immune-medited encephlitis. (5.7) Infusion rections: Discontinue for severe nd life-thretening infusion rections. Interrupt or slow the rte of infusion in ptients with mild or moderte infusion rections. (5.9) Complictions of llogeneic HSCT fter : Monitor for hypercute grft-versushost-disese (GVHD), grde cute GVHD, steroid-requiring ferile syndrome, heptic veno-occlusive disese, nd other immune-medited dverse rections. Trnsplnt-relted mortlity hs occurred. (5.10) Emryo-fetl toxicity: Cn cuse fetl hrm. Advise of potentil risk to fetus nd use of effective contrception. (5.11, 8.1, 8.3) ------------------------------- ADVERSE REACTIONS ------------------------------- Most common dverse rections ( 20%) in ptients were: s single gent: ftigue, rsh, musculoskeletl pin, pruritus, dirrhe, nuse, stheni, cough, dyspne, constiption, decresed ppetite, ck pin, rthrlgi, upper respirtory trct infection, pyrexi. (6.1) with ipilimum: ftigue, rsh, dirrhe, nuse, pyrexi, vomiting, nd dyspne. (6.1) To report SUSPECTED ADVERSE REACTIONS, contct Bristol-Myers Squi t 1-800-721-5072 or FDA t 1-800-FDA-1088 or www.fd.gov/medwtch. -------------------------- USE IN SPECIFIC POPULATIONS -------------------------- Lcttion: Discontinue restfeeding. (8.2) See 17 for PATIENT COUNSELING INFORMATION nd Mediction Guide. Revised: 11/2016 6 ADVERSE REACTIONS 6.1 Clinicl Trils Experience 6.2 Immunogenicity 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnncy 8.2 Lcttion 8.3 Femles nd Mles of Reproductive Potentil 8.4 Peditric Use 8.5 Geritric Use 8.6 Renl Impirment 8.7 Heptic Impirment 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechnism of Action 12.2 Phrmcodynmics 12.3 Phrmcokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Crcinogenesis, Mutgenesis, Impirment of Fertility 13.2 Animl Toxicology nd/or Phrmcology 14 CLINICAL STUDIES 14.1 Unresectle or Metsttic Melnom 14.2 Metsttic Non-Smll Cell Lung Cncer (NSCLC) 14.3 Renl Cell Crcinom 14.4 Clssicl Hodgkin Lymphom 14.5 Recurrent or Metsttic Squmous Cell Crcinom of the Hed nd Neck (SCCHN) 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION *Sections or susections omitted from the full prescriing informtion re not listed. 1
FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE 1.1 Unresectle or Metsttic Melnom (nivolum) s single gent is indicted for the tretment of ptients with BRAF V600 wild-type unresectle or metsttic melnom [see Clinicl Studies (14.1)]. s single gent is indicted for the tretment of ptients with BRAF V600 muttion-positive unresectle or metsttic melnom [see Clinicl Studies (14.1)]. This indiction is pproved under ccelerted pprovl sed on progression-free survivl. Continued pprovl for this indiction my e contingent upon verifiction nd description of clinicl enefit in the confirmtory trils., in comintion with ipilimum, is indicted for the tretment of ptients with unresectle or metsttic melnom [see Clinicl Studies (14.1)]. This indiction is pproved under ccelerted pprovl sed on progression-free survivl. Continued pprovl for this indiction my e contingent upon verifiction nd description of clinicl enefit in the confirmtory trils. 1.2 Metsttic Non-Smll Cell Lung Cncer is indicted for the tretment of ptients with metsttic non-smll cell lung cncer (NSCLC) with progression on or fter pltinum-sed chemotherpy. Ptients with EGFR or ALK genomic tumor errtions should hve disese progression on FDA-pproved therpy for these errtions prior to receiving [see Clinicl Studies (14.2)]. 1.3 Renl Cell Crcinom is indicted for the tretment of ptients with dvnced renl cell crcinom (RCC) who hve received prior nti-ngiogenic therpy [see Clinicl Studies (14.3)]. 1.4 Clssicl Hodgkin Lymphom is indicted for the tretment of ptients with clssicl Hodgkin lymphom (chl) tht hs relpsed or progressed fter utologous hemtopoietic stem cell trnsplnttion (HSCT) nd post-trnsplnttion rentuxim vedotin [see Clinicl Studies (14.4)]. This indiction is pproved under ccelerted pprovl sed on overll response rte. Continued pprovl for this indiction my e contingent upon verifiction nd description of clinicl enefit in confirmtory trils [see Clinicl Studies (14.4)]. 1.5 Squmous Cell Crcinom of the Hed nd Neck is indicted for the tretment of ptients with recurrent or metsttic squmous cell crcinom of the hed nd neck (SCCHN) with disese progression on or fter pltinum-sed therpy [see Clinicl Studies (14.5)]. 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosge for Melnom The recommended dose of s single gent is 240 mg dministered s n intrvenous infusion over 60 minutes every 2 weeks until disese progression or uncceptle toxicity. The recommended dose of is 1 mg/kg dministered s n intrvenous infusion over 60 minutes, followed y ipilimum on the sme dy, every 3 weeks for 4 doses [see Clinicl Studies (14.1)]. The recommended susequent dose of, s single gent, is 240 mg dministered s n intrvenous infusion over 60 minutes every 2 weeks until disese progression or uncceptle toxicity. Review the Full Prescriing Informtion for ipilimum prior to initition. 2.2 Recommended Dosge for NSCLC The recommended dose of is 240 mg dministered s n intrvenous infusion over 60 minutes every 2 weeks until disese progression or uncceptle toxicity. 2.3 Recommended Dosge for RCC The recommended dose of is 240 mg dministered s n intrvenous infusion over 60 minutes every 2 weeks until disese progression or uncceptle toxicity. 2.4 Recommended Dosge for chl The recommended dose of is 3 mg/kg dministered s n intrvenous infusion over 60 minutes every 2 weeks until disese progression or uncceptle toxicity. 2.5 Recommended Dosge for SCCHN The recommended dose of is 3 mg/kg dministered s n intrvenous infusion over 60 minutes every 2 weeks until disese progression or uncceptle toxicity. 2.6 Dose Modifictions Recommendtions for modifictions re provided in Tle 1. When is dministered in comintion with ipilimum, if is withheld, ipilimum should lso e withheld. There re no recommended dose modifictions for hypothyroidism or hyperthyroidism. Interrupt or slow the rte of infusion in ptients with mild or moderte infusion rections. Discontinue in ptients with severe or life-thretening infusion rections. (nivolum) Tle 1: Recommended Dose Modifictions for Adverse Rection Severity* Dose Modifiction Grde 2 dirrhe or colitis Withhold dose Colitis Grde 3 dirrhe or colitis Withhold dose when dministered s single gent Permnently discontinue when dministered with ipilimum Grde 4 dirrhe or colitis Permnently discontinue Pneumonitis Grde 2 pneumonitis Withhold dose Grde 3 or 4 pneumonitis Permnently discontinue Asprtte minotrnsferse (AST)/or lnine minotrnsferse (ALT) more thn 3 nd up to 5 times the upper limit of norml or totl Withhold dose Heptitis iliruin more thn 1.5 nd up to 3 times the upper limit of norml AST or ALT more thn 5 times the upper limit of norml or totl iliruin more thn 3 times Permnently discontinue the upper limit of norml Hypophysitis Grde 2 or 3 hypophysitis Withhold dose Grde 4 hypophysitis Permnently discontinue Grde 2 drenl insufficiency Withhold dose Adrenl Insufficiency Grde 3 or 4 drenl insufficiency Permnently discontinue Type 1 Dietes Mellitus Grde 3 hyperglycemi Withhold dose Grde 4 hyperglycemi Permnently discontinue Nephritis nd Renl Dysfunction Skin Encephlitis Other Serum cretinine more thn 1.5 nd up to 6 times the upper limit of norml Serum cretinine more thn 6 times the upper limit of norml Grde 3 rsh or suspected Stevens-Johnson syndrome (SJS) or toxic epiderml necrolysis (TEN) Grde 4 rsh or confirmed SJS or TEN New-onset moderte or severe neurologic signs or symptoms Immune-medited encephlitis Other Grde 3 dverse rection First occurrence Recurrence of sme Grde 3 dverse rections Life-thretening or Grde 4 dverse rection Requirement for 10 mg per dy or greter prednisone or equivlent for more thn 12 weeks Persistent Grde 2 or 3 dverse rections lsting 12 weeks or longer Withhold dose Permnently discontinue Withhold dose Permnently discontinue Withhold dose Permnently discontinue Withhold dose Permnently discontinue Permnently discontinue Permnently discontinue Permnently discontinue * Toxicity ws grded per Ntionl Cncer Institute Common Terminology Criteri for Adverse Events. Version 4.0 (NCI CTCAE v4). Resume tretment when dverse rection returns to Grde 0 or 1. 2.7 Preprtion nd Administrtion Visully inspect drug product solution for prticulte mtter nd discolortion prior to dministrtion. is cler to oplescent, colorless to ple-yellow solution. Discrd the vil if the solution is cloudy, discolored, or contins extrneous prticulte mtter other thn few trnslucent-to-white, proteinceous prticles. Do not shke the vil. Preprtion Withdrw the required volume of nd trnsfer into n intrvenous continer. Dilute with either 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP to prepre n infusion with finl concentrtion rnging from 1 mg/ml to 10 mg/ml. 2
(nivolum) Mix diluted solution y gentle inversion. Do not shke. Discrd prtilly used vils or empty vils of. Storge of Infusion The product does not contin preservtive. After preprtion, store the infusion either: t room temperture for no more thn 4 hours from the time of preprtion. This includes room temperture storge of the infusion in the IV continer nd time for dministrtion of the infusion or under refrigertion t 2 C to 8 C (36 F to 46 F) for no more thn 24 hours from the time of infusion preprtion. Do not freeze. Administrtion Administer the infusion over 60 minutes through n intrvenous line contining sterile, non-pyrogenic, low protein inding in-line filter (pore size of 0.2 micrometer to 1.2 micrometer). Do not codminister other drugs through the sme intrvenous line. Flush the intrvenous line t end of infusion. When dministered in comintion with ipilimum, infuse first followed y ipilimum on the sme dy. Use seprte infusion gs nd filters for ech infusion. 3 DOSAGE FORMS AND STRENGTHS Injection: 40 mg/4 ml (10 mg/ml) nd 100 mg/10 ml (10 mg/ml) solution in single-dose vil. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Immune-Medited Pneumonitis cn cuse immune-medited pneumonitis, defined s requiring use of corticosteroids nd no cler lternte etiology. Ftl cses hve een reported. Monitor ptients for signs with rdiogrphic imging nd for symptoms of pneumonitis. Administer corticosteroids t dose of 1 to 2 mg/kg/dy prednisone equivlents for moderte (Grde 2) or more severe (Grde ) pneumonitis, followed y corticosteroid tper. Permnently discontinue for severe (Grde 3) or life-thretening (Grde 4) pneumonitis nd withhold until resolution for moderte (Grde 2) pneumonitis [see Dosge nd Administrtion (2.6)]. s Single Agent In ptients receiving s single gent, immune-medited pneumonitis occurred in 3.1% (61/1994) of ptients. The medin time to onset of immune-medited pneumonitis ws 3.5 months (rnge: 1 dy to 22.3 months). Immune-medited pneumonitis led to permnent discontinution of in 1.1%, nd withholding of in 1.3% of ptients. Approximtely 89% of ptients with pneumonitis received high-dose corticosteroids (t lest 40 mg prednisone equivlents per dy) for medin durtion of 26 dys (rnge: 1 dy to 6 months). Complete resolution of symptoms following corticosteroid tper occurred in 67% of ptients. Approximtely 8% of ptients hd recurrence of pneumonitis fter re-initition of. with Ipilimum In ptients receiving with ipilimum, immune-medited pneumonitis occurred in 6% (25/407) of ptients. The medin time to onset of immune-medited pneumonitis ws 1.6 months (rnge: 24 dys to 10.1 months). Immune-medited pneumonitis led to permnent discontinution or withholding of with ipilimum in 2.2% nd 3.7% of ptients, respectively. Approximtely 84% of ptients with pneumonitis received high-dose corticosteroids (t lest 40 mg prednisone equivlents per dy) for medin durtion of 30 dys (rnge: 5 dys to 11.8 months). Complete resolution occurred in 68% of ptients. Approximtely 13% of ptients hd recurrence of pneumonitis fter re-initition of with ipilimum. 5.2 Immune-Medited Colitis cn cuse immune-medited colitis, defined s requiring use of corticosteroids with no cler lternte etiology. Monitor ptients for signs nd symptoms of colitis. Administer corticosteroids t dose of 1 to 2 mg/kg/dy prednisone equivlents followed y corticosteroid tper for severe (Grde 3) or life-thretening (Grde 4) colitis. Administer corticosteroids t dose of 0.5 to 1 mg/kg/dy prednisone equivlents followed y corticosteroid tper for moderte (Grde 2) colitis of more thn 5 dys durtion; if worsening or no improvement occurs despite initition of corticosteroids, increse dose to 1 to 2 mg/kg/dy prednisone equivlents. Withhold for moderte or severe (Grde 2 or 3) colitis. Permnently discontinue for life-thretening (Grde 4) or for recurrent colitis upon re-initition of [see Dosge nd Administrtion (2.6)]. (nivolum) When dministered in comintion with ipilimum, withhold nd ipilimum for moderte colitis (Grde 2). Permnently discontinue nd ipilimum for severe or life-thretening (Grde 3 or 4) colitis or for recurrent colitis [see Dosge nd Administrtion (2.6)]. s Single Agent In ptients receiving s single gent, immune-medited colitis occurred in 2.9% (58/1994) of ptients; the medin time to onset ws 5.3 months (rnge: 2 dys to 20.9 months). Immune-medited colitis led to permnent discontinution of in 0.7% nd withholding of in 1% of ptients. Approximtely 91% of ptients with colitis received high-dose corticosteroids (t lest 40 mg prednisone equivlents per dy) for medin durtion of 23 dys (rnge: 1 dy to 9.3 months). Four ptients required ddition of inflixim to high-dose corticosteroids. Complete resolution occurred in 74% of ptients. Approximtely 16% of ptients hd recurrence of colitis fter re-initition of. with Ipilimum In ptients receiving with ipilimum, immune-medited colitis occurred in 26% (107/407) of ptients including three ftl cses. The medin time to onset of immune-medited colitis ws 1.6 months (rnge: 3 dys to 15.2 months). Immune-medited colitis led to permnent discontinution or withholding of with ipilimum in 16% nd 7% of ptients, respectively. Approximtely 96% of ptients with colitis received high-dose corticosteroids (t lest 40 mg prednisone equivlents per dy) for medin durtion of 1.1 month (rnge: 1 dy to 12 months). Approximtely 23% of ptients required ddition of inflixim to high-dose corticosteroids. Complete resolution occurred in 75% of ptients. Approximtely 28% of ptients hd recurrence of colitis fter re-initition of with ipilimum. 5.3 Immune-Medited Heptitis cn cuse immune-medited heptitis, defined s requiring use of corticosteroids nd no cler lternte etiology. Monitor ptients for norml liver tests prior to nd periodiclly during tretment. Administer corticosteroids t dose of 1 to 2 mg/kg/dy prednisone equivlents followed y corticosteroid tper for severe (Grde 3) or life-thretening (Grde 4) trnsminse elevtions, with or without concomitnt elevtion in totl iliruin. Administer corticosteroids t dose of 0.5 to 1 mg/kg/dy prednisone equivlents for moderte (Grde 2) trnsminse elevtions. Withhold for moderte (Grde 2) nd permnently discontinue for severe (Grde 3) or life-thretening (Grde 4) immune-medited heptitis [see Dosge nd Administrtion (2.6)]. s Single Agent In ptients receiving s single gent, immune-medited heptitis occurred in 1.8% (35/1994) of ptients; the medin time to onset ws 3.3 months (rnge: 6 dys to 9 months). Immune-medited heptitis led to permnent discontinution of in 0.7% nd withholding of in 1% of ptients. ptients with heptitis received high-dose corticosteroids (t lest 40 mg prednisone equivlents) for medin durtion of 23 dys (rnge: 1 dy to 2 months). Two ptients required the ddition of mycophenolic cid to high-dose corticosteroids. Complete resolution occurred in 74% of ptients. Approximtely 29% of ptients hd recurrence of heptitis fter re-initition of. with Ipilimum In ptients receiving with ipilimum, immune-medited heptitis occurred in 13% (51/407) of ptients; the medin time to onset ws 2.1 months (rnge: 15 dys to 11 months). Immune-medited heptitis led to permnent discontinution or withholding of with ipilimum in 6% nd 5% of ptients, respectively. Approximtely 92% of ptients with heptitis received high-dose corticosteroids (t lest 40 mg prednisone equivlents per dy) for medin durtion of 1.1 month (rnge: 1 dy to 13.2 months). Complete resolution occurred in 75% of ptients. Approximtely 11% of ptients hd recurrence of heptitis fter re-initition of with ipilimum. 5.4 Immune-Medited Endocrinopthies Hypophysitis cn cuse immune-medited hypophysitis. Monitor ptients for signs nd symptoms of hypophysitis. Administer hormone replcement s cliniclly indicted nd corticosteroids t dose of 1 mg/kg/dy prednisone equivlents followed y corticosteroid tper for moderte (Grde 2) or greter hypophysitis. Withhold for moderte (Grde 2) or severe (Grde 3). Permnently discontinue for life-thretening (Grde 4) hypophysitis [see Dosge nd Administrtion (2.6)]. In ptients receiving s single gent, hypophysitis occurred in 0.6% (12/1994) of ptients; the medin time to onset ws 4.9 months (rnge: 1.4 to 11 months). Hypophysitis led to permnent discontinution of in 0.1% nd withholding of in 0.2% of ptients. Approximtely 67% of ptients with hypophysitis received hormone replcement therpy nd 33% received high-dose corticosteroids (t lest 40 mg prednisone equivlents per dy) for medin durtion of 14 dys (rnge: 5 to 26 dys). In ptients receiving with ipilimum, hypophysitis occurred in 9% (36/407) of ptients; the medin time to onset ws 2.7 months (rnge: 27 dys to 5.5 months). Hypophysitis led to permnent discontinution or withholding of with ipilimum in 1.0% nd 3.9% of ptients, respectively. Approximtely 75% of ptients with hypophysitis received hormone replcement therpy nd 56% received high-dose corticosteroids (t lest 40 mg prednisone equivlents per dy) for medin durtion of 19 dys (rnge: 1 dy to 2.0 months). 3
(nivolum) Adrenl Insufficiency cn cuse immune-medited drenl insufficiency. Monitor ptients for signs nd symptoms of drenl insufficiency. Administer corticosteroids t dose of 1 to 2 mg/kg/dy prednisone equivlents followed y corticosteroid tper for severe (Grde 3) or life-thretening (Grde 4) drenl insufficiency. Withhold for moderte (Grde 2) nd permnently discontinue for severe (Grde 3) or life-thretening (Grde 4) drenl insufficiency [see Dosge nd Administrtion (2.6)]. In ptients receiving s single gent, drenl insufficiency occurred in 1% (20/1994) of ptients nd the medin time to onset ws 4.3 months (rnge: 15 dys to 21 months). Adrenl insufficiency led to permnent discontinution of in 0.1% nd withholding of in 0.5% of ptients. Approximtely 85% of ptients with drenl insufficiency received hormone replcement therpy nd 25% received high-dose corticosteroids (t lest 40 mg prednisone equivlents per dy) for medin durtion of 11 dys (rnge: 1 dy to 1 month). In ptients receiving with ipilimum, drenl insufficiency occurred in 5% (21/407) of ptients nd the medin time to onset ws 3.0 months (rnge: 21 dys to 9.4 months). Adrenl insufficiency led to permnent discontinution or withholding of with ipilimum in 0.5% nd 1.7% of ptients, respectively. Approximtely 57% of ptients with drenl insufficiency received hormone replcement therpy nd 33% received high-dose corticosteroids (t lest 40 mg prednisone equivlents per dy) for medin durtion of 9 dys (rnge: 1 dy to 2.7 months). Hypothyroidism nd Hyperthyroidism cn cuse utoimmune thyroid disorders. Monitor thyroid function prior to nd periodiclly during tretment. Administer hormone-replcement therpy for hypothyroidism. Initite medicl mngement for control of hyperthyroidism. There re no recommended dose djustments of for hypothyroidism or hyperthyroidism. In ptients receiving s single gent, hypothyroidism or thyroiditis resulting in hypothyroidism occurred in 9% (171/1994) of ptients; the medin time to onset ws 2.9 months (rnge: 1 dy to 16.6 months). Approximtely 79% of ptients with hypothyroidism received levothyroxine nd 4% lso required corticosteroids. Resolution occurred in 35% of ptients. Hyperthyroidism occurred in 2.7% (54/1994) of ptients receiving s single gent; the medin time to onset ws 1.5 months (rnge: 1 dy to 14.2 months). Approximtely 26% of ptients with hyperthyroidism received methimzole, 9% received crimzole, 4% received propylthiourcil, nd 9% received corticosteroids. Resolution occurred in 76% of ptients. In ptients receiving with ipilimum, hypothyroidism or thyroiditis resulting in hypothyroidism occurred in 22% (89/407) of ptients; the medin time to onset ws 2.1 months (rnge: 1 dy to 10.1 months). Approximtely 73% of ptients with hypothyroidism or thyroiditis received levothyroxine. Resolution occurred in 45% of ptients. Hyperthyroidism occurred in 8% (34/407) of ptients receiving with ipilimum: the medin time to onset ws 23 dys (rnge: 3 dys to 3.7 months). Approximtely 29% of ptients with hyperthyroidism received methimzole nd 24% received crimzole. Resolution occurred in 94% of ptients. Type 1 Dietes Mellitus cn cuse Type 1 dietes mellitus. Monitor for hyperglycemi. Withhold in cses of severe (Grde 3) hyperglycemi until metolic control is chieved. Permnently discontinue for life-thretening (Grde 4) hyperglycemi [see Dosge nd Administrtion (2.6)]. In ptients receiving s single gent, dietes occurred in 0.9% (17/1994) of ptients including two cses of dietic ketocidosis. The medin time to onset ws 4.4 months (rnge: 15 dys to 22 months). In ptients receiving with ipilimum, dietes occurred in 1.5% (6/407) of ptients; the medin time to onset ws 2.5 months (rnge: 1.3 to 4.4 months). with ipilimum ws withheld in ptient nd permnently discontinued in second ptient who developed dietes. 5.5 Immune-Medited Nephritis nd Renl Dysfunction cn cuse immune-medited nephritis, defined s renl dysfunction or Grde 2 incresed cretinine, requirement for corticosteroids, nd no cler lternte etiology. Monitor ptients for elevted serum cretinine prior to nd periodiclly during tretment. Administer corticosteroids t dose of 1 to 2 mg/kg/dy prednisone equivlents followed y corticosteroid tper for life-thretening (Grde 4) incresed serum cretinine. Administer corticosteroids t dose of 0.5 to 1 mg/kg/dy prednisone equivlents for moderte (Grde 2) or severe (Grde 3) incresed serum cretinine, if worsening or no improvement occurs, increse dose of corticosteroids to 1 to 2 mg/kg/dy prednisone equivlents. Withhold for moderte (Grde 2) or severe (Grde 3) incresed serum cretinine. Permnently discontinue for life-thretening (Grde 4) incresed serum cretinine. [see Dosge nd Administrtion (2.6) nd Adverse Rections (6.1)]. s Single Agent In ptients receiving s single gent, immune-medited nephritis nd renl dysfunction occurred in 1.2% (23/1994) of ptients; the medin time to onset ws 4.6 months (rnge: 23 dys to 12.3 months). Immune-medited nephritis nd renl dysfunction led to permnent discontinution of in 0.3% nd withholding of in 0.8% of ptients. ptients received high-dose corticosteroids (t lest 40 mg prednisone equivlents per dy) for medin durtion of 21 dys (rnge: 1 dy 4 (nivolum) to 15.4 months). Complete resolution occurred in 48% of ptients. No ptients hd recurrence of nephritis or renl dysfunction fter re-initition of. with Ipilimum In ptients receiving with ipilimum, immune-medited nephritis nd renl dysfunction occurred in 2.2% (9/407) of ptients; the medin time to onset ws 2.7 months (rnge: 9 dys to 7.9 months). Immune-medited nephritis nd renl dysfunction led to permnent discontinution or withholding of with ipilimum in 0.7% nd 0.5% of ptients, respectively. Approximtely 67% of ptients received high-dose corticosteroids (t lest 40 mg prednisone equivlents per dy) for medin durtion of 13.5 dys (rnge: 1 dy to 1.1 months). Complete resolution occurred in ll ptients. Two ptients resumed with ipilimum without recurrence of nephritis or renl dysfunction. 5.6 Immune-Medited Skin Adverse Rections cn cuse immune-medited rsh, including Stevens-Johnson syndrome (SJS) nd toxic epiderml necrolysis (TEN), some cses with ftl outcome. For symptoms or signs of SJS or TEN, withhold nd refer the ptient for specilized cre for ssessment nd tretment. If SJS or TEN is confirmed, permnently discontinue [see Dosge nd Administrtion (2.6)]. For immune-medited rsh, dminister corticosteroids t dose of 1 to 2 mg/kg/dy prednisone equivlents followed y corticosteroid tper for severe (Grde 3) or life-thretening (Grde 4) rsh. Withhold for severe (Grde 3) rsh nd permnently discontinue for life-thretening (Grde 4) rsh. s Single Agent In ptients receiving s single gent, immune-medited rsh occurred in 9% (171/1994) of ptients; the medin time to onset ws 2.8 months (rnge: <1 dy to 25.8 months). Immune-medited rsh led to permnent discontinution of in 0.3% nd withholding of in 0.8% of ptients. Approximtely 16% of ptients with rsh received high-dose corticosteroids (t lest 40 mg prednisone equivlents per dy) for medin durtion of 12 dys (rnge: 1 dys to 8.9 months) nd 85% received topicl corticosteroids. Complete resolution occurred in 48% of ptients. Recurrence of rsh occurred in 1.4% of ptients who resumed fter resolution of rsh. with Ipilimum In ptients receiving with ipilimum, immune-medited rsh occurred in 22.6% (92/407) of ptients; the medin time to onset ws 18 dys (rnge: 1 dy to 9.7 months). Immune-medited rsh led to permnent discontinution or withholding of with ipilimum in 0.5% nd 3.9% of ptients, respectively. Approximtely 17% of ptients with rsh received high-dose corticosteroids (t lest 40 mg prednisone equivlents per dy) for medin durtion of 14 dys (rnge: 2 dys to 4.7 months). Complete resolution occurred in 47% of ptients. Approximtely 6% of ptients who resumed nd ipilimum fter resolution hd recurrence of rsh. 5.7 Immune-Medited Encephlitis cn cuse immune-medited encephlitis with no cler lternte etiology. Evlution of ptients with neurologic symptoms my include, ut not e limited to, consulttion with neurologist, rin MRI, nd lumr puncture. Withhold in ptients with new-onset moderte to severe neurologic signs or symptoms nd evlute to rule out infectious or other cuses of moderte to severe neurologic deteriortion. If other etiologies re ruled out, dminister corticosteroids t dose of 1 to 2 mg/kg/dy prednisone equivlents for ptients with immune-medited encephlitis, followed y corticosteroid tper. Permnently discontinue for immune-medited encephlitis [see Dosge nd Administrtion (2.6)]. s Single Agent In ptients receiving s single gent, encephlitis occurred in 0.2% (3/1994). Ftl limic encephlitis occurred in one ptient fter 7.2 months of exposure despite discontinution of nd dministrtion of corticosteroids. In the other two ptients encephlitis occurred post-llogeneic HSCT [see Wrnings nd Precutions (5.10)]. with Ipilimum Encephlitis occurred in one ptient receiving with ipilimum (0.2%) fter 1.7 months of exposure. 5.8 Other Immune-Medited Adverse Rections cn cuse other cliniclly significnt immune-medited dverse rections. Immune-medited dverse rections my occur fter discontinution of therpy. For ny suspected immune-medited dverse rections, exclude other cuses. Bsed on the severity of the dverse rection, permnently discontinue or withhold, dminister high-dose corticosteroids, nd if pproprite, initite hormone-replcement therpy. Upon improvement to Grde 1 or less, initite corticosteroid tper nd continue to tper over t lest 1 month. Consider restrting fter completion of corticosteroid tper sed on the severity of the event [see Dosge nd Administrtion (2.6)]. Across clinicl trils of dministered s single gent or in comintion with ipilimum, the following cliniclly significnt immune-medited dverse rections occurred in less thn 1.0% of ptients receiving : uveitis, iritis, pncretitis, fcil nd ducens nerve presis, demyelintion, polymylgi rheumtic, utoimmune neuropthy, Guillin-Brré syndrome, hypopituitrism, systemic inflmmtory response syndrome, gstritis, duodenitis, srcoidosis, histiocytic necrotizing lymphdenitis (Kikuchi lymphdenitis), myositis, myocrditis, rhdomyolysis, motor dysfunction, vsculitis, nd mysthenic syndrome.
(nivolum) 5.9 Infusion Rections cn cuse severe infusion rections, which hve een reported in less thn 1.0% of ptients in clinicl trils. Discontinue in ptients with severe or life-thretening infusion rections. Interrupt or slow the rte of infusion in ptients with mild or moderte infusion rections [see Dosge nd Administrtion (2.6)]. s Single Agent In ptients receiving s single gent, infusion-relted rections occurred in 6.4% (127/1994) of ptients. with Ipilimum In ptients receiving with ipilimum, infusion-relted rections occurred in 2.5% (10/407) of ptients. 5.10 Complictions of ogeneic HSCT fter Complictions, including ftl events, occurred in ptients who received llogeneic HSCT fter. Outcomes were evluted in 17 ptients from Trils 8 nd 9 who underwent llogeneic HSCT fter discontinuing (15 with reduced-intensity conditioning, two with myeloltive conditioning). The medin ge t HSCT ws 33 (rnge: 18 to 56), nd medin of 9 doses of hd een dministered (rnge: 4 to 16). Six of 17 ptients (35%) died from complictions of llogeneic HSCT fter. Five deths occurred in the setting of severe or refrctory GVHD. Grde 3 or higher cute GVHD ws reported in 5/17 ptients (29%). Hypercute GVHD, defined s GVHD occurring within 14 dys fter stem cell infusion, ws reported in 2 ptients (20%). A steroid-requiring ferile syndrome, without n identified infectious cuse, ws reported in six ptients (35%) within the first 6 weeks post-trnsplnttion, with five ptients responding to steroids. Two cses of encephlitis were reported: one cse of Grde 3 lymphocytic encephlitis without n identified infectious cuse, which occurred nd resolved on steroids, nd one cse of Grde 3 suspected virl encephlitis which ws resolved with ntivirl tretment. Heptic veno-occlusive disese (VOD) occurred in one ptient, who received reducedintensity conditioned llogeneic HSCT nd died of GVHD nd multi-orgn filure. Other cses of heptic VOD fter reduced-intensity conditioned llogeneic HSCT hve lso een reported in ptients with lymphom who received PD-1 receptor locking ntiody efore trnsplnttion. Cses of ftl hypercute GVHD hve lso een reported. These complictions my occur despite intervening therpy etween PD-1 lockde nd llogeneic HSCT. Follow ptients closely for erly evidence of trnsplnt-relted complictions such s hypercute GVHD, severe (Grde 3 to 4) cute GVHD, steroid-requiring ferile syndrome, heptic VOD, nd other immune-medited dverse rections, nd intervene promptly. 5.11 Emryo-Fetl Toxicity Bsed on its mechnism of ction nd dt from niml studies, cn cuse fetl hrm when dministered to pregnnt womn. In niml reproduction studies, dministrtion of nivolum to cynomolgus monkeys from the onset of orgnogenesis through delivery resulted in incresed ortion nd premture infnt deth. Advise pregnnt women of the potentil risk to fetus. Advise femles of reproductive potentil to use effective contrception during tretment with n -contining regimen nd for t lest 5 months fter the lst dose of [see Use in Specific Popultions (8.1, 8.3)]. 6 ADVERSE REACTIONS The following dverse rections re discussed in greter detil in other sections of the leling. Immune-Medited Pneumonitis [see Wrnings nd Precutions (5.1)] Immune-Medited Colitis [see Wrnings nd Precutions (5.2)] Immune-Medited Heptitis [see Wrnings nd Precutions (5.3)] Immune-Medited Endocrinopthies [see Wrnings nd Precutions (5.4)] Immune-Medited Nephritis nd Renl Dysfunction [see Wrnings nd Precutions (5.5)] Immune-Medited Skin Adverse Rections [see Wrnings nd Precutions (5.6)] Immune-Medited Encephlitis [see Wrnings nd Precutions (5.7)] Other Immune-Medited Adverse Rections [see Wrnings nd Precutions (5.8)] Infusion Rections [see Wrnings nd Precutions (5.9)] Complictions of ogeneic HSCT fter [see Wrnings nd Precutions (5.10)] 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. The dt in the Wrnings nd Precutions section reflect exposure to, s single gent, for cliniclly significnt dverse rections in 1994 ptients enrolled in Trils 1 through 8 or single-rm tril in NSCLC (n=117) dministering s single gent [see Wrnings nd Precutions (5.1, 5.8)]. In ddition, cliniclly significnt dverse rections of dministered with ipilimum were evluted in 407 ptients with melnom enrolled in Tril 6 (n=313) or Phse 2 rndomized study (n=94), dministering with ipilimum, supplemented y immune-medited dverse rection reports in ongoing clinicl trils [see Wrnings nd Precutions (5.1, 5.8)]. (nivolum) The dt descried elow reflect exposure to s single gent in Trils 1, 4, nd 6, nd to with ipilimum in Tril 6, which re rndomized, ctive-controlled trils conducted in ptients with unresectle or metsttic melnom. Also descried elow re single-gent dt from Trils 2 nd 3, which re rndomized trils in ptients with metsttic NSCLC, Tril 5, which is rndomized tril in ptients with dvnced RCC, Trils 7 nd 8, which re open-lel, multiple-cohort trils in ptients with chl, nd Tril 9, rndomized tril in ptients with recurrent or metsttic SCCHN. Unresectle or Metsttic Melnom Previously Treted Metsttic Melnom The sfety of s single gent ws evluted in Tril 1, rndomized, open-lel tril in which 370 ptients with unresectle or metsttic melnom received 3 mg/kg every 2 weeks (n=268) or investigtor s choice of chemotherpy (n=102), either dcrzine 1000 mg/m 2 every 3 weeks or the comintion of cropltin AUC 6 every 3 weeks plus pclitxel 175 mg/m 2 every 3 weeks [see Clinicl Studies (14.1)]. The medin durtion of exposure ws 5.3 months (rnge: 1 dy to 13.8+ months) in -treted ptients nd ws 2 months (rnge: 1 dy to 9.6+ months) in chemotherpy-treted ptients. In this ongoing tril, 24% of ptients received for greter thn 6 months nd 3% of ptients received for greter thn 1 yer. In Tril 1, ptients hd documented disese progression following tretment with ipilimum nd, if BRAF V600 muttion positive, BRAF inhiitor. The tril excluded ptients with utoimmune disese, prior ipilimum-relted Grde 4 dverse rections (except for endocrinopthies) or Grde 3 ipilimum-relted dverse rections tht hd not resolved or were indequtely controlled within 12 weeks of the inititing event, ptients with condition requiring chronic systemic tretment with corticosteroids (>10 mg dily prednisone equivlent) or other immunosuppressive medictions, positive test for heptitis B or C, nd history of HIV. The tril popultion chrcteristics in the group nd the chemotherpy group were similr: 66% mle, medin ge 59.5 yers, 98% white, seline Estern Coopertive Oncology Group (ECOG) performnce sttus 0 (59%) or 1 (41%), 74% with M1c stge disese, 73% with cutneous melnom, 11% with mucosl melnom, 73% received two or more prior therpies for dvnced or metsttic disese, nd 18% hd rin metstsis. There were more ptients in the group with elevted LDH t seline (51% vs. 38%). ws discontinued for dverse rections in 9% of ptients. Twenty-six percent of ptients receiving hd drug dely for n dverse rection. Serious dverse rections occurred in 41% of ptients receiving. Grde 3 nd 4 dverse rections occurred in 42% of ptients receiving. The most frequent Grde 3 nd 4 dverse rections reported in 2% to less thn 5% of ptients receiving were dominl pin, hypontremi, incresed sprtte minotrnsferse, nd incresed lipse. Tle 2 summrizes the dverse rections tht occurred in t lest 10% of -treted ptients in Tril 1. The most common dverse rection (reported in t lest 20% of ptients) ws rsh. Tle 2: Adverse Rections Occurring in 10% of -Treted Ptients nd t Higher Incidence thn in the Chemotherpy Arm (Between Arm Difference of 5% [ ] or 2% [ ]) (Tril 1) (n=268) Chemotherpy (n=102) Adverse Rection Percentge (%) of Ptients Skin nd Sucutneous Tissue Disorders Rsh 21 0.4 7 0 Pruritus 19 0 3.9 0 Respirtory, Thorcic, nd Medistinl Disorders Cough 17 0 6 0 Infections Upper respirtory trct infection 11 0 2.0 0 Generl Disorders nd Administrtion Site Conditions Peripherl edem 10 0 5 0 Toxicity ws grded per NCI CTCAE v4. Rsh is composite term which includes mculoppulr rsh, erythemtous rsh, pruritic rsh, folliculr rsh, mculr rsh, ppulr rsh, pustulr rsh, vesiculr rsh, nd cneiform dermtitis. Upper respirtory trct infection is composite term which includes rhinitis, phryngitis, nd nsophryngitis. Other cliniclly importnt dverse rections in less thn 10% of ptients treted with in Tril 1 were: Crdic Disorders: ventriculr rrhythmi Eye Disorders: iridocyclitis 5