A REFERENCE GUIDE TO Reimbursement and Coding OPDIVO (nivolumab) In Appropriate Patients With Previously Treated Unresectable or Metastatic Melanoma INDICATION OPDIVO (nivolumab) is indicated for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. SELECT IMPORTANT SAFETY INFORMATION OPDIVO is associated with the following Warnings and Precautions including immune-mediated: pneumonitis, colitis, hepatitis, nephritis and renal dysfunction, hypothyroidism, hyperthyroidism, other adverse reactions; and embryofetal toxicity. Please see additional Important Safety Information on pages 21-22.
Bristol-Myers Squibb Is Committed to Helping Support Access This brochure is designed to assist oncology teams with access and reimbursement for appropriate patients through commercial insurers, Medicare, and Medicaid. The brochure includes helpful information to facilitate the reimbursement process. Healthcare benefits vary significantly; therefore, it is important that oncology offices verify each patient s insurance coverage prior to initiating therapy. TABLE OF 3 6 10 11 12 14 15 16 16 18 20 21 ICD-9 Codes ICD-10 Codes HCPCS and CPT Codes NDC Codes Coding and Billing Units OPDIVO Distribution Ordering OPDIVO Dosing and Administration Reimbursement Co-Pay Program Patient Affordability Important Safety Information Healthcare providers should code healthcare claims based upon the service that is rendered, the patient s medical record, the coding requirements of each health insurer, and best coding practices. The accurate completion of reimbursementor coverage-related documentation is the responsibility of the healthcare provider and patient. Bristol-Myers Squibb and its agents make no guarantee regarding reimbursement for any service or item. Please see Important Safety Information on pages 21-22 and accompanying Full Prescribing Information at the end of this document. 2
ICD-9-CM Codes for OPDIVO (nivolumab) Use the following ICD-9-CM diagnosis codes for the labeled indication for OPDIVO. Please code to the level of location specificity documented in the medical record. ICD-9-CM codes are used to identify a patient s diagnosis. The codes provided below by Bristol-Myers Squibb should be verified with the payer. Some health plan and Medicare insurers may specify which codes are covered under their policies. For coding assistance, call BMS Access Support at 1-800-861-0048 or visit www.bmsaccesssupport.com. ICD-9-CM Codes for OPDIVO 1 172 Malignant melanoma of the skin 172.0 Malignant melanoma of skin of lip 172.1 Malignant melanoma of skin of eyelid including canthus 172.2 Malignant melanoma of skin of ear and external auditory canal 172.3 Malignant melanoma of skin of other and unspecified parts of face 172.4 Malignant melanoma of skin of scalp and neck 172.5 Malignant melanoma of skin of trunk except scrotum 172.6 Malignant melanoma of skin of upper limb including shoulder 172.7 Malignant melanoma of skin of lower limb including hip 172.8 Malignant melanoma of other specified sites of skin 172.9 Malignant melanoma of skin, site unspecified 172 Note: If infusion is the only reason for the patient encounter, physicians and hospitals may report V58.12 as the primary diagnosis. Some payers may differ with this guideline. Check with payers before sequencing this way. 1 For reimbursement assistance, call the Support Center at 1-800-861-0048, 8 AM to 8 PM ET, Monday Friday, or visit www.bmsaccesssupport.com. 3
ICD-9-CM Codes for OPDIVO (nivolumab) (cont d) Per ICD-9-CM Official Guidelines for Coding and Reporting, an excludes note under a code indicates that the terms excluded from the code are to be coded elsewhere. 1 The note included with codes 172.0-172.9 states that this range 1 : Includes melanocarcinoma, melanoma (skin) NOS, and melanoma in situ of skin Excludes skin of genital organs For sites other than skin, code to the malignant neoplasm of the site. 1 Some sites where melanoma is commonly seen include the following: ICD-9-CM Codes for OPDIVO 1 * 154 Malignant neoplasm of the rectum, rectosigmoid junction, and anus 154.2 Malignant neoplasm of anal canal 154.3 Malignant neoplasm of anus, unspecified 184 Malignant neoplasm of other and unspecified female genital organs 184.0 Malignant neoplasm of vagina 184.1 Malignant neoplasm of labia majora 184.2 Malignant neoplasm of labia minora 184.3 Malignant neoplasm of the clitoris 184.4 Malignant neoplasm of vulva, unspecified 184.8 Malignant neoplasm of other specified sites of female genital organs 184.9 Malignant neoplasm of female genital organ, site unspecified 187 Malignant neoplasm of the penis and other male genital organs 187.1 Malignant neoplasm of prepuce 187.2 Malignant neoplasm of glans penis 187.4 Malignant neoplasm of penis, part unspecified 187.5 Malignant neoplasm of epididymis 187.6 Malignant neoplasm of spermatic cord 187.7 Malignant neoplasm of scrotum 187.8 Malignant neoplasm of other specified sites of male genital organs 187.9 Malignant neoplasm of male genital organ, site unspecified 154/184/187 *Melanoma may originate in the anal-genital areas of the body. 2 Please see Important Safety Information on pages 21-22 and accompanying Full Prescribing Information at the end of this document. 4
ICD-9-CM Codes for OPDIVO 1 190.0 Malignant neoplasm of eyeball, except conjunctiva, cornea, retina, and choroid 190.1 Malignant neoplasm of orbit 190.2 Malignant neoplasm of lacrimal gland 190.3 Malignant neoplasm of conjunctiva 190.4 Malignant neoplasm of cornea 190.5 Malignant neoplasm of retina 190.6 Malignant neoplasm of choroid 190.7 Malignant neoplasm of lacrimal duct 190.8 Malignant neoplasm of other specified sites of eye 190.9 Malignant neoplasm of eye, part unspecified 190.0 The accurate completion of reimbursement- or coverage-related documentation is the responsibility of the healthcare provider and patient. Bristol-Myers Squibb and its agents make no guarantee regarding reimbursement for any service or item. For reimbursement assistance, call the Support Center at 1-800-861-0048, 8 AM to 8 PM ET, Monday Friday, or visit www.bmsaccesssupport.com. 5
ICD-10-CM Codes for OPDIVO (nivolumab) ICD-10-CM codes are used to identify a patient s diagnosis. The codes provided below by Bristol-Myers Squibb should be verified with the payer. Some health plan and Medicare insurers may specify which codes are covered under their policies. Use the following ICD-10-CM diagnosis codes for the labeled indication for OPDIVO The ICD-10-CM diagnosis codes contain categories, subcategories, and codes. Characters for categories, subcategories, and codes may be letters or numerals All categories are 3 characters Subcategories are either 4 or 5 characters Codes may be 3, 4, 5, 6, or 7 characters Implementation of ICD-10 codes was scheduled to begin October 1, 2014, but has been postponed to at least October 2015 ICD-10-CM Codes for OPDIVO 3 C43 Malignant melanoma of skin C43.0 Malignant melanoma of lip C43.10 Malignant melanoma of unspecified eyelid, including canthus C43.11 Malignant melanoma of right eyelid, including canthus C43.12 Malignant melanoma of left eyelid, including canthus C43.20 Malignant melanoma of unspecified ear and external auricular canal C43.21 Malignant melanoma of right ear and external auricular canal C43.22 Malignant melanoma of left ear and external auricular canal C43.30 Malignant melanoma of unspecified part of face C43.31 Malignant melanoma of nose C43.39 Malignant melanoma of other parts of face C43.4 Malignant melanoma of scalp and neck C43.51 Malignant melanoma of anal skin C43.52 Malignant melanoma of skin of breast C43.59 Malignant melanoma of other part of trunk C43.60 Malignant melanoma of unspecified upper limb, including shoulder C43.61 Malignant melanoma of right upper limb, including shoulder C43.62 Malignant melanoma of left upper limb, including shoulder C43.70 Malignant melanoma of unspecified lower limb, including hip C43.71 Malignant melanoma of right lower limb, including hip C43.72 Malignant melanoma of left lower limb, including hip C43.8 Malignant melanoma of overlapping sites of skin C43.9 Malignant melanoma of skin, unspecified C43 Please see Important Safety Information on pages 21-22 and accompanying Full Prescribing Information at the end of this document. 6
Per ICD-10-CM official guidelines, an Excludes2 note under a code represents Not included here. An Excludes2 note indicates that the condition excluded is not part of the condition represented by the code, but a patient may have both conditions at the same time. When an Excludes2 note appears under a code, it is acceptable to use both the code and the excluded code together, when appropriate. 3 The note for C43 excludes 3 : Malignant melanoma of skin of genital organs C51; see http://www.codeitrightonline.com/code-set.php?set=icd10cm&i=21422"=c51 C52; see http://www.codeitrightonline.com/code.php?set=icd10cm&c=c52 C60; see http://www.codeitrightonline.com/code-set.php?set=icd10cm&i=21430"=c60 C63; see http://www.codeitrightonline.com/code-setphp?set=icd10cm&i=21435"=c63 Merkel cell carcinoma (C4A; see http://www.codeitrightonline.com/code-set. php?set=icd10cm&i=21365) For sites other than skin, code to the malignant neoplasm of the site. 3 Some sites where melanoma is commonly seen include the following: C21 Malignant neoplasm of anus and anal canal C21.0 Malignant neoplasm of anus, unspecified C21.1 Malignant neoplasm of anal canal C51 Malignant neoplasm of vulva C51.0 Malignant neoplasm of labium majus C51.1 Malignant neoplasm of labium minus C51.2 Malignant neoplasm of clitoris C51.9 Malignant neoplasm of vulva, unspecified C52 Malignant neoplasm of vagina ICD-10-CM Codes for OPDIVO 3 C21/C51/C52 The accurate completion of reimbursement- or coverage-related documentation is the responsibility of the healthcare provider and patient. Bristol-Myers Squibb and its agents make no guarantee regarding reimbursement for any service or item. For reimbursement assistance, call the Support Center at 1-800-861-0048, 8 AM to 8 PM ET, Monday Friday, or visit www.bmsaccesssupport.com. 7
ICD-10-CM Codes for OPDIVO (nivolumab) (cont d) C57 Malignant neoplasm of other and unspecified female genital organs C57.7 Malignant neoplasm of other specified female genital organs C57.8 Malignant neoplasm of overlapping sites of female genital organs C57.9 Malignant neoplasm of female genital organ, site unspecified C60 Malignant neoplasm of penis ICD-10-CM Codes for OPDIVO 3 C60.0 Malignant neoplasm of prepuce C60.1 Malignant neoplasm of glans penis C60.8 Malignant neoplasm of overlapping sites of penis C60.9 Malignant neoplasm of penis, unspecified C63 Malignant neoplasm of other and unspecified male genital organs C63.00 Malignant neoplasm of unspecified epididymis C63.01 Malignant neoplasm of right epididymis C63.02 Malignant neoplasm of left epididymis C63.10 Malignant neoplasm of unspecified spermatic cord C63.11 Malignant neoplasm of right spermatic cord C63.12 Malignant neoplasm of left spermatic cord C63.2 Malignant neoplasm of scrotum C63.7 Malignant neoplasm of other specified male genital organs C63.8 Malignant neoplasm of overlapping sites of male genital organs C63.9 Malignant neoplasm of male genital organ, unspecified C69 Malignant neoplasm of eye and adnexa C69.0 Malignant neoplasm of conjunctiva C69.00 Malignant neoplasm of unspecified conjunctiva C69.01 Malignant neoplasm of right conjunctiva C69.02 Malignant neoplasm of left conjunctiva C69.1 Malignant neoplasm of cornea C69.10 Malignant neoplasm of unspecified cornea C69.11 Malignant neoplasm of right cornea C69.12 Malignant neoplasm of left cornea C69.2 Malignant neoplasm of retina C69.20 Malignant neoplasm of unspecified retina C69.21 Malignant neoplasm of right retina C69.22 Malignant neoplasm of left retina C57/C60/C63/C69 Please see Important Safety Information on pages 21-22 and accompanying Full Prescribing Information at the end of this document. 8
ICD-10-CM Codes for OPDIVO 3 C69 Malignant neoplasm of eye and adnexa (cont d) C69.3 Malignant neoplasm of choroid C69.30 Malignant neoplasm of unspecified choroid C69.31 Malignant neoplasm of right choroid C69.32 Malignant neoplasm of left choroid C69.4 Malignant neoplasm of ciliary body C69.40 Malignant neoplasm of unspecified ciliary body C69.41 Malignant neoplasm of right ciliary body C69.42 Malignant neoplasm of left ciliary body C69.5 Malignant neoplasm of lacrimal gland and duct C69.50 Malignant neoplasm of unspecified lacrimal gland and duct C69.51 Malignant neoplasm of right lacrimal gland and duct C69.52 Malignant neoplasm of left lacrimal gland and duct C69.6 Malignant neoplasm of orbit C69.60 Malignant neoplasm of unspecified orbit C69.61 Malignant neoplasm of right orbit C69.62 Malignant neoplasm of left orbit C69.8 Malignant neoplasm of overlapping sites of eye and adnexa C69.80 Malignant neoplasm of overlapping sites of unspecified eye and adnexa C69.81 Malignant neoplasm of overlapping sites of right eye and adnexa C69.82 Malignant neoplasm of overlapping sites of left eye and adnexa C69.9 Malignant neoplasm of unspecified site of eye C69.90 Malignant neoplasm of unspecified site of unspecified eye C69.91 Malignant neoplasm of unspecified site of right eye C69.92 Malignant neoplasm of unspecified site of left eye C69 The accurate completion of reimbursement- or coverage-related documentation is the responsibility of the healthcare provider and patient. Bristol-Myers Squibb and its agents make no guarantee regarding reimbursement for any service or item. For reimbursement assistance, call the Support Center at 1-800-861-0048, 8 AM to 8 PM ET, Monday Friday, or visit www.bmsaccesssupport.com. 9
HCPCS and CPT Codes for OPDIVO (nivolumab) HCPCS codes for physician offices Following FDA approval of new physician-administered therapies, physician providers may need to use temporary codes until unique drug codes are assigned J9999 is the most commonly used not otherwise classified (NOC) code for anticancer therapies 4 J3590 may also be used, and J3490 may be used in rare cases 4,5 When submitting an NOC claim using HCPCS code J9999 (J3490 or J3590), include specific information in Box 19 5,6 : The drug name (chemical name) Total dosage and strength Method of administration Prescription number (11-digit NDC) Basis of measurement (mg, units, etc) Payer requirements for coding of newly approved therapies may vary. Please contact the payer or BMS Access Support for additional coding information HCPCS code for Hospital Outpatient setting is C9453 7 (Injection, nivolumab, 1 mg) OPDIVO was assigned a pass-through status indicator under the Hospital Outpatient Prospective Payment System (OPPS) effective July 1, 2015 The new HCPCS code, C9453, nivolumab, 1 mg, replaces the miscellaneous HCPCS code C9399 that Hospital Outpatient Departments have used to bill for OPDIVO to date 7 C9453 and miscellaneous codes J9999 (not otherwise classified, antineoplastic drugs), J3590 (unclassified biologics), and J3490 (unclassified drugs) may be used until a permanent J-code has been assigned 4,5,8 CPT code The Current Procedural Terminology (CPT)* code that may be appropriate when administering OPDIVO appears in the table below Recommended CPT Code for OPDIVO 9 CPT Code Description APC 96413 Chemotherapy administration, intravenous infusion technique, 16 to 90 minutes in length; single or initial substance/drug 0440 Please contact the payer or BMS Access Support for additional coding information regarding OPDIVO. * CPT codes and descriptions only are 2014 by American Medical Association (AMA). All rights reserved. The AMA assumes no liability for data contained or not contained herein. CPT is a registered trademark of the American Medical Association. Please see Important Safety Information on pages 21-22 and accompanying Full Prescribing Information at the end of this document. 10
NDC Codes for OPDIVO (nivolumab) The National Drug Codes (NDCs) for OPDIVO, listed in the table below, are often necessary in addition to the appropriate J- or C-code when filing a claim for reimbursement. NDC Codes for OPDIVO 10 0003-3772-11 00003-3772-11 0003-3774-12 00003-3774-12 One 40 mg/4 ml (10 mg/ml) single-use vial One 100 mg/10 ml (10 mg/ml) single-use vial 5010 electronic transaction coding for OPDIVO For electronic transactions, including 837P and 837I, the NDC is to be preceded with the qualifier N4 and followed immediately by the 11-digit NDC code for payers who require it 6 This is typically followed by the NDC unit of measure: UN (units), F2 (international units), GR (gram), or ML (milliliter) of the amount administered 6 5010 Transaction for OPDIVO How Supplied NDC NDC Qualifier NDC Basis of Measurement Sample NDC 5010 Format 40-mg/4-mL single-use vial (10 mg/ml) 100-mg/10-mL single-use vial (10 mg/ml) 00003-3772-11 N4 ML N400003377211ML4 00003-3774-12 N4 ML N400003377412ML10 The example given in the far right column demonstrates NDC quantity reporting for 1 vial of OPDIVO. The actual amount of drug used can vary based on factors such as indication or patient weight. Currently, reporting NCD quantity varies from payer to payer, so the provider should consult each specific payer to determine the required format. The accurate completion of reimbursement- or coverage-related documentation is the responsibility of the healthcare provider and patient. Bristol-Myers Squibb and its agents make no guarantee regarding reimbursement for any service or item. For reimbursement assistance, call the Support Center at 1-800-861-0048, 8 AM to 8 PM ET, Monday Friday, or visit www.bmsaccesssupport.com. 11
Coding and Billing Units for OPDIVO (nivolumab) Payers may require the number of units to be 1 regardless of amount administered with an unspecified HCPCS code, but this can vary from payer to payer. Please contact the payer or BMS Access Support for additional information on coding and billing units CMS-1500 Form Professional claims Item 19: When an NOC code is used in Item 24D, many payers require detailed information about the drug in Box 19. 6 Typically, payers require the drug name, total dosage and strength, method of administration, 11-digit NDC, and basis of measurement Item 21: Enter the site-specific ICD-9-CM or ICD-10-CM codes 6 Item 24A: NDC information is required in the shaded area above the line on which a drug is reported in 24D. 6 Enter N400003377211ML4 for the 40 mg/4 ml vial or N400003377412ML10 for the 100 mg/10 ml vial Item 24D: Enter J9999 under column heading CPT/HCPCS 6 Item 24E: Enter the diagnosis code reference letter or number from Box 21 that represents the services or procedures performed to the primary diagnosis as noted in 24D 6 Item 24G: Billing units are reported here 6 Please see Important Safety Information on pages 21-22 and accompanying Full Prescribing Information at the end of this document. 12
1 2 3a PAT. 4 TYPE CNTL # OF BILL b. MED. REC. # 6 STATEMENT COVERS PERIOD 7 5 FED. TAX NO. FROM THROUGH 8 PATIENT NAME a 9 PATIENT ADDRESS a b b c d e 10 BIRTHDATE 11 SEX ADMISSION CONDITION CODES 12 DATE 13 HR 14 TYPE 15 SRC 16 DHR 29 ACDT 30 17 STAT 18 19 20 21 22 23 24 25 26 27 28 STATE 31 OCCURRENCE 32 OCCURRENCE 33 OCCURRENCE 34 OCCURRENCE 35 OCCURRENCE SPAN 36 OCCURRENCE SPAN 37 CODE DATE CODE DATE CODE DATE CODE DATE CODE FROM THROUGH CODE FROM THROUGH a b 38 39 VALUE CODES 40 VALUE CODES 41 VALUE CODES CODE AMOUNT CODE AMOUNT CODE AMOUNT a b c d 42 REV. CD. 43 DESCRIPTION 44 HCPCS / RATE / HIPPS CODE 45 SERV. DATE 46 SERV. UNITS 47 TOTAL CHARGES 48 NON-COVERED CHARGES 49 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 PAGE OF CREATION DATE TOTALS 52 REL. 53 ASG. 50 PAYER NAME 51 HEALTH PLAN ID 54 PRIOR PAYMENTS 55 EST. AMOUNT DUE 56 NPI INFO BEN. A 57 B OTHER C PRV ID 58 INSURED S NAME 59 P.REL 60 INSURED S UNIQUE ID 61 GROUP NAME 62 INSURANCE GROUP NO. A B C A B 63 TREATMENT AUTHORIZATION CODES UB-04 Form 64 DOCUMENT CONTROL NUMBER 65 EMPLOYER NAME C 66 68 DX 67 A B C D E F G H I J K L M N O P Q 69 ADMIT 70 PATIENT 71 PPS 72 73 DX REASON DX a b c CODE ECI a b c 74 PRINCIPAL PROCEDURE a. OTHER PROCEDURE b. OTHER PROCEDURE 75 CODE DATE CODE DATE CODE DATE 76 ATTENDING NPI QUAL LAST FIRST c. OTHER PROCEDURE d. OTHER PROCEDURE e. OTHER PROCEDURE CODE DATE CODE DATE 77 OPERATING NPI QUAL CODE DATE LAST FIRST 81CC 80 REMARKS a 78 OTHER NPI QUAL b LAST FIRST c 79 OTHER NPI QUAL d LAST FIRST UB-04 CMS-1450 APPROVED OMB NO. 0938-0997 THE CERTIFICATIONS ON THE REVERSE APPLY TO THIS BILL AND ARE MADE A PART HEREOF. The accurate completion of reimbursement- or coverage-related documentation is the responsibility of the healthcare provider and patient. Bristol-Myers Squibb and its agents make no guarantee regarding reimbursement for any service or item. a b 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 A B C A B C A B C Institutional claims Form Locator (FL) 42: Enter a 4-digit revenue code that best describes the service provided, in accordance with hospital billing policy. For chemotherapy administration, revenue codes 0260 (IV therapy) or 0335 (radiology therapeutic: chemotherapy-iv) could be used. CMS recommends using revenue code 0636 (drugs requiring detailed coding) 11 FL 43: Enter the modifier N4 followed by the 11-digit NDC in positions 01-13. Report the quantity modifier (ML) followed by the quantity (40 mg/4 ml or 100 mg/10 ml) N400003377211ML4 for the 40 mg/4 ml vial or N400003377412ML10 for the 100 mg/10 ml vial) 11 FL 44: Enter HCPCS code C9453 and CPT code 96413 7,9 FL 46: Billing units are called service units and are placed here 11 FLs 67A-67Q: Enter the site-specific ICD-9-CM or ICD-10-CM diagnosis codes for the malignancy being treated 11 FL 80: When an NOC code is used in FL 44, most payers require detailed information about the drug in FL 80. 6,11 Typically, payers require the drug name, total dosage and strength, method of administration, 11-digit NDC, and basis of measurement For reimbursement assistance, call the Support Center at 1-800-861-0048, 8 AM to 8 PM ET, Monday Friday, or visit www.bmsaccesssupport.com. 13
How OPDIVO (nivolumab) Is Distributed Physician Offices Specialty Distributor Phone Orders Website Cardinal Health Specialty Pharmaceutical Distribution CuraScript SD Specialty Distribution 1-866-677-4844 Monday-Friday, 7 AM-6 PM CT (24-hour emergency on call) 1-866-433-3589 Monday-Friday 8:30 AM-7 PM EST https://specialtyonline.cardinalhealth.com https://www.curascriptsd.com McKesson Specialty Health 1-800-482-6700 Monday-Friday, 7 AM-7 PM CT Oncology Supply 1-800-633-7555 Monday-Thursday, 8 AM-7:30 PM CT Friday, 8 AM-7 PM CT https://connect.mckesson.com https://www.oncologysupply.com For offices that prefer to use the services of a specialty pharmacy, specialty pharmacies can obtain OPDIVO from the distributors listed above. Hospitals and Infusion Centers Specialty Distributor Phone Orders Fax Orders and Website ASD Healthcare 1-800-746-6273 Monday-Thursday, 7:30 AM-6:30 PM CT Friday, 7 AM-6 PM CT (24-hour emergency on call) 1-800-547-9413 https://www.asdhealthcare.com Cardinal Health Specialty Pharmaceutical Distribution 1-866-677-4844 Monday-Friday, 7 AM-6 PM CT (24-hour emergency on call) 1-888-345-4916 https://specialtyonline.cardinalhealth.com DMS Pharmaceutical Group, Inc. 1-877-788-1100 Monday-Friday, 7:30 AM-6 PM CT Smith Medical Partners 1-800-292-9653 Monday-Thursday, 8 AM-6 PM CT Friday, 8 AM-4:30 PM CT McKesson Plasma and Biologics 1-877-625-2566 Monday-Friday, 8 AM-6:30 PM CT 1-847-518-1105 www.dmspharma.com 1-630-227-9220 www.smpspecialty.com. 1-888-752-7626 https://connect.mckesson.com Above information is accurate as of 05/2015. The OPDIVO distribution program includes extended payment terms to BMS authorized OPDIVO distributors. Healthcare providers and institutions should contact their OPDIVO distributor to understand specific payment terms that may be available to them from their distributor. Please see Important Safety Information on pages 21-22 and accompanying Full Prescribing Information at the end of this document. 14
Determining Your Order for OPDIVO (nivolumab) Dosing for OPDIVO is weight-based; therefore, the dosage of OPDIVO will vary by patient. 10 Patient s weight in kg x 3 mg = Total dosage in mg needed For example: A person weighing 64 kg (140 lbs) would require a total dosage of 192 mg of OPDIVO A person weighing 109 kg (240 lbs) would require a total dosage of 327 mg of OPDIVO How to Store OPDIVO Store OPDIVO at 2 C-8 C (36 F-46 F) Protect vials from light Do not freeze or shake Unopened vial: 2 years The OPDIVO infusion must be completed with 24 hours of preparation. If not used immediately, the infusion solution may be stored under refrigeration conditions: 2 C-8 C (36 F-46 F) and protected from light for 24 hours (a maximum of 4 hours of the total 24 hours can be at room temperature 20 C-25 C [68 F-77 F] and room light) For reimbursement assistance, call the Support Center at 1-800-861-0048, 8 AM to 8 PM ET, Monday Friday, or visit www.bmsaccesssupport.com. 15
Dosing and Administration for OPDIVO (nivolumab) The recommended dose of OPDIVO (nivolumab) is 3 mg/kg administered intravenously (IV) over 60 minutes every 2 weeks. 10 Continue treatment until disease progression or unacceptable toxicity Medicare Drug Reimbursement for OPDIVO What is the Medicare reimbursement allowable for OPDIVO? Physicians The payment allowance limits for drugs and biologicals that are not included in the Average Sales Price (ASP) Medicare Part B Drug Pricing File or Not Otherwise Classified (NOC) Pricing File are based on the published Wholesale Acquisition Cost (WAC) or invoice pricing, except under the Outpatient Prospective Payment System (OPPS), where the payment allowance limit is 95% of the published Average Wholesale Price (AWP) 4 The payment allowance limit in the Medicare Part B Pricing File currently 106% of the ASP does not apply for OPDIVO until the medication is published in the NOC list 4 Hospital outpatient clinics Under OPPS, the payment allowance limit is 95% of the published AWP until an ASP is published. Then, the payment allowance limit becomes ASP+6% 4 Hospital inpatient settings Reimbursement in the inpatient setting is bundled into the Medicare Diagnosis-Related Group (MS-DRG) payment that the hospital receives for all items and services provided during an inpatient stay Please see Important Safety Information on pages 21-22 and accompanying Full Prescribing Information at the end of this document. 16
Commercial Insurance Reimbursement for OPDIVO (nivolumab) Physicians Drug reimbursement, like service reimbursement, is usually based on a fee schedule The fee schedules are based on the ASP or AWP, as published by a credible source (eg, Red Book), or an average costing methodology as determined by the payer, such as usual, customary, and reasonable (UC&R). In rare cases, drug allowances are based on charges Hospital outpatient clinics Drug reimbursement may be based on the same methodologies as outlined for physicians Alternatively, hospitals may negotiate rates that are a ratio of costs to charges, a percentage of charges, or rates are capitated, meaning they are paid at a per-member-per-month basis without regard to individual charges Hospitals may negotiate to carve new drugs out of capitated rates Hospital inpatient settings Inpatient rates are prospective, meaning they are predetermined per discharge There are private payers and payers such as CHAMPUS that pay on a version of the DRGs There are also payers that pay on a negotiated and fixed rate per day called a per diem. There are capitated rates for inpatients as well New drugs may be carved out of per diems or capitated rates, if the hospital negotiates to do so For reimbursement assistance, call the Support Center at 1-800-861-0048, 8 AM to 8 PM ET, Monday Friday, or visit www.bmsaccesssupport.com. 17
How Does the Co-Pay Program Work? 1 2 Your office collects the patient s name, address, insurance carrier, and member identification number. Your office completes the application and certification documents and enrolls your patient through BMS Access Support in one of the following ways: Call the Support Center at 1-800-861-0048 or fax 1-888-776-2370, 8 AM to 8 PM ET, Monday through Friday Log on to www.mybmsoncologycases.com 3 BMS Access Support determines patient eligibility, including verifying commercial insurance coverage to establish the appropriate benefit amount. BMS Access Support then notifies the provider and patient of enrollment and the appropriate next steps. Visit www.bmsaccesssupport.com to download an application form. Fax the completed form to 1-888-776-2370. Understanding the BMS Oncology Co-Pay Program Access for eligible commercially insured patients Bristol-Myers Squibb supports access to certain BMS oncology products. That s why we ve created the BMS Oncology Co-Pay Program. It s designed to assist eligible patients who have been prescribed certain BMS oncology products with out-of-pocket deductibles, co-pay, or coinsurance requirements. Financial Assistance to Patients ENROLLED PATIENTS pay the first $25 BMS WILL COVER the remaining amount up to of their co-pay per infusion $25,000 per product, per year Restrictions may apply. Final determination of Program eligibility is based upon review of completed application. Please see page 19 for full Terms and Conditions. Please note: The Program will cover the out-of-pocket expenses of the BMS product only. It does not cover the costs of any other healthcare provider charges or any other treatment costs. Patients may be responsible for non drug-related out-of-pocket costs, depending on their specific healthcare benefits. Please see Important Safety Information on pages 21-22 and accompanying Full Prescribing Information at the end of this document. 18
Co-Pay Program Terms and Conditions This Program covers select Bristol-Myers Squibb oncology products. Please contact Access Support for a complete list of covered products Enrolled patients pay the first $25 of their co-pay per infusion. BMS will cover the remaining amount up to $25,000 per year This Program will cover the out-of-pocket costs of the BMS product only. It does not cover the cost of any other healthcare provider charges or any other treatment costs The Program may apply to retroactive out-of-pocket expenses that occurred within 120 days prior to the date of enrollment, subject to the annual Program maximum of $25,000 This offer is not valid for patients whose infusions are covered by a federal or state government-related healthcare program which pays in whole or in part for prescription drugs such as Medicare, Medicaid, TRICARE, or VA programs, or where the entire cost of the infusion or monthly prescription is covered by commercial insurance. Patients may not submit a claim for reimbursement under any of these programs. Patients who move from commercial to Federal Healthcare Programs will no longer be eligible for the Program Patients who accept this offer confirm that the offer is consistent with his/her insurance and that he/she will report the value of the co-pay assistance as required by his/her insurance provider. Patients must not seek reimbursement from any healthcare reimbursement accounts or flexible spending accounts Patients must enroll by December 31, 2015 Explanation of Benefits (EOB) must be submitted within 180 days post-infusion/prescription to receive co-pay assistance Proof required for payment must be a valid Explanation of Benefits (EOB) with product code-specific information. An EOB must be submitted regardless of assigned J-code This offer is valid only in the United States and Puerto Rico This offer is not an insurance benefit This offer is void where prohibited by law, taxed, or restricted This offer may not be combined with any other offer, rebate, coupon, or free trial This offer is non-transferrable Bristol-Myers Squibb reserves the right to rescind, revoke, amend, or terminate this offer or the Program in its entirety at any time Absent a change in Massachusetts law, effective July 1, 2015, Massachusetts residents will no longer be eligible to participate in the program For reimbursement assistance, call the Support Center at 1-800-861-0048, 8 AM to 8 PM ET, Monday Friday, or visit www.bmsaccesssupport.com. 19
Bristol-Myers Squibb Helping Patients Afford Treatments For patients with commercial (private) insurance BMS product co-pay programs may be available For patients with insurance through Federal Healthcare Programs They are not eligible for co-pay assistance programs sponsored by Bristol-Myers Squibb However, BMS Access Support can help refer patients to an independent foundation that offers the best support for their individual needs For patients without prescription drug coverage Access Support can refer them to independent charitable foundations that may be able to provide financial support, including the Bristol-Myers Squibb Patient Assistance Foundation (BMSPAF), a charitable organization that provides medicine, free of charge, to eligible, uninsured patients who have an established financial hardship. The BMSPAF accepts the Access Support application. For more information, visit www.bmspaf.org Patients may be eligible for BMSPAF if they: Do not have insurance coverage, or have been denied coverage for a requested medicine Are enrolled in a Medicare Part D plan that covers the medication and have spent at least 3% of their yearly household income on out-of-pocket costs for prescription medications this year Are being treated on an outpatient basis Live in the United States, Puerto Rico, or the US Virgin Islands Meet the income limits for the requested medicine Other eligibility criteria apply. BMS Access Support cannot guarantee acceptance by BMSPAF It is important to note that charitable foundations are independent from Bristol-Myers Squibb Company. Each foundation, including the BMSPAF, has its own eligibility criteria and evaluation process. Bristol-Myers Squibb cannot guarantee that a patient will receive assistance Please see Important Safety Information on pages 21-22 and accompanying Full Prescribing Information at the end of this document. 20
Important Safety Information for OPDIVO (nivolumab) Immune-Mediated Pneumonitis Severe pneumonitis or interstitial lung disease, including fatal cases, occurred with OPDIVO treatment. Across the clinical trial experience in 691 patients with solid tumors, fatal immunemediated pneumonitis occurred in 0.7% (5/691) of patients receiving OPDIVO; no cases occurred in Trial 1. In Trial 1, pneumonitis, including interstitial lung disease, occurred in 3.4% (9/268) of patients receiving OPDIVO and none of the 102 patients receiving chemotherapy. Immunemediated pneumonitis occurred in 2.2% (6/268) of patients receiving OPDIVO; one with Grade 3 and five with Grade 2. Monitor patients for signs and symptoms of pneumonitis. Administer corticosteroids for Grade 2 or greater pneumonitis. Permanently discontinue OPDIVO for Grade 3 or 4 and withhold OPDIVO until resolution for Grade 2. Immune-Mediated Colitis In Trial 1, diarrhea or colitis occurred in 21% (57/268) of patients receiving OPDIVO and 18% (18/102) of patients receiving chemotherapy. Immune-mediated colitis occurred in 2.2% (6/268) of patients receiving OPDIVO; five with Grade 3 and one with Grade 2. Monitor patients for immune-mediated colitis. Administer corticosteroids for Grade 2 (of more than 5 days duration), 3, or 4 colitis. Withhold OPDIVO for Grade 2 or 3. Permanently discontinue OPDIVO for Grade 4 colitis or recurrent colitis upon restarting OPDIVO. Immune-Mediated Hepatitis In Trial 1, there was an increased incidence of liver test abnormalities in the OPDIVO-treated group as compared to the chemotherapy-treated group, with increases in AST (28% vs 12%), alkaline phosphatase (22% vs 13%), ALT (16% vs 5%), and total bilirubin (9% vs 0). Immunemediated hepatitis occurred in 1.1% (3/268) of patients receiving OPDIVO; two with Grade 3 and one with Grade 2. Monitor patients for abnormal liver tests prior to and periodically during treatment. Administer corticosteroids for Grade 2 or greater transaminase elevations. Withhold OPDIVO for Grade 2 and permanently discontinue OPDIVO for Grade 3 or 4 immune-mediated hepatitis. Immune-Mediated Nephritis and Renal Dysfunction In Trial 1, there was an increased incidence of elevated creatinine in the OPDIVO-treated group as compared to the chemotherapy-treated group (13% vs 9%). Grade 2 or 3 immune-mediated nephritis or renal dysfunction occurred in 0.7% (2/268) of patients. Monitor patients for elevated serum creatinine prior to and periodically during treatment. For Grade 2 or 3 serum creatinine elevation, withhold OPDIVO and administer corticosteroids; if worsening or no improvement occurs, permanently discontinue OPDIVO. Administer corticosteroids for Grade 4 serum creatinine elevation and permanently discontinue OPDIVO. Immune-Mediated Hypothyroidism and Hyperthyroidism In Trial 1, Grade 1 or 2 hypothyroidism occurred in 8% (21/268) of patients receiving OPDIVO and none of the 102 patients receiving chemotherapy. Grade 1 or 2 hyperthyroidism occurred in 3% (8/268) of patients receiving OPDIVO and 1% (1/102) of patients receiving chemotherapy. Monitor thyroid function prior to and periodically during treatment. Administer hormone replacement therapy for hypothyroidism. Initiate medical management for control of hyperthyroidism. continued on next page For reimbursement assistance, call the Support Center at 1-800-861-0048, 8 AM to 8 PM ET, Monday Friday, or visit www.bmsaccesssupport.com. 21
Important Safety Information (cont d) Other Immune-Mediated Adverse Reactions The following clinically significant, immune-mediated adverse reactions occurred in less than 2% of OPDIVO-treated patients: adrenal insufficiency, uveitis, pancreatitis, facial and abducens nerve paresis, demyelination, autoimmune neuropathy, motor dysfunction, and vasculitis. Across clinical trials of OPDIVO administered at doses 3 mg/kg and 10 mg/kg, additional clinically significant, immune-mediated adverse reactions were identified: hypophysitis, diabetic ketoacidosis, hypopituitarism, Guillain-Barré syndrome, and myasthenic syndrome. Based on the severity of adverse reaction, withhold OPDIVO, administer high-dose corticosteroids, and, if appropriate, initiate hormone-replacement therapy. Embryofetal Toxicity Based on its mechanism of action, OPDIVO can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with OPDIVO and for at least 5 months after the last dose of OPDIVO. Lactation It is not known whether OPDIVO is present in human milk. Because many drugs, including antibodies, are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from OPDIVO, advise women to discontinue breastfeeding during treatment. Serious Adverse Reactions Serious adverse reactions occurred in 41% of patients receiving OPDIVO. Grade 3 and 4 adverse reactions occurred in 42% of patients receiving OPDIVO. The most frequent Grade 3 and 4 adverse drug reactions reported in 2% to <5% of patients receiving OPDIVO were abdominal pain, hyponatremia, increased aspartate aminotransferase, and increased lipase. Common Adverse Reactions The most common adverse reaction ( 20%) reported with OPDIVO was rash (21%). Please see accompanying Full Prescribing Information at the end of this document. 22
Please see accompanying Full Prescribing Information at the end of this document. References 1. American Medical Association. 2015 ICD-9-CM Professional Edition for Physicians, Vol 1&2. Chicago, IL: American Medical Association; 2014. 2. Rogers RS III, Gibson LE. Mucosal, genital, and unusual clinical variants of melanoma. Mayo Clin Proc. 1997;72(4):362-366. 3. American Medical Association. 2015 ICD-10-CM: The Complete Official Draft Codebook. Chicago, IL: American Medical Association; 2014. 4. Centers for Medicare & Medicaid Services. Medicare Claims Processing Manual. Chapter 17 Drugs and Biologicals. Revision 3055, August 29, 2014. www.cms.gov/regulations-and-guidance/guidance/manuals/downloads/clm104c17.pdf. Accessed May 28, 2015. 5. Medi-Cal. Injections: an overview. https://files.medi-cal.ca.gov/pubsdoco/publications/masters-mtp/part2/injectanover_ m00o03o04o11p00.doc. Accessed May 28, 2015. 6. Centers for Medicare & Medicaid Services. Medicare Claims Processing Manual. Chapter 26 Completing and Processing Form CMS-1500 Data Set. Revision 3103, November 3, 2014. www.cms.gov/regulations-and-guidance/guidance/manuals/ downloads/clm104c26.pdf. Accessed May 28, 2015. 7. Centers for Medicare & Medicaid Services. HCPCS C-codes Effective July 1, 2015. www.cms.gov/medicare/coding/ HCPCSReleaseCodeSets/Downloads/C-Codes-July-2015.zip. Accessed May 28, 2015. 8. 2015 Alpha-Numeric HCPCS. Centers for Medicare & Medicaid Services. www.cms.gov/medicare/coding/ HCPCSReleaseCodeSets/Downloads/2015-Annual-Alpha-Numeric-HCPCS-File.zip. Accessed May 28, 2015. 9. American Medical Association. Current Procedural Terminology 2015. Professional ed. Chicago, IL: American Medical Association; 2014. 10. OPDIVO [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2015. 11. Centers for Medicare & Medicaid Services. Medicare Claims Processing Manual. Chapter 25 Completing and Processing the Form CMS-1450 Data Set. Revision 2922, April 3, 2014. www.cms.gov/regulations-and-guidance/guidance/manuals/ downloads/clm104c25.pdf. Accessed May 28, 2015. For reimbursement assistance, call the Support Center at 1-800-861-0048, 8 AM to 8 PM ET, Monday Friday, or visit www.bmsaccesssupport.com. 23
Your Source for Reimbursement Information and Support 1 Contact your Area Reimbursement Manager for assistance and to schedule an office visit Call the Support Center at 1-800-861-0048 8 AM to 8 PM ET, Monday Friday Visit www.bmsaccesssupport.com for resources to help your patients with access to Bristol-Myers Squibb oncology products Bristol-Myers Squibb Oncology is committed to helping appropriate patients get access to our medications by providing reimbursement support services for healthcare offices. OPDIVO, Access Support, and their related logos are trademarks of Bristol-Myers Squibb Company. 2015 Bristol-Myers Squibb Company All rights reserved 1506US15BR00778-04-01 06/15
HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use OPDIVO safely and effectively. See full prescribing information for OPDIVO. OPDIVO (nivolumab) injection, for intravenous use Initial U.S. Approval: 2014 -----------------------------RECENT MAJOR CHANGES ---------------------------- Indications and Usage (1.2) 3/2015 Warnings and Precautions (5.1, 5.2, 5.3, 5.4, 5.5, 5.6) 3/2015 ----------------------------- INDICATIONS AND USAGE ----------------------------- OPDIVO is a programmed death receptor-1 (PD-1) blocking antibody indicated for the treatment of patients with: unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. (1.1) This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. (1.1, 14.1) metastatic squamous non-small cell lung cancer with progression on or after platinum-based chemotherapy. (1.2) -------------------------- DOSAGE AND ADMINISTRATION -------------------------- Administer 3 mg/kg as an intravenous infusion over 60 minutes every 2 weeks. (2.1) -------------------------DOSAGE FORMS AND STRENGTHS ------------------------ Injection: 40 mg/4 ml and 100 mg/10 ml solution in a single-use vial. (3) ------------------------------- CONTRAINDICATIONS ------------------------------- None. (4) -------------------------- WARNINGS AND PRECAUTIONS -------------------------- Immune-mediated adverse reactions: Administer corticosteroids based on the severity of the reaction. (5.1, 5.2, 5.3, 5.4, 5.6) Immune-mediated pneumonitis: Withhold for moderate and permanently discontinue for severe or life-threatening pneumonitis. (5.1) Immune-mediated colitis: Withhold for moderate or severe and permanently discontinue for life-threatening colitis. (5.2) Immune-mediated hepatitis: Monitor for changes in liver function. Withhold for moderate and permanently discontinue for severe or life-threatening transaminase or total bilirubin elevation. (5.3) Immune-mediated nephritis and renal dysfunction: Monitor for changes in renal function. Withhold for moderate or severe and permanently discontinue for life-threatening serum creatinine elevation. (5.4) Immune-mediated hypothyroidism and hyperthyroidism: Monitor for changes in thyroid function. Initiate thyroid hormone replacement as needed. (5.5) Embryofetal toxicity: Can cause fetal harm. Advise of potential risk to a fetus and use of effective contraception. (5.7, 8.1, 8.3) ------------------------------- ADVERSE REACTIONS ------------------------------- Most common adverse reaction ( 20%) in patients with melanoma was rash. (6.1) Most common adverse reactions ( 20%) in patients with advanced squamous non-small cell lung cancer were fatigue, dyspnea, musculoskeletal pain, decreased appetite, cough, nausea, and constipation. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers Squibb at 1-800-721-5072 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. -------------------------- USE IN SPECIFIC POPULATIONS -------------------------- Lactation: Discontinue breastfeeding. (8.2) See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. Revised: 3/2015 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 1.1 Unresectable or Metastatic Melanoma 1.2 Metastatic Squamous Non-Small Cell Lung Cancer 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosage 2.2 Dose Modifications 2.3 Preparation and Administration 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Immune-Mediated Pneumonitis 5.2 Immune-Mediated Colitis 5.3 Immune-Mediated Hepatitis 5.4 Immune-Mediated Nephritis and Renal Dysfunction 5.5 Immune-Mediated Hypothyroidism and Hyperthyroidism 5.6 Other Immune-Mediated Adverse Reactions 5.7 Embryofetal Toxicity 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Immunogenicity 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Renal Impairment 8.7 Hepatic Impairment 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 13.2 Animal Toxicology and/or Pharmacology 14 CLINICAL STUDIES 14.1 Unresectable or Metastatic Melanoma 14.2 Metastatic Squamous Non-Small Cell Lung Cancer 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION * Sections or subsections omitted from the full prescribing information are not listed.
FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE 1.1 Unresectable or Metastatic Melanoma OPDIVO (nivolumab) is indicated for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor [see Clinical Studies (14.1)]. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. 1.2 Metastatic Squamous Non-Small Cell Lung Cancer OPDIVO (nivolumab) is indicated for the treatment of patients with metastatic squamous non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy [see Clinical Studies (14.2)]. 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosage The recommended dose of OPDIVO is 3 mg/kg administered as an intravenous infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity. 2.2 Dose Modifications There are no recommended dose modifications for hypothyroidism or hyperthyroidism. Withhold OPDIVO for any of the following: Grade 2 pneumonitis [see Warnings and Precautions (5.1)] Grade 2 or 3 colitis [see Warnings and Precautions (5.2)] Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) greater than 3 and up to 5 times upper limit of normal (ULN) or total bilirubin greater than 1.5 and up to 3 times ULN [see Warnings and Precautions (5.3)] Creatinine greater than 1.5 and up to 6 times ULN or greater than 1.5 times baseline [see Warnings and Precautions (5.4)] Any other severe or Grade 3 treatment-related adverse reactions [see Warnings and Precautions (5.6)] Resume OPDIVO in patients whose adverse reactions recover to Grade 0 to 1. Permanently discontinue OPDIVO for any of the following: Any life-threatening or Grade 4 adverse reaction Grade 3 or 4 pneumonitis [see Warnings and Precautions (5.1)] Grade 4 colitis [see Warnings and Precautions (5.2)] AST or ALT greater than 5 times ULN or total bilirubin greater than 3 times ULN [see Warnings and Precautions (5.3)] Creatinine greater than 6 times ULN [see Warnings and Precautions (5.4)] Any severe or Grade 3 treatment-related adverse reaction that recurs Inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks Persistent Grade 2 or 3 treatment-related adverse reactions that do not recover to Grade 1 or resolve within 12 weeks after last dose of OPDIVO 2.3 Preparation and Administration Visually inspect drug product solution for particulate matter and discoloration prior to administration. OPDIVO is a clear to opalescent, colorless to pale-yellow solution. Discard the vial if the solution is cloudy, is discolored, or contains extraneous particulate matter other than a few translucent-to-white, proteinaceous particles. Do not shake the vial. Preparation Withdraw the required volume of OPDIVO and transfer into an intravenous container. Dilute OPDIVO with either 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP, to prepare an infusion with a final concentration ranging from 1 mg/ml to 10 mg/ml. Mix diluted solution by gentle inversion. Do not shake. Discard partially used vials or empty vials of OPDIVO. Storage of Infusion The product does not contain a preservative. After preparation, store the OPDIVO infusion either: at room temperature for no more than 4 hours from the time of preparation. This includes room temperature storage of the infusion in the IV container and time for administration of the infusion or under refrigeration at 2 C to 8 C (36 F-46 F) for no more than 24 hours from the time of infusion preparation. Do not freeze. Administration Administer the infusion over 60 minutes through an intravenous line containing a sterile, non-pyrogenic, low protein binding in-line filter (pore size of 0.2 micrometer to 1.2 micrometer). Do not coadminister other drugs through the same intravenous line. Flush the intravenous line at end of infusion. 3 DOSAGE FORMS AND STRENGTHS Injection: 40 mg/4 ml (10 mg/ml) and 100 mg/10 ml (10 mg/ml) solution in a single-use vial. 4 CONTRAINDICATIONS None. OPDIVO (nivolumab) 5 WARNINGS AND PRECAUTIONS 5.1 Immune-Mediated Pneumonitis Severe pneumonitis or interstitial lung disease, including fatal cases, occurred with OPDIVO treatment. Across the clinical trial experience in 691 patients with solid tumors, fatal immune-mediated pneumonitis occurred in 0.7% (5/691) of patients receiving OPDIVO. No cases of fatal pneumonitis occurred in Trial 1 or Trial 3; all five fatal cases occurred in a dose-finding study with OPDIVO doses of 1 mg/kg (two patients), 3 mg/kg (two patients), and 10 mg/kg (one patient). In Trial 1, pneumonitis, including interstitial lung disease, occurred in 3.4% (9/268) of patients receiving OPDIVO and none of the 102 patients receiving chemotherapy. Immune-mediated pneumonitis, defined as requiring use of corticosteroids and no clear alternate etiology, occurred in 2.2% (6/268) of patients receiving OPDIVO: one with Grade 3 and five with Grade 2 pneumonitis. The median time to onset for the six cases was 2.2 months (range: 25 days to 3.5 months). In two patients, pneumonitis was diagnosed after discontinuation of OPDIVO for other reasons, and Grade 2 pneumonitis led to interruption or permanent discontinuation of OPDIVO in the remaining four patients. All six patients received high-dose corticosteroids (at least 40 mg prednisone equivalents per day); immune-mediated pneumonitis improved to Grade 0 or 1 with corticosteroids in all six patients. There were two patients with Grade 2 pneumonitis that completely resolved (defined as complete resolution of symptoms with completion of corticosteroids) and OPDIVO was restarted without recurrence of pneumonitis. In Trial 3, pneumonitis occurred in 6% (7/117) of patients receiving OPDIVO, including five Grade 3 and two Grade 2 cases, all immune-mediated. The median time to onset was 3.3 months (range: 1.4 to 13.5 months). All seven patients discontinued OPDIVO for pneumonitis or another event and all seven patients experienced complete resolution of pneumonitis following receipt of high-dose corticosteroids (at least 40 mg prednisone equivalents per day). Monitor patients for signs and symptoms of pneumonitis. Administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents for Grade 2 or greater pneumonitis, followed by corticosteroid taper. Permanently discontinue OPDIVO for severe (Grade 3) or life-threatening (Grade 4) pneumonitis and withhold OPDIVO until resolution for moderate (Grade 2) pneumonitis [see Dosage and Administration (2.2)]. 5.2 Immune-Mediated Colitis In Trial 1, diarrhea or colitis occurred in 21% (57/268) of patients receiving OPDIVO and 18% (18/102) of patients receiving chemotherapy. Immune-mediated colitis, defined as requiring use of corticosteroids with no clear alternate etiology, occurred in 2.2% (6/268) of patients receiving OPDIVO: five patients with Grade 3 and one patient with Grade 2 colitis. The median time to onset of immune-mediated colitis from initiation of OPDIVO was 2.5 months (range: 1 to 6 months). In three patients, colitis was diagnosed after discontinuation of OPDIVO for other reasons, and Grade 2 or 3 colitis led to interruption or permanent discontinuation of OPDIVO in the remaining three patients. Five of these six patients received high-dose corticosteroids (at least 40 mg prednisone equivalents) for a median duration of 1.4 months (range: 3 days to 2.4 months) preceding corticosteroid taper. The sixth patient continued on low-dose corticosteroids started for another immune-mediated adverse reaction. Immune-mediated colitis improved to Grade 0 with corticosteroids in five patients, including one patient with Grade 3 colitis retreated after complete resolution (defined as improved to Grade 0 with completion of corticosteroids) without additional events of colitis. Grade 2 colitis was ongoing in one patient. In Trial 3, diarrhea occurred in 21% (24/117) of patients. Immune-mediated colitis (Grade 3) occurred in 0.9% (1/117) of patients. The time to onset in this patient was 6.7 months. The patient received high-dose corticosteroids and was permanently discontinued from OPDIVO. Complete resolution occurred. Monitor patients for immune-mediated colitis. Administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents followed by corticosteroid taper for severe (Grade 3) or life-threatening (Grade 4) colitis. Administer corticosteroids at a dose of 0.5 to 1 mg/kg/day prednisone equivalents followed by corticosteroid taper for moderate (Grade 2) colitis of more than 5 days duration; if worsening or no improvement occurs despite initiation of corticosteroids, increase dose to 1 to 2 mg/kg/day prednisone equivalents. Withhold OPDIVO for Grade 2 or 3 immune-mediated colitis. Permanently discontinue OPDIVO for Grade 4 colitis or for recurrent colitis upon restarting OPDIVO [see Dosage and Administration (2.2)]. 5.3 Immune-Mediated Hepatitis In Trial 1, there was an increased incidence of liver test abnormalities in the OPDIVOtreated group as compared to the chemotherapy-treated group, with increases in AST (28% vs. 12%), alkaline phosphatase (22% vs. 13%), ALT (16% vs. 5%), and total bilirubin (9% vs. 0). Immune-mediated hepatitis, defined as requirement for corticosteroids and no clear alternate etiology, occurred in 1.1% (3/268) of patients receiving OPDIVO: two patients with Grade 3 and one patient with Grade 2 hepatitis. The time to onset was 97, 113, and 86 days after initiation of OPDIVO. In one patient, hepatitis was diagnosed after discontinuation of OPDIVO for other reasons. In two patients, OPDIVO was withheld. All three patients received high-dose corticosteroids (at least 40 mg prednisone equivalents). Liver tests improved to Grade 1 within 4 to 15 days of initiation of corticosteroids. Immune-mediated hepatitis resolved and did not recur with continuation of corticosteroids in two patients; the third patient died of disease progression with persistent hepatitis. The two patients with Grade 3 hepatitis that resolved restarted OPDIVO and, in one patient, Grade 3 immune-mediated hepatitis recurred resulting in permanent discontinuation of OPDIVO. In Trial 3, the incidences of increased liver test values were AST (16%), alkaline phosphatase (14%), ALT (12%), and total bilirubin (2.7%). No cases of immune-mediated hepatitis occurred in this trial. Monitor patients for abnormal liver tests prior to and periodically during treatment. Administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents for Grade 2 or greater transaminase elevations, with or without concomitant elevation in total bilirubin. Withhold OPDIVO for moderate (Grade 2) and permanently discontinue