Distribution Nivolumab exhibits linear pharmacokinetics in the dose range of 0.1 to 20 mg/kg.

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1 Drug Monograph Drug Name Mechanism of Action and Pharmacokinetics Indications and Status Adverse ffects Dosing Administration Guidelines Special Precautions Interactions Recommended Clinical Monitoring Supplementary Public Funding References Disclaimer A - Drug Name nivolumab SYNONYM(S): BMS COMMON TRAD NAM(S): Opdivo (Bristol-Myers Squibb) B - Mechanism of Action and Pharmacokinetics Nivolumab is a human monoclonal antibody (IgG4) that binds to the PD-1 receptor on T-cells, blocking interaction with PD-L1 and PD-L2 and preventing PD-1 pathway-mediated inhibition of the tumour immune response. Distribution Nivolumab exhibits linear pharmacokinetics in the dose range of 0.1 to 20 mg/kg. Metabolism Monoclonal antibodies are catabolised into peptides and amino acids. limination Nivolumab clearance increases with increasing body weight. Dosing normalized to body weight produces approximately uniform steady state drug levels. Half-life (terminal): 27 days Page 1 of 13

2 C - Indications and Status Health Canada Approvals: For the treatment of unresectable or metastatic BRAF V600 wild-type melanoma in previously untreated patients. (BRAF V600 mutations must be ruled out with a validated test). For the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC)* with progression on or after platinum-based chemotherapy. Patients with GFR or ALK mutations should have disease progression on a targeted therapy for these mutations prior to receiving nivolumab. For the treatment of patients with advanced or metastatic renal cell cancer (RCC) who have received prior anti-angiogenic therapy. *Note: patients with non-squamous NSCLC and no or non-quantifiable PD-L1 expression should be monitored closely for progression during the first month of treatment. Nivolumab should not be used in the first-line setting. Health Canada Conditional Approvals (pending the result of studies to verify the drug s clinical benefit. Patients should be advised of the nature of the marketing authorization granted.) Notes: For the treatment of unresectable or metastatic BRAF V600 mutation positive melanoma in previously untreated patients. For the treatment of unresectable or metastatic melanoma in previously untreated patients in combination with ipilimumab. For the treatment of unresectable or metastatic melanoma and disease progression following ipilimumab, and if BRAF V600 mutation positive, a BRAF inhibitor. An improvement in overall survival has not yet been established for melanoma conditional approvals. An improvement in progression-free survival with nivolumab plus ipilimumab therapy was seen only in patients with tumour PD-L1 expression < 5%. Other Uses: Hematologic malignancies Page 2 of 13

3 D - Adverse ffects metogenic Potential: Minimal xtravasation Potential: None The following adverse effects are mainly from a phase III study comparing nivolumab 3 mg/kg monotherapy to dacarbazine. for unresectable or metastatic melanoma. Rare or severe adverse effects from other trials are also included. ORGAN SIT SID FFCT* (%) ONST** Cardiovascular Arrhythmia (rare) Cardiotoxicity (including myocarditis; rare) Hypertension (rare) Venous thromboembolism (rare) Dermatological Alopecia (3%) Rash (21%) (may be severe) Skin hypopigmentation (11%) (vitiligo) Gastrointestinal Abdominal pain (4%) Anorexia (5%) Constipation (11%) Diarrhea (16%) (may be severe) Nausea, vomiting (17%) General dema (3%) Hematological Fatigue (30%) Fever (7%) Hemolysis (immune-mediated, also thrombocytopenia; rare) Other (histocytic necrotizing lymphadenitis; rare, NSCLC) D Hepatobiliary LFTs (7%) (hepatitis; may be severe) D Pancreatitis (rare) Hypersensitivity Infusion related reaction (4%) I Infection Infection (2%) Metabolic / ndocrine Hyperglycemia (2%) (including diabetes) Hyperthyroidism (3%) Hypopituitarism (1.5%) (also hypophysitis - rare) Hypothyroidism (4%) D D Page 3 of 13

4 Other (Adrenal insufficiency; rare) D Musculoskeletal Musculoskeletal pain (9%) Rhabdomyolysis (also myopathy; rare) Nervous System ncephalitis (rare) Guillain-Barre syndrome (rare) Headache (4%) Other (demyelination, myasthenia; rare) Peripheral neuropathy (3%) Ophthalmic Uveitis (rare) Renal Nephrotoxicity (2%) (includes nephritis) D Respiratory Cough, dyspnea (3%) Pneumonitis (3%) (NSCLC) D nivolumab * "Incidence" may refer to an absolute value or the higher value from a reported range. "Rare" may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies, isolated data or anecdotal reports. Dose-limiting side effects are underlined. ** I = immediate (onset in hours to days) = early (days to weeks) D = delayed (weeks to months) L = late (months to years) The most common side effects for nivolumab include fatigue, rash, nausea, vomiting, diarrhea, constipation, skin hypopigmentation, musculoskeletal pain, lfts, fever and anorexia. The presentation may be different compared to other anti-cancer agents and early diagnosis and appropriate management is critical. Monitor for fatigue, weight changes, headache and mental status changes, abdominal pain, hypotension and changes in bowel habits. Immune-mediated adverse effects are more common when nivolumab is given in combination with ipilimumab compared to nivolumab monotherapy (more than 60% were grade 3 or higher). Most adverse effects improved or resolved with appropriate management. Cardiac and pulmonary reactions have been reported with combination therapy and may be severe. See section for management recommendations. Immune-mediated endocrinopathies, including hypo or hyperthyroidism, hypophysitis, adrenal insufficiency, diabetes mellitus and diabetic ketoacidosis were reported, may be severe and delayed (median time to onset 12 weeks). Other immune-mediated reactions include colitis and elevated liver enzymes, with a median onset of about 2 months. Pneumonitis may be severe with a delayed median onset at 3.6 months. Nephrotoxicity presents as slowly increasing creatinine, with a median onset at 2.3 months. Biopsy shows tubule-interstitial nephritis. Severe rash, including rare cases of Steven-Johnson syndrome (SJS) and toxic epidermal Page 4 of 13

5 necrolysis (TN), has been reported with an earlier median onset at 1.4 months. Hepatic and renal effects were most common in RCC, GI and skin reactions were most common in melanoma, and pulmonary reactions were most common in RCC and NSCLC. See the dosage with toxicity section for recommendations on how to manage immune-mediated adverse effects. Infusion reactions are uncommon, but may be severe. Patients with mild to moderate infusion reactions may receive nivolumamb with premedication and close monitoring. Anti-product antibodies, including neutralizing antibodies have been found in less than 11% of patients. The clinical significance of these is unclear. - Dosing Refer to protocol by which patient is being treated. Adults: Nivolumab monotherapy: Nivolumab 3 mg/kg IV over 60 minutes every 2 weeks until disease progression or unacceptable toxicity Combination therapy (melanoma): Nivolumab 1 mg/kg IV over 60 minutes in combination with Ipilimumab 3 mg/kg IV over 90 minutes very 3 weeks x 4 doses, followed by nivolumab monotherapy every 2 weeks until disease progression or unacceptable toxicity Page 5 of 13

6 Dosage with Toxicity: Doses should be held or discontinued due to toxicity, as indicated below, and infectious or other causes ruled out. Corticosteroids should be used as indicated, and the dose increased in case of no response. If used, corticosteroids should be tapered off over at least one month. Do not retreat until prednisone (or equivalent) doses 10 mg/day. Non-corticosteroid immunosuppressives should be added if no improvement. Prophylactic antibiotics should be used to prevent opportunistic infections in patients receiving immunosuppressive medications. Refer to the NIVL+IPIL regimen monograph for dose modifications for combination therapy Toxicity Severity Action Adrenal insufficiency Hypophysitis Hypothyroidism Hyperthyroidism Diabetes Symptomatic grade 2 Grade 3 or 4 Symptomatic grade 2 Grade 3 or 4 Symptomatic grade 2 or 3 Grade 4 Symptomatic grade 2 or 3 Grade 4 Symptomatic grade 2 or 3 Grade 4 Hold and start physiologic corticosteroid replacement. Discontinue and treat with physiologic corticosteroid replacement. Hold and initiate appropriate hormone therapy. Consider corticosteroids 2 for severe symptoms. Discontinue and treat with hormone therapy. Consider corticosteroids 2 for severe symptoms. Hold and start thyroid replacement therapy. Discontinue and treat with thyroid replacement therapy. Hold and start anti-thyroid therapy. Consider corticosteroids 2 for severe symptoms. Discontinue and consider corticosteroids 2 for severe symptoms. Hold and initiate insulin replacement as needed. Discontinue Diarrhea / colitis Grade 2 Hold until symptoms resolve and treat with corticosteroids 1 Page 6 of 13

7 If worsening or no improvement, discontinue and increase corticosteroid dose 2 nivolumab Grade 3 Hold until symptoms resolve and treat with corticosteroids 2 Discontinue and treat with corticosteroids 2 if occurs when nivolumab is used in combination with ipilimumab. Grade 4 Discontinue and treat with corticosteroids 2 Hepatitis Grade 2 AST/ALT or total bilirubin elevation Grade 3 or 4 AST/ALT or total bilirubin elevation Hold until recovery to baseline and treat with corticosteroids 1 If worsening or no improvement, discontinue and increase corticosteroid dose 2 Discontinue and treat with corticosteroids 2 Pneumonitis Symptomatic Grade 2 Hold until symptoms resolve, radiographic abnormalities improve and treat with corticosteroids 2. If worsening or no improvement, discontinue and increase corticosteroid dose 3 Grade 3 or 4 Discontinue and treat with corticosteroids 3 Nephritis / renal dysfunction Grade 2 Hold until creatinine returns to baseline and treat with corticosteroids 1 If worsening or no improvement, discontinue and increase corticosteroid dose 2 Grade 3 or 4 Discontinue and treat with corticosteroids 2 Rash Grade 3 Hold until symptoms resolve. Grade 4 or SJS/TN Discontinue and treat with corticosteroids 2 For suspected SJS/TN, refer patients to a specialized unit for assessment and treatment. Discontinue if confirmed SJS/TN. Page 7 of 13

8 ncephalitis New onset moderate or severe neurologic signs or symptoms Immune-mediated encephalitis Hold and evaluate to rule out infectious or other causes. If other causes ruled out, treat with corticosteroids 2 Discontinue and treat with corticosteroids 2 nivolumab Cardiac and pulmonary events Life-threatening or recurrent severe Discontinue Other immunemediated: Uveitis Pancreatitis Myasthenia Demyelination Guillian-Barre syndrome Hypopituitarism Grade 3 first occurrence Recurrent gade 3 Persistent grade 2 or 3 despite treatment modification Hold until symptoms resolve and treat with corticosteroids as required. Upon recovery, resume after corticosteroid taper. Discontinue and treat with corticosteroids 2 Life-threatening or grade 4 Inability to reduce corticosteroid dose to prednisone 10 mg or equivalent per day. Infusion reaction Grade 1 or 2 Monitor carefully, use premedication with next infusion Grade 3 or 4 Discontinue and treat appropriately mg/kg methylprednisolone equivalents. Upon recovery, resume after corticosteroid taper mg/kg methylprednisolone equivalents. Upon recovery, resume after corticosteroid taper mg/kg methylprednisolone equivalents. Upon recovery, resume after corticosteroid taper. Page 8 of 13

9 Dosage with Hepatic Impairment: No dosage adjustment is required for mild hepatic impairment. No clinically important differences in drug clearance were found between patients with mild hepatic impairment and normal hepatic function. No data are available for moderate to severe hepatic impairment. Dosage with Renal Impairment: No clinically important differences in drug clearance were found between patients with mild or moderate renal impairment and patients with normal renal function. Insufficient data are available for severe renal impairment (GFR < 30 ml/min). Dosage in the elderly: No overall differences in safety or efficacy were reported for patients aged 65 and older compared to younger patients. Children: Safety and efficacy have not been established in pediatric patients. F - Administration Guidelines Nivolumab may be diluted with normal saline or D5W to a final concentration of 1 to 10 mg/ml (no dilution required if 10 mg/ml desired) Mix diluted solution by gentle inversion. Do not shake. If not given immediately, infusion solution may be stored under refrigeration and protected from light up to 24 hours (max of 4 hours at room temp) Administer by IV infusion over 60 minutes via a sterile, non-pyrogenic, low protein binding inline filter (pore size 0.2 to 1.2 micrometer) Page 9 of 13

10 Do not infuse concomitantly with other agents Flush the line with normal saline or D5W after each dose If given with ipilimumab, administer nivolumab first G - Special Precautions Contraindications: Patients who have a hypersensitivity to this drug or any of its components Other Warnings/Precautions: Use with caution in patients on a controlled sodium diet. ach ml contains 0.1 mmol (2.3 mg) sodium. Patients with active brain metastases, uveal melanoma and a history of serious autoimmune disease were excluded from the melanoma clinical trial. Patients with autoimmune disease were excluded from lung clinical trials. Other Drug Properties: Carcinogenicity: Unknown Pregnancy and Lactation: Mutagenicity: Unknown Fetotoxicity: Yes Nivolumab is not recommended for use in pregnancy. Adequate contraception should be used by both sexes during treatment, and for at least 5 months after the last dose. xcretion into breast milk: Probable Breastfeeding is not recommended. Fertility effects: Unknown H - Interactions No formal drug interaction studies have been conducted. Nivolumab is unlikely to affect the pharmacokinetics of other drugs. The use of systemic corticosteroids and other immunosuppressants before starting nivolumab should be avoided because of their potential interference with its activity. However, systemic Page 10 of 13

11 corticosteroids may be used after starting nivolumab to treat immune-mediated adverse effects. nivolumab I - Recommended Clinical Monitoring Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph. Monitor for immune-mediated reactions up to 5 months after the last dose of nivolumab. Recommended Clinical Monitoring Monitor Type Liver function tests Thyroid function tests, other tests of hormone and pituitary function Renal function tests, including electrolytes Blood glucose Response assessment Clinical toxicity assessment for infusion reactions, hypotension and cardiac effects, immune-mediated reactions, including diarrhea, rash, respiratory, neurologic and ophthalmic effects, fatigue and muscle weakness Monitor Frequency Baseline and before each dose Baseline and periodic, especially when on physiologic replacement therapy Baseline and before each dose Baseline, at each visit and as clinically indicated patients with non-squamous NSCLC and no or non-quantifiable PD-L1 expression should be monitored closely for progression during the first month of treatment. At each visit Grade toxicity using the current NCI-CTCA (Common Terminology Criteria for Adverse vents) version Page 11 of 13

12 K - References Opdivo (nivolumab) product monograph. Bristol-Myers Squibb Canada. October 26, Larkin J, Hodi FS, Wolchok JD. Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. N ngl J Med Sept 24; 373(13): Motzer RJ, scudier B, McDermott DF, et al. CheckMate 025 Investigators. Nivolumab versus verolimus in Advanced Renal-Cell Carcinoma. N ngl J Med Nov 5;373(19): Robert C, Long GV, Brady B, Dutriaux C, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N ngl J Med Jan 22;372(4): November 2016 added conditional approvals for melanoma, updated adverse effects, dosage and monitoring sections L - Disclaimer Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information. The information set out in the drug monographs, regimen monographs, appendices and symptom management information (for health professionals) contained in the Drug Formulary (the "Formulary") is intended for healthcare providers and is to be used for informational purposes only. The information is not intended to cover all possible uses, directions, precautions, drug interactions or adverse effects of a particular drug, nor should it be construed to indicate that use of a particular drug is safe, appropriate or effective for a given condition. The information in the Formulary is not intended to constitute or be a substitute for medical advice and should not be relied upon in any such regard. All uses of the Formulary are subject to clinical judgment and actual prescribing patterns may not follow the information provided in the Formulary. The format and content of the drug monographs, regimen monographs, appendices and symptom management information contained in the Formulary will change as they are reviewed and revised on a periodic basis. The date of last revision will be visible on each page of the monograph and regimen. Since standards of usage are constantly evolving, it is advised that the Formulary not be used as the sole source of information. It is strongly recommended that original references or product monograph be consulted prior to using a chemotherapy regimen for the first time. Some Formulary documents, such as the medication information sheets, regimen information sheets and symptom management information (for patients), are intended for patients. Patients should always consult with their healthcare provider if they have questions regarding any information set out in the Formulary documents. Page 12 of 13

13 While care has been taken in the preparation of the information contained in the Formulary, such information is provided on an as-is basis, without any representation, warranty, or condition, whether express, or implied, statutory or otherwise, as to the information s quality, accuracy, currency, completeness, or reliability. CCO and the Formulary s content providers shall have no liability, whether direct, indirect, consequential, contingent, special, or incidental, related to or arising from the information in the Formulary or its use thereof, whether based on breach of contract or tort (including negligence), and even if advised of the possibility thereof. Anyone using the information in the Formulary does so at his or her own risk, and by using such information, agrees to indemnify CCO and its content providers from any and all liability, loss, damages, costs and expenses (including legal fees and expenses) arising from such person s use of the information in the Formulary. Page 13 of 13