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nivolumab
Drug Monograph
Drug Name | Mechanism of Action and Pharmacokinetics | Indications and Status | Adverse Effects | Dosing | Administration
Guidelines | Special Precautions | Interactions | Recommended Clinical Monitoring | Supplementary Public Funding |
References | Disclaimer A - Drug Name
nivolumab
SYNONYM(S): BMS-936558
COMMON TRADE NAME(S): Opdivo (Bristol-Myers Squibb)
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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.
Elimination
Nivolumab clearance increases with increasing body weight. Dosing
normalized to body weight produces approximately uniform steady state drug
levels.
Half-life
(terminal): 27 days
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CCO Formulary - March 2017
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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 EGFR 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.)
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.
Notes:
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
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D - Adverse Effects
Emetogenic Potential: Minimal Extravasation 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 SITE
SIDE EFFECT* (%)
ONSET**
Cardiovascular
Arrhythmia (rare)
E
Cardiotoxicity (including myocarditis; rare)
E D
Hypertension (rare)
E
Venous thromboembolism (rare)
E
Alopecia (3%)
E
Rash (21%) (may be severe)
E
Skin hypopigmentation (11%) (vitiligo)
E
Abdominal pain (4%)
E
Anorexia (5%)
E
Constipation (11%)
E
Diarrhea (16%) (may be severe)
E
Nausea, vomiting (17%)
E
Edema (3%)
E
Fatigue (30%)
E
Fever (7%)
E
Dermatological
Gastrointestinal
General
Hematological
Hemolysis (immune-mediated, also thrombocytopenia; rare) E
Other (histocytic necrotizing lymphadenitis; rare, NSCLC)
E
↑ LFTs (7%) (hepatitis; may be severe)
E D
Pancreatitis (rare)
E
Hypersensitivity
Infusion related reaction (4%)
I E
Infection
Infection (2%)
E
Hepatobiliary
Metabolic / Endocrine Hyperglycemia (2%) (including diabetes)
E
Hyperthyroidism (3%)
E
Hypopituitarism (1.5%) (also hypophysitis - rare)
E D
Hypothyroidism (4%)
E D
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Other (Adrenal insufficiency; rare)
E D
Musculoskeletal pain (9%)
E
Rhabdomyolysis (also myopathy; rare)
E
Encephalitis (rare)
E
Guillain-Barre syndrome (rare)
E
Headache (4%)
E
Other (demyelination, myasthenia; rare)
E
Peripheral neuropathy (3%)
E
Ophthalmic
Uveitis (rare)
E
Renal
Nephrotoxicity (2%) (includes nephritis)
E D
Respiratory
Cough, dyspnea (3%)
E
Pneumonitis (3%) (NSCLC)
E D
Musculoskeletal
Nervous System
* "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) E = 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 E 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
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necrolysis (TEN), 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 nivolumab 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.
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E - 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
Every 3 weeks x 4 doses, followed by nivolumab monotherapy every 2 weeks until disease
progression or unacceptable toxicity
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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
Symptomatic grade
2
Hold and start physiologic corticosteroid
replacement.4
Grade 3 or 4
Discontinue and treat with physiologic
corticosteroid replacement.
Symptomatic grade
2
Hold and initiate appropriate hormone
therapy.4 Consider corticosteroids2 for severe
symptoms.
Grade 3 or 4
Discontinue and treat with hormone therapy.
Consider corticosteroids2 for severe
symptoms.
Symptomatic grade
2 or 3
Hold and start thyroid replacement therapy.4
Grade 4
Discontinue and treat with thyroid replacement
therapy.
Symptomatic grade
2 or 3
Hold and start anti-thyroid therapy.4 Consider
corticosteroids2 for severe symptoms.
Grade 4
Discontinue and consider corticosteroids2 for
severe symptoms.
Symptomatic grade
2 or 3
Hold and initiate insulin replacement as
needed.4
Grade 4
Discontinue
Grade 2
Hold until symptoms resolve and treat
Hypophysitis
Hypothyroidism
Hyperthyroidism
Diabetes
Diarrhea / colitis
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with corticosteroids1
If worsening or no improvement, discontinue
and increase corticosteroid dose2
Grade 3
Hold until symptoms resolve and treat with
corticosteroids2
Discontinue and treat with corticosteroids2 if
occurs when nivolumab is used in combination
with ipilimumab.
Grade 4
Hepatitis
Discontinue and treat with corticosteroids2
Grade 2 AST/ALT or Hold until recovery to baseline and treat with
total bilirubin
corticosteroids1
elevation
If worsening or no improvement, discontinue
and increase corticosteroid dose2
Grade 3 or 4
AST/ALT or total
bilirubin elevation
Discontinue and treat with corticosteroids2
Pneumonitis
Nephritis / renal
dysfunction
Symptomatic Grade Hold until symptoms resolve, radiographic
2
abnormalities improve and treat with
corticosteroids2. If worsening or no
improvement, discontinue and increase
corticosteroid dose3
Grade 3 or 4
Discontinue and treat with corticosteroids3
Grade 2
Hold until creatinine returns to baseline and
treat with corticosteroids1
If worsening or no improvement, discontinue
and increase corticosteroid dose2
Rash
Grade 3 or 4
Discontinue and treat with corticosteroids2
Grade 3
Hold until symptoms resolve.
Grade 4
Discontinue and treat with corticosteroids2
or SJS/TEN
For suspected SJS/TEN, refer patients to a
specialized unit for assessment and treatment.
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Discontinue if confirmed SJS/TEN.
Encephalitis
New
onset moderate or
severe neurologic
signs or symptoms
Hold and evaluate to rule out infectious or
other causes. If other causes ruled out, treat
with corticosteroids2
Immune-mediated
encephalitis
Discontinue and treat with corticosteroids2
Cardiac and
pulmonary events
Life-threatening or
recurrent severe
Discontinue
Other immunemediated:
Grade 3 first
occurrence
Hold until symptoms resolve and treat with
corticosteroids as required. Upon recovery,
resume after corticosteroid taper.
Recurrent grade 3
Discontinue and treat with corticosteroids2
Uveitis
Pancreatitis
Myasthenia
Demyelination
Guillian-Barre
syndrome
Hypopituitarism
Persistent grade 2
or 3 despite
treatment
modification
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
1. 0.5-1 mg/kg methylprednisolone equivalents. Upon recovery, resume after
corticosteroid taper.
2. 1-2 mg/kg methylprednisolone equivalents. Upon recovery, resume after corticosteroid
taper.
3. 2-4 mg/kg methylprednisolone equivalents. Upon recovery, resume after corticosteroid
taper.
4. May restart treatment after physiological replacement therapy started.
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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.
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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)
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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)
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
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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. Each 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.
Excretion into breast milk: Probable
Breastfeeding is not recommended.
Fertility effects: Unknown
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H - Interactions
No formal drug interaction studies have been conducted. Nivolumab is unlikely to affect the
pharmacokinetics of other drugs.
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CCO Formulary - March 2017
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The use of systemic corticosteroids and other immunosuppressants before starting nivolumab
should be avoided because of their potential interference with its activity. However, systemic
corticosteroids may be used after starting nivolumab to treat immune-mediated adverse effects.
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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
Monitor Frequency
Liver function tests
Baseline and before each dose
Thyroid function tests, other tests of hormone and
pituitary function
Baseline and periodic, especially
when on physiologic replacement
therapy
Renal function tests, including electrolytes
Baseline and before each dose
Blood glucose
Baseline, at each visit and as
clinically indicated
Response assessment
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.
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
At each visit
Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events)
version
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J - Supplementary Public Funding
New Drug Funding Program (
NDFP Website
)
Nivolumab - Advanced Melanoma (Unresectable or Metastatic Melanoma)
Nivolumab - Advanced or Metastatic Non-Small Cell Lung Cancer
Nivolumab - Advanced or Metastatic Renal Cell Carcinoma and No Prior mTOR Inhibitor
Nivolumab - Advanced or Metastatic Renal Cell Carcinoma and Prior mTOR Inhibitor
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K - References
Opdivo (nivolumab) product monograph. Bristol-Myers Squibb Canada. February 17, 2017.
Larkin J, Hodi FS, Wolchok JD. Combined Nivolumab and Ipilimumab or Monotherapy in Untreated
Melanoma. N Engl J Med. 2015 Sept 24; 373(13):1270-1.
Motzer RJ, Escudier B, McDermott DF, et al. CheckMate 025 Investigators. Nivolumab versus
Everolimus in Advanced Renal-Cell Carcinoma. N Engl J Med. 2015 Nov 5;373(19):1803-13.
Robert C, Long GV, Brady B, Dutriaux C, et al. Nivolumab in previously untreated melanoma without
BRAF mutation. N Engl J Med. 2015 Jan 22;372(4):320-30.
March 2017 added supplementary public funding
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L - Disclaimer
Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public
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CCO Formulary - March 2017
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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
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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
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Some Formulary documents, such as the medication information sheets, regimen information sheets and symptom
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While care has been taken in the preparation of the information contained in the Formulary, such information is
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