Treatment must be initiated and supervised by physicians experienced in the treatment of cancer.
Posology
OPDIVO as monotherapy
The recommended dose of OPDIVO is 3 mg/kg nivolumab administered intravenously over 60 minutes every 2 weeks.
OPDIVO in combination with ipilimumab
The recommended dose is 1 mg/kg nivolumab administered as an intravenous infusion over 60 minutes every 3 weeks for the first 4 doses in combination with 3 mg/kg ipilimumab administered intravenously over 90 minutes.
This is then followed by a second phase in which 3 mg/kg nivolumab is administered as an intravenous infusion over 60 minutes every 2 weeks.
Treatment with OPDIVO, either as a monotherapy or in combination with ipilimumab, should be continued as long as clinical benefit is observed or until treatment is no longer tolerated by the patient.
Dose escalation or reduction is not recommended. Dosing delay or discontinuation may be required based on individual safety and tolerability. Guidelines for permanent discontinuation or withholding of doses are described in Table 1. Detailed guidelines for the management of immune-related adverse reactions are described in section 4.4.
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Table 1: Recommended treatment modifications for OPDIVO or OPDIVO in combination with ipilimumab
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Immune-related adverse reaction
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Severity
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Treatment modification
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Immune-related pneumonitis
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Grade 2 pneumonitis
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Withhold dose(s) until symptoms resolve, radiographic abnormalities improve, and management with corticosteroids is complete
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Grade 3 or 4 pneumonitis
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Permanently discontinue treatment
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Immune-related colitis
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Grade 2 diarrhoea or colitis
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Withhold dose(s) until symptoms resolve and management with corticosteroids, if needed, is complete
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Grade 3 diarrhoea or colitis
- OPDIVO monotherapy
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Withhold dose(s) until symptoms resolve and management with corticosteroids is complete
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- OPDIVO+ipilimumab
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Permanently discontinue treatment
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Grade 4 diarrhoea or colitis
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Permanently discontinue treatment
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Immune-related hepatitis
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Grade 2 elevation in aspartate aminotransferase (AST), alanine aminotransferase (ALT), or total bilirubin
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Withhold dose(s) until laboratory values return to baseline and management with corticosteroids, if needed, is complete
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Grade 3 or 4 elevation in AST, ALT, or total bilirubin
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Permanently discontinue treatment
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Immune-related nephritis and renal dysfunction
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Grade 2 or 3 creatinine elevation
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Withhold dose(s) until creatinine returns to baseline and management with corticosteroids is complete
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Grade 4 creatinine elevation
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Permanently discontinue treatment
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Immune-related endocrinopathies
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Symptomatic Grade 2 or 3 hypothyroidism, hyperthyroidism, hypophysitis,
Grade 2 adrenal insufficiency
Grade 3 diabetes
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Withhold dose(s) until symptoms resolve and management with corticosteroids (if needed for symptoms of acute inflammation) is complete. Treatment should be continued in the presence of hormone replacement therapya as long as no symptoms are present
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Grade 4 hypothyroidism
Grade 4 hyperthyroidism
Grade 4 hypophysitis
Grade 3 or 4 adrenal insufficiency
Grade 4 diabetes
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Permanently discontinue treatment
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Immune-related rash
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Grade 3 rash
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Withhold dose(s) until symptoms resolve and management with corticosteroids is complete
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Grade 4 rash
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Permanently discontinue treatment
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Other adverse reactions
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Grade 3 (first occurrence)
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Withhold dose(s)
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Grade 4 or recurrent Grade 3 ; persistent Grade 2 or 3 despite treatment modification ; inability to reduce corticosteroid dose to 10 mg prednisone or equivalent per day
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Permanently discontinue treatment
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Note: Toxicity grades are in accordance with National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI-CTCAE v4).
a Recommendation for the use of hormone replacement therapy is provided in section 4.4.
Patients treated with OPDIVO must be given the patient alert card and be informed about the risks of OPDIVO (see also package leaflet).
When OPDIVO is administered in combination with ipilimumab, if either agent is withheld, the other agent should also be withheld. If dosing is resumed after a delay, either the combination treatment or OPDIVO monotherapy could be resumed based on the eva luation of the individual patient.
Special populations
Paediatric population
The safety and efficacy of OPDIVO in children below 18 years of age have not been established. No data are available.
Elderly
No dose adjustment is required for elderly patients (≥ 65 years) (see sections 5.1 and 5.2).
Non-Small Cell Lung Cancer
Data from patients 75 years of age or older are too limited to draw conclusions on this population.
Renal impairment
Based on the population pharmacokinetic (PK) results, no dose adjustment is required in patients with mild or moderate renal impairment (see section 5.2). Data from patients with severe renal impairment are too limited to draw conclusions on this population.
Hepatic impairment
Based on the population PK results, no dose adjustment is required in patients with mild hepatic impairment (see section 5.2). Data from patients with moderate or severe hepatic impairment are too limited to draw conclusions on these populations. OPDIVO must be administered with caution in patients with moderate (total bilirubin > 1.5 × to 3 × the upper limit of normal [ULN] and any AST) or severe (total bilirubin > 3 × ULN and any AST) hepatic impairment.
Non-small cell lung cancer
Patients with Eastern Cooperative Oncology Group (ECOG) performance status score ≥ 2 were excluded from the clinical trials of NSCLC (see sections 4.4 and 5.1).
Method of administration
OPDIVO is for intravenous use only. It is to be administered as an intravenous infusion over a period of 60 minutes. The infusion must be administered through a sterile, non-pyrogenic, low protein binding in-line filter with a pore size of 0.2-1.2 μm.
OPDIVO must not be administered as an intravenous push or bolus injection.
The total dose of OPDIVO required can be infused directly as a 10 mg/mL solution or can be diluted to as low as 1 mg/mL with sodium chloride 9 mg/mL (0.9%) solution for injection or glucose 50 mg/mL (5%) solution for injection.
When administered in combination with ipilimumab, OPDIVO should be given first followed by ipilimumab on the same day. Use separate infusion bags and filters for each infusion.
For instructions on the handling of the medicinal product before administration, see section 6.6.
When nivolumab is administered in combination with ipilimumab, refer to the Summary of Product Characteristics for ipilimumab prior to initiation of treatment. Immune-related adverse reactions have occurred at higher frequencies when nivolumab was administered in combination with ipilimumab compared with nivolumab as monotherapy. Most immune-related adverse reactions improved or resolved with appropriate management, including initiation of corticosteroids and treatment modifications (see section 4.2).
Cardiac adverse events and pulmonary embolism have also been reported with combination therapy. Patients should be monitored for cardiac and pulmonary adverse reactions continuously, as well as for clinical signs, symptoms, and laboratory abnormalities indicative of electrolyte disturbances and dehydration prior to and periodically during treatment. Nivolumab in combination with ipilimumab should be discontinued for life-threatening or recurrent severe cardiac and pulmonary adverse reactions.
Patients should be monitored continuously (at least up to 5 months after the last dose) as an adverse reaction with nivolumab or nivolumab in combination with ipilimumab may occur at any time during or after discontinuation of therapy.
For suspected immune-related adverse reactions, adequate eva luation should be performed to confirm aetiology or exclude other causes. Based on the severity of the adverse reaction, nivolumab or nivolumab in combination with ipilimumab should be withheld and corticosteroids administered. If immunosuppression with corticosteroids is used to treat an adverse reaction, a taper of at least 1 month duration should be initiated upon improvement. Rapid tapering may lead to worsening or recurrence of the adverse reaction. Non-corticosteroid immunosuppressive therapy should be added if there is worsening or no improvement despite corticosteroid use.
Nivolumab or nivolumab in combination with ipilimumab should not be resumed while the patient is receiving immunosuppressive doses of corticosteroids or other immunosuppressive therapy. Prophylactic antibiotics should be used to prevent opportunistic infections in patients receiving immunosuppressive therapy.
Nivolumab or nivolumab in combination with ipilimumab must be permanently discontinued for any severe immune-related adverse reaction that recurs and for any life-threatening immune-related adverse reaction.
Use of nivolumab in melanoma patients with rapidly progressing disease
Physicians should consider the delayed onset of nivolumab effect before initiating treatment in patients with rapidly progressing disease (see section 5.1).
Use of nivolumab in non-squamous NSCLC
Physicians should consider the delayed onset of nivolumab effect before initiating treatment in patients with poorer prognostic features and/or aggressive disease. In non-squamous NSCLC, a higher number of deaths within 3 months was observed in nivolumab compared to docetaxel. Factors associated with early deaths were poorer prognostic factors and/or more aggressive disease combined with low or no tumour PD-L1 expression (see section 5.1).
Immune-related pneumonitis
Severe pneumonitis or interstitial lung disease, including fatal cases, has been observed with nivolumab monotherapy or nivolumab in combination with ipilimumab (see section 4.8). Patients should be monitored for signs and symptoms of pneumonitis such as radiographic changes (e.g., focal ground glass opacities, patchy filtrates), dyspnoea, and hypoxia. Infectious and disease-related aetiologies should be ruled out.
For Grade 3 or 4 pneumonitis, nivolumab or nivolumab in combination with ipilimumab must be permanently discontinued, and corticosteroids should be initiated at a dose of 2 to 4 mg/kg/day methylprednisolone equivalents.
For Grade 2 (symptomatic) pneumonitis, nivolumab or nivolumab in combination with ipilimumab should be withheld and corticosteroids initiated at a dose of 1 mg/kg/day methylprednisolone equivalents. Upon improvement, nivolumab or nivolumab in combination with ipilimumab may be resumed after corticosteroid taper. If worsening or no improvement occurs despite initiation of corticosteroids, corticosteroid dose should be increased to 2 to 4 mg/kg/day methylprednisolone equivalents and nivolumab or nivolumab in combination with ipilimumab must be permanently discontinued.
Immune-related colitis
Severe diarrhoea or colitis has been observed with nivolumab monotherapy or nivolumab in combination with ipilimumab (see section 4.8). Patients should be monitored for diarrhoea and additional symptoms of colitis, such as abdominal pain and mucus or blood in stool. Infectious and disease-related aetiologies should be ruled out.
For Grade 4 diarrhoea or colitis, nivolumab or nivolumab in combination with ipilimumab must be permanently discontinued, and corticosteroids should be initiated at a dose of 1 to 2 mg/kg/day methylprednisolone equivalents.
Nivolumab monotherapy should be withheld for Grade 3 diarrhoea or colitis, and corticosteroids initiated at a dose of 1 to 2 mg/kg/day methylprednisolone equivalents. Upon improvement, nivolumab monotherapy may be resumed after corticosteroid taper. If worsening or no improvement occurs despite initiation of corticosteroids, nivolumab monotherapy must be permanently discontinued. Grade 3 diarrhoea or colitis observed with nivolumab in combination with ipilimumab requires permanent discontinuation of treatment and initiation of corticosteroids at a dose of 1 to 2 mg/kg/day methylprednisolone equivalents.
For Grade 2 diarrhoea or colitis, nivolumab or nivolumab in combination with ipilimumab should be withheld. Persistent diarrhoea or colitis should be managed with corticosteroids at a dose of 0.5 to 1 mg/kg/day methylprednisolone equivalents. Upon improvement, nivolumab or nivolumab in combination with ipilimumab may be resumed after corticosteroid taper, if needed. If worsening or no improvement occurs despite initiation of corticosteroids, corticosteroid dose should be increased to 1 to 2 mg/kg/day methylprednisolone equivalents and nivolumab or nivolumab in combination with ipilimumab must be permanently discontinued.
Immune-related hepatitis
Severe hepatitis has been observed with nivolumab monotherapy or nivolumab in combination with ipilimumab (see section 4.8). Patients should be monitored for signs and symptoms of hepatitis such as transaminase and total bilirubin elevations. Infectious and disease-related aetiologies should be ruled out.
For Grade 3 or 4 transaminase or total bilirubin elevation, nivolumab or nivolumab in combination with ipilimumab must be permanently discontinued, and corticosteroids should be initiated at a dose of 1 to 2 mg/kg/day methylprednisolone equivalents.
For Grade 2 transaminase or total bilirubin elevation, nivolumab or nivolumab in combination with ipilimumab should be withheld. Persistent elevations in these laboratory values should be managed with corticosteroids at a dose of 0.5 to 1 mg/kg/day methylprednisolone equivalents. Upon improvement, nivolumab or nivolumab in combination with ipilimumab may be resumed after corticosteroid taper, if needed. If worsening or no improvement occurs despite initiation of corticosteroids, corticosteroid dose should be increased to 1 to 2 mg/kg/day methylprednisolone equivalents and nivolumab or nivolumab in combination with ipilimumab must be permanently discontinued.
Immune-related nephritis and renal dysfunction
Severe nephritis and renal dysfunction have been observed with monotherapy treatment or nivolumab in combination with ipilimumab (see section 4.8). Patients should be monitored for signs and symptoms of nephritis or renal dysfunction. Most patients present with asymptomatic increases in serum creatinine. Disease-related aetiologies should be ruled out.
For Grade 4 serum creatinine elevation, nivolumab or nivolumab in combination with ipilimumab must be permanently discontinued, and corticosteroids should be initiated at a dose of 1 to 2 mg/kg/day methylprednisolone equivalents.
For Grade 2 or 3 serum creatinine elevation, nivolumab or nivolumab in combination with ipilimumab should be withheld, and corticosteroids should be initiated at a dose of 0.5 to 1 mg/kg/day methylprednisolone equivalents. Upon improvement, nivolumab or nivolumab in combination with ipilimumab may be resumed after corticosteroid taper. If worsening or no improvement occurs despite initiation of corticosteroids, corticosteroid dose should be increased to 1 to 2 mg/kg/day methylprednisolone equivalents, and nivolumab or nivolumab in combination with ipilimumab must be permanently discontinued.
Immune-related endocrinopathies
Severe endocrinopathies, including hypothyroidism, hyperthyroidism, adrenal insufficiency, hypophysitis, diabetes mellitus, and diabetic ketoacidosis have been observed with nivolumab monotherapy or nivolumab in combination with ipilimumab (see section 4.8).
Patients should be monitored for clinical signs and symptoms of endocrinopathies and for hyperglycaemia and changes in thyroid function (at the start of treatment, periodically during treatment, and as indicated based on clinical eva luation). Patients may present with fatigue, headache, mental status changes, abdominal pain, unusual bowel habits, and hypotension, or nonspecific symptoms which may resemble other causes such as brain metastasis or underlying disease. Unless an alternate etiology has been identified, signs or symptoms of endocrinopathies should be considered immune-related.
For symptomatic hypothyroidism, nivolumab or nivolumab in combination with ipilimumab should be withheld, and thyroid hormone replacement should be initiated as needed. For symptomatic hyperthyroidism, nivolumab or nivolumab in combination with ipilimumab should be withheld and antithyroid medication should be initiated as needed. Corticosteroids at a dose of 1 to 2 mg/kg/day methylprednisolone equivalents should also be considered if acute inflammation of the thyroid is suspected. Upon improvement, nivolumab or nivolumab in combination with ipilimumab may be resumed after corticosteroid taper, if needed. Monitoring of thyroid function should continue to ensure appropriate hormone replacement is utilised. Nivolumab or nivolumab in combination with ipilimumab must be permanently discontinued for life-threatening hyperthyroidism or hypothyroidism.
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