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NIVL

Cancer Type: Hematologic, Lymphoma - Hodgkin  Intent: Palliative
Regimen Category: Evidence-Informed
Funding:
New Drug Funding Program
    Nivolumab - Relapsed Classical Hodgkin Lymphoma (cHL) Post-Autologous Stem Cell Transplant (ASCT)
A - Regimen Name

NIVL Regimen
nivolumab


Disease Site
Hematologic - Lymphoma - Hodgkin

Intent
Palliative

Regimen Category
Evidence-Informed :

Regimen is considered appropriate as part of the standard care of patients; meaningfully improves outcomes (survival, quality of life), tolerability or costs compared to alternatives (recommended by the Disease Site Team and national consensus body e.g. pan-Canadian Oncology Drug Review, pCODR).  Recommendation is based on an appropriately conducted phase III clinical trial relevant to the Canadian context OR (where phase III trials are not feasible) an appropriately sized phase II trial. Regimens where one or more drugs are not approved by Health Canada for any indication will be identified under Rationale and Use.


Rationale and Uses

For the treatment of patients with classical Hodgkin Lymphoma (cHL) that has relapsed or progressed after autologous stem cell transplantation (ASCT) and brentuximab vedotin

An improvement in survival or disease-related symptoms has not been established. 

 


Supplementary Public Funding

nivolumab
New Drug Funding Program (Nivolumab - Relapsed Classical Hodgkin Lymphoma (cHL) Post-Autologous Stem Cell Transplant (ASCT)) (NDFP Website )

 
B - Drug Regimen

nivolumab
3 mg /kg IV (max 240 mg)* Day 1

 

OR

nivolumab
6 mg /kg IV (max 480 mg)* Day 1

*Dosing based on NDFP funding criteria

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C - Cycle Frequency

Nivolumab 3 mg/kg dosing: REPEAT EVERY 2 WEEKS

Nivolumab 6 mg/kg dosing: REPEAT EVERY 4 WEEKS

Until disease progression or unacceptable toxicity

 
D - Premedication and Supportive Measures

Antiemetic Regimen:

Minimal

Other Supportive Care:

Also refer to CCO Antiemetic Recommendations.

Prophylactic antibiotics should be used to prevent opportunistic infections in patients receiving immunosuppressive medications.

 

Pre-medications (prophylaxis for infusion reaction):

  • Routine pre-medication is not recommended. 
  • May consider pre-medication with antipyretics and H1-receptor antagonists if an IR has occurred in the past.

 

 
E - Dose Modifications

Doses should be modified according to the protocol by which the patient is being treated. 

Dosage with toxicity

  • Healthcare professionals should also consult the most recent nivolumab product monograph for additional information.
     

Summary of Principles of Management

  • Immune-related adverse effects (irAEs) are different in their presentation, onset and duration compared to conventional chemotherapy. Patient and provider education is essential.

  • Initial irAE presentation can occur months after completion of treatment and affect multiple organs.

  • Dose escalation or reduction is not recommended.

  • If no other cause can be identified (such as infection), any new symptom should be considered immune-related and prompt treatment initiated.

  • Organ-specific system-based toxicity management is recommended.

  • Refer to the CCO guideline for detailed description of Immune-mediated toxicities and their management
     

Management of Infusion-related reactions:

Also refer to the CCO guideline for detailed description of Management of Cancer Medication-Related Infusion Reactions.

Grade Management Re-challenge
1 or 2
  • Stop or slow the infusion rate.
  • Manage the symptoms.

Restart:

  • Once symptoms have resolved, the infusion may be restarted with close monitoring.
  • Re-challenge with close monitoring and pre-medications. 
3 or 4
  • Stop treatment
  • Aggressively manage symptoms.
  • Discontinue permanently (do not re-challenge).



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 available for moderate to severe hepatic impairment.


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 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.


 
F - Adverse Effects

Refer to nivolumab drug monograph(s) for additional details of adverse effects.

The presentation of immune-mediated adverse effects may be different compared to other anti-cancer agents and early diagnosis and appropriate management is critical.

Complications such as graft vs. host disease (GVHD) and multi-organ failure occurred in HL patients who received allogeneic HSCT after nivolumab treatment. Follow patients at risk closely for early evidence of transplant-related complications and intervene promptly. 


Common (25-49%)

Less common (10-24%)

Uncommon (< 10%),

but may be severe or life-threatening

  • Fatigue
  • ↑ LFTs (may be severe)
  • Rash (may be severe)
  • Electrolyte imbalances (including potassium, calcium, magnesium, sodium)
  • Nausea, vomiting
  • Diarrhea (may be severe)
  • Vitiligo
  • Constipation
  • Increased creatinine (maybe severe)
  • Rhabdomyolysis
  • Hypo / hyperthyroidism
  • Hypopituitarism (also hypophysitis)
  • Adrenal insufficiency
  • Hyperglycemia (including diabetes and DKA)
  • Infusion related reaction
  • Peripheral neuropathy
  • Immunosuppression +/- Infection (may be severe)
  • Arrhythmia
  • Cardiotoxicity (including myocarditis)
  • Veno-occlusive disease
  • Venous thromboembolism
  • Hemolysis (immune-mediated, also thrombocytopenia)
  • Encephalitis/meningitis
  • Pancreatitis
  • Pneumonitis
  • Graft-versus-host disease (GVHD)
  • Guillain-Barre syndrome
  • Solid organ transplant rejection
  • Vogt-Koyanagi-Harada syndrome
  • Uveitis
  • Myasthenia gravis
  • Vasculitis
  • Histiocytic necrotizing lymphadenitis
 
G - Interactions

Refer to nivolumab drug monograph(s) for additional details


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. 

 
H - Drug Administration and Special Precautions

Refer to nivolumab drug monograph(s) for additional details


Administration

  • For drug preparation, the manufacturer's guidelines in the product monograph recommend: 
    • Withdraw the required volume of nivolumab 10 mg/mL injection and aseptically transfer into a sterile IV container (PVC container, non-PVC container, or glass bottle). Nivolumab may be diluted with either 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP.
    • The 3 mg/kg dosage may be diluted to prepare an infusion with a final concentration ranging from 1 to 10 mg/mL.
    • For fixed-dose, the 240 mg or 480 mg dosage may be diluted so as not to exceed a total infusion volume of 120 mL.
  • Mix diluted solution by gentle inversion. Do not shake.

  • Discard if solution is cloudy, if there is pronounced discolouration or if there is foreign particulate matter.

  • Administer by IV infusion over 30 minutes via a sterile, non-pyrogenic, low protein binding in-line 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.

  • Store unopened nivolumab vials in original packaging between 2oC to 8oC. Protect from light.
     

Also refer to the CCO guideline for detailed description of Management of Cancer Medication-Related Infusion Reactions.

 

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.

  • Use in caution in patients with:

    • autoimmune disease

    • history of pneumonitis or interstitial lung disease or recent chest radiation

    • prior or planned allogeneic stem cell transplant

    • infection with HIV, or active coinfection with HBV/HCV or HBV/HDV as these patients were excluded from clinical trials
       

Pregnancy/Lactation:

  • 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.

  • Breastfeeding is not recommended.  Immunoglobulins are known to be secreted into breast milk; therefore as a human IgG4 antibody, there is potential for infant exposure to nivolumab via breast milk.

  • Fertility effects:  Unknown

 
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.

 

Recommended Clinical Monitoring

  • Liver function tests; Baseline, before each dose and as clinically indicated for at least up to 5 months after the last dose

  • Renal function tests, including electrolytes; Baseline, before each dose and as clinically indicated for at least up to 5 months after the last dose.

  • Thyroid function tests, other tests of hormone, pituitary and adrenal function; Baseline, periodic, especially when on physiologic replacement therapy and for at least up to 5 months after the last dose.

  • Blood glucose; Baseline, at each visit, as clinically indicated and for at least up to 5 months after the last dose

  • GVHD (with prior to planned ASCT), solid organ transplant rejection (if applicable); As clinically indicated

  • 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 and for at least up to 5 months after the last dose

  • Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version


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J - Administrative Information

Approximate Patient Visit
1.5 hours
Pharmacy Workload (average time per visit)
18.7 minutes
Nursing Workload (average time per visit)
40.75 minutes
 
K - References

Ansell SM, Lesokhin AM, Borrello I, et al.  PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma. ;N Engl J Med 2015;372:311-9.

Nivolumab drug monograph, Cancer Care Ontario.

January 2020 Added NDFP form; updated rationale/uses, dosing and cycle frequency based on NDFP criteria


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M - Disclaimer

Regimen Abstracts
A Regimen Abstract is an abbreviated version of a Regimen Monograph and contains only top level information on usage, dosing, schedule, cycle length and special notes (if available). It is intended for healthcare providers and is to be used for informational purposes only. It is not intended to constitute or be a substitute for medical advice, and all uses of the Regimen Abstract are subject to clinical judgment. 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, and Cancer Care Ontario disclaims all liability for the use of this information, and for any claims, actions, demands or suits that arise from such use.
Information in regimen abstracts is accurate to the extent of the ST-QBP regimen master listings, and has not undergone the full review process of a regimen monograph.  Full regimen monographs will be published for each ST-QBP regimen as they are developed.
Regimen Monographs
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.
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.