Nivolumab (Opdivo) is a human programmed death receptor-1 (PD-1) blocking antibody that is used to treat various cancers.

Nivolumab (Opdivo) Uses:

In addition, it is used off Label for the treatment of melanoma in patients whose disease has metastasized to the brain

Nivolumab (Opdivo) Dose in Adults

Nivolumab (Opdivo) Dose in Children

Dosing adjustment for toxicity:

Permanently discontinue in the following situations:

• Infusion-related reaction: 

Discontinue the treatment in severe reactions. In mild to moderate reactions, reduce the infusion rate or temporarily withhold the infusion.

• Hypothyroidism or Hyperthyroidism:

There are no specific recommendations with regard to treatment interruption or withholding the treatment, however, treat hypo and hyperthyroidism appropriately with thyroxine or antithyroid drugs respectively. 

Pregnancy Risk Category: D

Nivolumab may cause harm if administered to pregnant women based on animal reproduction studies and mechanism of action.

It is important to verify pregnancy status before starting treatment in females with reproductive potential and to use effective contraception during therapy and for at least five months following the last treatment.

The use of Nivolumab while breastfeeding is not recommended as it is unknown if breast milk contains nivolumab, and breastfeeding should be stopped during treatment and for the first five months following the last dose.

Nivolumab (Opdivo) Dose in Kidney Disease:

Nivolumab (Opdivo) Dose in Liver Disease:

Hepatic impairment prior to treatment initiation:

• Hepatotoxicity during treatment:​​​​​

Common Side Effects of Nivolumab (Opdivo):

• Cardiovascular:

  • Edema
  • Peripheral Edema
  • Hypertension

• Neurological Side effects:

  • Fatigue and lethargy
  • Malaise
  • Headache
  • Dizziness and vertigo
  • Peripheral Neuropathy

• Skin-related side effects

  • Rashes
  • Pruritus
  • Vitiligo

• Endocrine & Metabolic:

  • Hyperglycemia
  • Hyponatremia
  • Hypertriglyceridemia (raised TG) and total cholesterol levels
  • Hyperkalemia or Hypokalemia
  • Increased Thyroid Stimulating Hormone Level
  • Hypocalcemia or Hypercalcemia
  • Thyroiditis, Hypothyroidism, or thyroid dysfunction
  • Hypomagnesemia

• Gastrointestinal:

  • Diarrhea or constipation
  • Nausea and vomiting
  • Abdominal Pain
  • Increased Serum Lipase or Lipase
  • Loss of Appetite

• Genitourinary:

  • Urinary Tract Infection

• Hematologic & Oncologic:

  • Anemia
  • Lymphocytopenia
  • Leukopenia
  • Thrombocytopenia
  • Neutropenia

• Liver-related side effects:

  • Increased Serum ALT, AST, Alkaline Phosphatase, or elevated bilirubin levels

• Immunologic:

  • Graft Versus Host Disease
  • Antibody Development

• Neuromuscular & Skeletal:

  • Asthenia
  • Musculoskeletal Pain
  • Back Pain
  • Arthralgia

• Renal:

  • Increased Serum Creatinine

• Respiratory:

  • Upper Respiratory Tract Infections
  • Cough, SOB on exertion
  • Pneumonia including Bronchopneumonia
  • Nasal Congestion

• Miscellaneous:

  • Febrile Reaction
  • Fever
  • Infusion-Related Reaction

Less Common Side Effects Of Nivolumab (Opdivo):

• Cardiovascular:

  • Pulmonary Embolism

• Neurological Side effects:

  • Sleep disorder
  • Neuritis and nerve Palsy

• Dermatologic:

  • Skin redness
  • Dryness

• Endocrine side effects:

  • Weight Loss
  • Thyrotoxicosis
  • Addison disease

• Gastrointestinal:

  • Intestinal inflammation, colitis, and perforation
  • Stomatitis and aphthous ulcers

• Hepatic:

  • Hepatitis

• Immunologic:

  • Sjogren's Syndrome

• Infection:

  • Sepsis

• Neuromuscular & Skeletal:

  • Myopathy
  • Rheumatism

• Renal:

  • Renal insufficiency and Acute Renal Failure
  • Nephritis

• Respiratory:

  • Interstitial lung disease and pneumonitis
  • Pleural Effusion
  • Respiratory Failure

Side effects of Nivolumab (Opdivo) (Frequency unknown):

• Neurological Side effects:

  • Migraine headache

• Skin-related side effects:

  • Acne
  • Eczema including exfoliative dermatitis
  • Rash (macular, papular, psoriasiform, morbilliform, and pustular)
  • Palmar-Plantar Erythrodysesthesia
  • SJS and TEN
  • Toxic Epidermal Necrolysis

• Metabolic:

  • Volume depletion

• Skeletal:

  • Pain in the arms and legs

Contraindications to Nivolumab (Opdivo):

• Hypersensitivity to nivolumab and any component of the formula

Warnings and precautions

• Adrenal Insufficiency:

Adrenal insufficiency may develop, especially when high-dose corticosteroids are given in combination with Nivolumab. Adrenal insufficiency may take 3 to 4 months but it may develop rapidly (within two weeks) when higher doses of corticosteroids are used.

Patients should be monitored for the clinical features of adrenal insufficiency. For mild to moderate Addison's disease, corticosteroids in replacement doses should be given. For moderate to severe cases of Addison's disease, higher doses of corticosteroids should be given and then slowly tapered.

However, in life-threatening cases, Nivolumab treatment may be discontinued and replacement using intravenous corticosteroids should be used.

• Skin-related side effects:

Nivolumab patients have experienced immune-mediated rash (SJS) and toxic epidermal necrolysis, some fatal. If the rash appears within 18 days to 2 months, consult a specialist for evaluation, and permanently discontinue if confirmed.

Severe (Grade 3) rash warrants treatment withholding, while life-threatening (Grade 4) rash requires corticosteroids and close monitoring. High-dose systemic corticosteroids followed by a taper were given to some patients for 12-22 days. Topical corticosteroids can treat dermatologic toxicity. Rechallenge can treat recurrence in some patients.

• Diabetes mellitus

Hyperglycemia and Type 1 Diabetes mellitus is a side effect of Nivolumab. Cases of severe hyperglycemia including cases of DKA have been reported.

In clinical trials, diabetes was reported between 15 to 22 months of the treatment. Symptoms of hyperglycemia should be monitored and in severe cases of hyperglycemia, Nivolumab treatment should be discontinued.

• Encephalitis

Immune-mediated encephalitis has been reported in patients using Nivolumab (Opidvo). A case report of fatal limbic encephalitis has been reported. 

All patients should be evaluated for new-onset neurological symptoms. Evaluation should include CSF examination and MR of the brain.

Nivolumab treatment should be stopped and corticosteroids (or infliximab) should be administered to all patients who are diagnosed with immune-mediated limbic encephalitis.

• Gastrointestinal Toxicity:

Nivolumab can cause diarrhea and colitis in patients, and in some cases, it can be fatal. The median time for colitis to occur after taking nivolumab was 1.6-3 months, but it could also happen after stopping the treatment.

Corticosteroid therapy is the recommended treatment for severe or life-threatening colitis (grades 3-4), while a taper of corticosteroids is suggested for moderate colitis (grade 2) lasting more than 5 days.

If colitis persists or worsens, the dose of prednisone may need to be increased, and in some cases, infliximab may be necessary. If the patient experiences grade 4 colitis or diarrhea, nivolumab should be permanently discontinued. It is important to look out for signs and symptoms of colitis and seek medical attention if necessary.

• Hepatotoxicity

Patients treated with nivolumab have experienced liver enzyme elevations and immune-mediated liver disease. Most cases were grade 2 or 3 hepatitis, which occurred 2-3.3 months after starting nivolumab.

High-dose systemic corticosteroid therapy (and rarely mycophenolate mofetil) was used to treat immune-mediated hepatitis, which lasted an average of 23 days to 1.1 months.

Patients without hepatocellular cancer should start corticosteroids for grade 2 hepatitis, while severe or life-threatening disease should lead to permanent discontinuation of the medication.

HCC patients should be given corticosteroids if nivolumab is stopped due to immune-mediated liver disease. Discontinuation, withholding, or continuation of nivolumab depends on the severity of the disease. Liver function should be monitored at baseline and periodically.

• Hypophysitis:

Nivolumab can cause hypophysitis with grades 1, 2, and 3 toxicities reported. Most patients were treated with corticosteroids, and hormone replacement therapy should be considered for grade 2 and higher toxicities.

The median time from the onset was between 2.7 and 4.9 months. Patients should be monitored for hypophysitis symptoms and signs, and for moderate (grade 2) and severe (grade 3) toxicities, nivolumab should be withheld.

Treatment should be permanently stopped for hypophysitis grade 4. High-dose systemic corticosteroid therapy may be required for 13-19 days after which the corticosteroids are gradually tapered to the recommended maintenance dose.

• Infusion-related allergic reactions:

Infusion-related reactions can occur with nivolumab, both when used alone or in combination with other medications.

Severe reactions are rare but can occur with single-agent use. It's important to note the symptoms or signs of an infusion reaction and report them immediately to your healthcare provider. Mild or moderate reactions can often be managed by interrupting or decreasing infusion rates.

A study found that shortening the infusion time from 60 minutes to 30 minutes did not significantly increase the risk of infusion-related reactions, but a small percentage of patients did experience symptoms within 48 hours and required dose delay, permanent discontinuation, or withholding of nivolumab.

Nephrotoxicity:

Nivolumab therapy can cause renal dysfunction, specifically immune-mediated or autoimmune nephritis, which requires corticosteroid therapy. The median time from onset of symptoms is between 2.7 and 4.6 months.

High-dose systemic steroids are used to treat single-agent nivolumab-induced nephritis, with a median treatment duration of three weeks. The majority of patients experienced complete resolution without recurrence upon rechallenge.

Patients who received high-dose systemic steroids in combination with ipilimumab also experienced complete resolution, with some resuming combination therapy without recurrence.

Monitoring serum creatinine at baseline and during treatment is recommended, and corticosteroids should be initiated for life-threatening (grade 4) creatinine elevation, and nivolumab discontinued permanently.

Treatment should be withheld for severe (grade 2) or moderate (grade 3) creatinine levels, and corticosteroids and a taper should be administered. If toxicity persists, increasing the prednisone dosage may be necessary.

• Ocular toxicities:

Nivolumab therapy has been associated with uveitis and iritis. In patients who develop uveitis along with other immune-mediated adverse effects, a Vogt Koyanagi Harada-like syndrome should be considered.

Such patients may require systemic corticosteroids to prevent permanent vision loss. This syndrome has been reported in patients receiving nivolumab alone or in combination with Ipilimumab.

• Toxicity in the lungs:

Nivolumab may cause immune-mediated pneumonitis, which can be severe or interstitial and may lead to fatal cases. The median time from the onset was between 1.6 and 3.5 months, and some cases occurred after nivolumab was stopped for other reasons.

High-dose systemic corticosteroids were given for a median of 19-30 days, followed by a corticosteroid taper. Many patients achieved grade 0 or 1 in their treatment. Some patients with grade 2 and 3 pneumonitis experienced complete resolution after completing corticosteroid treatment.

To monitor for symptoms and signs of pneumonitis, radiographic imaging is necessary. You may need to interrupt treatment, discontinue corticosteroid therapy, and/or stop taking them permanently.

Following a corticosteroid taper for grades 3, and 4, pneumonitis should then be treated with corticosteroids. In some cases, infliximab may be added to corticosteroid therapy. For severe (Grade 3 or 4) immune-mediated pneumonitis, discontinue use immediately.

• Thyroid disorders:

Nivolumab may cause hypothyroidism/thyroiditis and immune-mediated hyperthyroidism. Most cases are mild (grades 1 & 2), but some cases of grade 3 have been reported with combination therapy.

Hyperthyroidism usually occurs between 23 days to 1.5 months after treatment. Hypothyroidism may occur with a median onset of 2-3 months. Monitor thyroid function and treatment with hormone replacement therapy or medical management as needed.

• Other immune-mediated toxicities:

Nivolumab may cause other potentially fatal immune-mediated diseases even after discontinuation, such as facial/abducens nerve palsy, autoimmune neuropathy, duodenitis, gastritis, histiocytic necrotizing lymphadenitis, hypopituitarism, motor dysfunction, myasthenic disorder, and myocarditis.

It is important to rule out other possible causes and discontinue or withhold nivolumab based on the severity of symptoms.

Hormone replacement therapy may be needed. Once the corticosteroid taper is completed and symptoms have improved to grade 0 or 1, reinitiating nivolumab may be considered based on the severity and duration of the immune-mediated reaction.

• Autoimmune disorders:

A study evaluated the safety and effectiveness of anti-PD-1 monoclonal antibody treatment in melanoma patients with preexisting autoimmune conditions or significant ipilimumab-mediated adverse immune reactions.

The study found that although some immune reactions occurred, they were rare and manageable, and did not require discontinuation of permanent medication. Most patients responded well to the therapy, despite prior adverse events or baseline autoimmunity.

• Hematopoietic stem cells transplant:

Patients who received anti-PD-1 therapy before or after allogeneic hematopoietic cell transplantation (HSCT) may experience complications such as hyperacute, chronic, and acute graft versus host disease (GVHD), sinusoidal obstructive syndrome (SOS), and non-infectious febrile conditions.

Some of these complications can be fatal or serious. Therefore, it is important to closely monitor patients for signs and symptoms of transplant-related complications and provide prompt treatment when necessary. The benefits and risks of using an anti-PD-1 antibody before or after allogeneic HSCT should be carefully considered.

• Multiple myeloma:

The use of PD-1 blockers, including nivolumab, in multiple myeloma patients treated with thalidomide analogs and dexamethasone has been associated with increased mortality in randomized studies.

Therefore, the use of nivolumab in multiple myeloma patients is not approved, and combining nivolumab with dexamethasone and thalidomide analogs is not recommended for multiple myeloma treatment.

​​​​Nivolumab: Drug Interaction

Note: Drug Interaction Categories:

• Risk Factor C: Monitor When Using Combination
• Risk Factor D: Consider Treatment Modification
• Risk Factor X: Avoid Concomitant Use

​​​​​​​Monitoring parameters:

• Tests of liver and renal function (baseline, periodic), and thyroid function (baseline, periodically [eg. at treatment day 1, and every 6 weeks]).
• Blood glucose
• Before treatment begins, confirm pregnancy status in females with reproductive potential.
• Watch out for signs and symptoms of adrenal insufficiency.
• Monitor for infusion reactions.

How to administer Nivolumab (Opdivo)?

• Use an IV infusion for 30 minutes.
• Refer to the protocol below for information on infusion rates when using off-label dosing. 
• Use a non-pyrogenic, sterile, low-protein binding, 0.2-1.2 micrometer inline filter to infuse.
• You should not give other medications via the same IV line.
• Flush IV line at end of infusion
• Combination therapy with Ipilimumab
  • If administered with ipilimumab, administer nivolumab in the morning followed by ipilimumab at night.
  • Separate infusion bags and filters should be used for each infusion.
  • If nivolumab treatment is stopped, you should withhold Ipilimumab.

Mechanism of action of Nivolumab (Opdivo):

• Nivolumab, a monoclonal human immunoglobulin G4(IgG4) monoclonal anti-PD-1 antibody, selectively inhibits programmed cells death-1 (PD-1) activity by binding to PD-1 receptor. This binds to ligands PD-1L1 and PD-2.
• Therefore, the negative PD-1 receptor signaling which regulates T-cell activation/proliferation is disrupted.
• This includes the antitumor immune reaction and releases PD-1 pathway-mediated inhibition. Combining nivolumab, anti-PD-1, with ipilimumab, anti-CTLA-4 results in enhanced T-cell function.
• This leads to improved anti-tumor response in metastatic melanoma and advanced renal cell carcinoma.

Distribution:

• The predicted exposure after a 30-min infusion is comparable to that seen with a 60-min infusion.

Half-life elimination:

• ~25 days

International Brands of Nivolumab:

• Opdivo

Nivolumab Brand Names in Pakistan:

No Brands are Available in Pakistan.​​​​​​​