Nivolumab

>10% (All grades)

Melanoma

• Increased AST (28%)
• Hyponatremia (25%)
• Increased alkaline phosphatase (22%)
• Rash (21%)
• Pruritus (19%)
• Cough (17%)
• Increased ALT (16%)
• Hyperkalemia (15%)
• URTI (11%)

NSCLC

• Fatigue (50%)
• Lymphopenia (47%)
• Dyspnea, hyponatremia (38%)
• Musculoskeletal pain (36%)
• Cough (32%)
• Nausea (29%), anemia (28%), constipation (24%)
• Increases creatinine (22%)
• Hypercalcemia, hypokalemia, hypomagnesemia (20%)
• Vomiting, asthenia (19%)
• Hypocalcemia, hyperkalemia, diarrhea (18%)
• Edema, pyrexia (17%)
• Abdominal pain, rash, increased AST (16%)
• Increased alkaline phosphatase, thrombocytopenia (14%)
• Chest pain, arthralgia, decreased appetite and weight (13%)
• Increased ALT (12%), pruritus (11%)

1-10% (all grades)

Melanoma

• Peripheral edema (10%)

NSCLC

• Pneumonia (10%)
• Pain (10%)

1-10% (grades 3-4)

Melanoma

• Hyponatremia (5%)
• Increased AST (2.4%)
• Increased alkaline phosphatase (2.4%)
• Hyperkalemia (2%)
• Increased ALT (1.6%)

NSCLC

• Dyspnea (9%)
• Fatigue (7%)
• Musculoskeletal pain (6%)
• Pneumonia (5%)
• Decreased appetite (2.6%)
• Pain (2.6%)
• Nausea (1.7%)
• Abdominal pain (1.7%)
• Asthenia (1.7%)
• Edema (1.7%)
• Cough (1.7%)

1-10% (other clinically important adverse effects)

Melanoma

• Cardiac disorders: Ventricular arrhythmia
• Eye disorders: Iridocyclitis
• General disorders and administration site conditions: Infusion-related reactions
• Immune-mediated disorders: Severe pneumonitis or interstitial lung disease, including fatal cases; colitis; hepatitis; nephritis; thyroid disorders; other immune disorders (pancreatitis, uveitis, demyelination, autoimmune neuropathy, adrenal insufficiency, facial and abducens nerve paresis, hypophysitis, polymyalgia rheumatica, diabetic ketoacidosis, hypopituitarism, Guillain-Barré syndrome, myasthenic syndrome)
• Investigations: Increased amylase, increased lipase
• Nervous system disorders: Dizziness, peripheral and sensory neuropathy
• Skin and subcutaneous tissue disorders: Exfoliative dermatitis, erythema multiforme, vitiligo, psoriasis

NSCLC

• General disorders and administration site conditions: Stomatitis
• Nervous system disorders: Peripheral neuropathy
• Infections and infestations: Bronchitis, upper respiratory tract infection

IV Preparation

Visually inspect drug for particulate matter and discoloration; it should be a clear to opalescent, colorless to pale-yellow solution

Discard vial if the solution is cloudy, discolored, or contains extraneous particulate matter other than a few translucent-to-white, proteinaceous particles

Do not shake the vial

Admixture

• Withdraw required volume for calculated dose and transfer to an IV container
• Dilute with either 0.9% NaCl or D5W to a final concentration ranging from 1-10 mg/mL
• Mix diluted solution by gentle inversion; do NOT shake
• Discard partially used vials or empty vials

IV Administration

Infuse IV over 1 hr

Infuse IV over 1 hr in an IV line containing a sterile, nonpyrogenic, low protein-binding inline filter (pore size of 0.2-1.2 microns)

Do not coadminister other drugs through the same IV line

When administered in combination with ipilimumab, infuse nivolumab first followed by ipilimumab on the same day; use separate infusion bags and filters for each infusion

Flush the IV line at end of infusion

Storage

Does not contain preservatives

Unopened vials

• Refrigerate at 2-8°C (36-46°F)
• Protect from light by storing in the original package
• Do not freeze

Diluted admixture

• Room temperature: 8 hr from time of preparation; this includes room temperature storage of the admixture in the IV container and time for administration of the infusion OR
• Refrigerate at 2-8°C (36-46°F) for no more than 24 hr from the time of admixture preparation
• Do not freeze

Nivolumab is a cancer medicine that works with your immune system to interfere with the growth and spread of cancer cells in the body.

Nivolumab is used to treat a certain type of melanoma (skin cancer) that cannot be treated with surgery, or that has spread to other parts of the body. Nivolumab was approved by the US Food and Drug Administration (FDA) on an "accelerated" basis. In clinical studies, nivolumab produced complete or partial response. However, further studies are needed to determine if this medicine can lengthen survival time in people with melanoma.

Nivolumab is also used to treat a certain type of non-small cell lung cancer. Nivolumab may increase the chance of a longer survival time in people with this type of lung cancer.

Nivolumab is used for melanoma or lung cancer only if your tumor has a specific genetic marker that your doctor will test for.

Nivolumab is also used to treat advanced kidney cancer that has not responded to other cancer medicines.

Nivolumab is given alone or in combination with other cancer medicines. Nivolumab is sometimes given after other medicines have been tried without success.

Nivolumab may also be used for purposes not listed in this medication guide.

Nivolumab can cause side effects that may cause symptoms in many different parts of your body. Some side effects may need to be treated with other medicine, and your cancer treatments may be delayed. You will need frequent medical tests to help your doctor determine if it is safe for you to keep receiving nivolumab.

You should not use nivolumab if you are allergic to it.

To make sure nivolumab is safe for you, tell your doctor if you have:

• lung disease;
• liver disease;
• kidney disease;
• a thyroid disorder;
• an autoimmune disorder such as lupus, Crohn's disease, or ulcerative colitis; or
• if you have received an organ transplant.

Do not use nivolumab if you are pregnant. It could harm the unborn baby. Use effective birth control to prevent pregnancy while you are using this medicine and for at least 5 months after your treatment ends.

It is not known whether nivolumab passes into breast milk or if it could harm a nursing baby. You should not breast-feed while using this medicine.

Get emergency medical help if you have signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Some side effects may occur during the injection. Tell your caregiver right away if you feel dizzy, light-headed, itchy, tingly, chilled, or feverish.

Call your doctor at once if you have:

• new or worsening cough;
• sudden chest pain or discomfort, wheezing, feeling short of breath;
• severe or ongoing diarrhea, severe stomach pain, bloody or tarry stools;
• new or worsening skin rash;
• severe muscle weakness, ongoing pain in your muscles or joints;
• symptoms of brain swelling--confusion, headache, memory problems, hallucinations, neck stiffness, drowsiness, seizure (convulsions);
• kidney problems--little or no urinating; blood in your urine; swelling in your feet or ankles;
• liver problems--nausea, upper stomach pain, itching, tiredness, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes); or
• signs of a hormonal disorder--frequent or unusual headaches, vision problems, feeling light-headed or very tired, rapid heartbeats, mood or behavior changes, hoarse or deepened voice, increased hunger or thirst, increased urination, constipation, hair loss, sweating, feeling cold, weight gain, or weight loss.

Your cancer treatments may be delayed or permanently discontinued if you have certain side effects.

Common side effects may include:

• nausea, vomiting, loss of appetite;
• diarrhea, constipation, stomach cramps;
• feeling tired or short of breath;
• body aches;
• cough;
• skin rash, itching; or
• headache.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Nivolumab is a prescription medication used to treat patients with:

• unresectable (cannot be removed by surgery) or metastatic melanoma who no longer respond to other drugs.
• advanced (metastatic) squamous non-small cell lung cancer (NSCLC) with progression after previous treatment with platinum-based chemotherapy.
• advanced (metastatic) renal (kidney) cancer
• with BRAF V600 wild-type and BRAF V600 mutation-positive unresectable or advanced (metastatic) skin cancer (melanoma) in combination with Yervoy (ipilimumab)
• untreated BRAF mutation-positive advanced (metastatic) skin cancer (melanoma)
• Hodgkin lymphoma that has returned or has worsened despite receiving a bone marrow transplant and Adcetris (brentuximab vedotin) after the transplant
• recurrent or advanced (metastatic) cancer of the head and neck (progression after platinum-based therapy)
• locally advanced or metastatic urinary system cancer (bladder cancer) who have disease progression during or following platinum-containing chemotherapy or have disease progression within 12 months of neoadjuvant or adjuvant treatment with a platinum-containing chemotherapy.
• adults and children 12 years of age and older with a type of colon or rectal cancer (colorectal cancer). Opdivo may be used to treat when the colon cancer or rectal cancer:
  • has spread to other parts of the body (metastatic),
  • has progressed after treatment with a fluoropyrimidine, oxaliplatin, and irinotecan, and
  • is mismatch repair deficient (dMMR) or microsatellite instability-high (MSI-H)

This medication may be prescribed for other uses. Ask your doctor or pharmacist for more information.

Common side effects of nivolumab include rash, itching, cough, upper respiratory tract infections, and fluid retention.

No drug interactions have been studied by the manufacturer. However, you should tell your doctor about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements. Not all drug interactions are known or reported and new drug interactions are continually being reported.

Tell your doctor if you are breastfeeding or plan to breastfeed.

It is not known if nivolumab crosses into human milk. Because many medications can cross into human milk and because of the possibility for serious adverse reactions in nursing infants with the use of this medication, it is advised for women to stop breastfeeding during treatment with nivolumab.

Storage

Parenteral

2–8°C.1 Do not freeze; protect from light.1 Discard unused solution after initial entry into vial.1

Diluted solution may be stored at room temperature for up to 4 hours after dilution (including infusion time) or 2–8°C for up to 24 hours after dilution.1 Do not freeze.1

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

(nye VOL ue mab)

Colorectal cancer, metastatic (microsatellite instability-high or mismatch repair deficient): Treatment of microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (CRC) in adults and pediatric patients 12 years and older that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.

Head and neck cancer, squamous cell (recurrent or metastatic): Treatment of recurrent or metastatic squamous cell carcinoma of the head and neck in patients with disease progression on or after platinum-based therapy.

Hodgkin lymphoma, classical: Treatment of classical Hodgkin lymphoma (cHL) in adult patients that have relapsed or progressed following autologous hematopoietic stem cell transplant (HSCT) and brentuximab vedotin, or 3 or more lines of systemic therapy that includes autologous HSCT.

Melanoma, unresectable or metastatic: Treatment (as a single agent) of BRAF V600 wild-type or BRAF V600 mutation-positive unresectable or metastatic melanoma; treatment of unresectable or metastatic melanoma (in combination with ipilimumab)

Non-small cell lung cancer, metastatic, progressive: Treatment of metastatic non-small cell lung cancer (NSCLC) that has progressed on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression (on approved EGFR- or ALK-directed therapy) prior to receiving nivolumab.

Renal cell cancer, advanced: Treatment of advanced renal cell cancer in patients who have received prior anti-angiogenic therapy.

Urothelial carcinoma, locally advanced or metastatic: Treatment of locally advanced or metastatic urothelial carcinoma in patients with disease progression during or following a platinum-containing therapy or disease progression within 12 months of neoadjuvant or adjuvant treatment with a platinum-containing therapy.

Colorectal cancer, metastatic (microsatellite instability-high or mismatch repair deficient): Children ≥12 years and Adolescents: IV: 240 mg (flat dose) once every 2 weeks until disease progression or unacceptable toxicity

Hepatic impairment prior to treatment initiation:

Mild impairment (total bilirubin ≤ ULN and AST > ULN or total bilirubin <1 to 1.5 times ULN and any AST): No dosage adjustment necessary.

Moderate (total bilirubin >1.5 to 3 times ULN and any AST) to severe (total bilirubin >3 times ULN and any AST) impairment: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).

Hepatotoxicity during treatment:

AST or ALT >3 to 5 times ULN or total bilirubin >1.5 to 3 times ULN: Withhold treatment; may resume therapy upon recovery to grade 0 or 1 toxicity.

AST or ALT >5 times ULN or total bilirubin >3 times ULN: Permanently discontinue.

Immune-mediated hepatitis:

Grade 2 transaminase elevations (with or without total bilirubin elevations): Withhold treatment and initiate high-dose systemic corticosteroids (prednisone 0.5 to 1 mg/kg daily or equivalent)

Severe (grade 3) or life-threatening (grade 4) transaminase elevations (with or without bilirubin elevations): Permanently discontinue treatment and initiate high-dose systemic corticosteroids (prednisone 1 to 2 mg/kg daily or equivalent)

Withhold treatment for any of the following (may resume upon recovery to grade 0 or 1 toxicity):

Note: If receiving combination therapy with ipilimumab, when nivolumab is withheld, ipilimumab should also be withheld.

Adrenal insufficiency (grade 2)

Colitis:

Grade 2 colitis or diarrhea; for grade 2 colitis with a duration >5 days; also administer systemic corticosteroids (prednisone 0.5 to 1 mg/kg daily or equivalent) followed by a corticosteroid taper; may increase to prednisone 1 to 2 mg/kg daily (or equivalent) if colitis worsens or does not improve despite corticosteroid use

Grade 3 colitis or diarrhea (single-agent nivolumab); also administer systemic corticosteroids (prednisone 1 to 2 mg/kg daily or equivalent) followed by a corticosteroid taper

Diabetes mellitus, type 1 (grade 3 hyperglycemia)

Encephalitis (new onset moderate or severe neurologic toxicity)

Hypophysitis (grade 2 or 3); also administer high-dose systemic corticosteroids (prednisone 1 mg/kg daily or equivalent)

Pneumonitis (grade 2); also administer high-dose systemic corticosteroids (prednisone 1 to 2 mg/kg daily or equivalent) followed by a corticosteroid taper

Rash (grade 3), suspected Stevens-Johnson syndrome or toxic epidermal necrolysis; also administer high-dose systemic corticosteroids (prednisone 1 to 2 mg/kg daily or equivalent)

Other immune-mediated toxicities; also administer high-dose systemic corticosteroids followed by a corticosteroid taper (over 1 month)

Other treatment-related toxicity (severe or grade 3, first occurrence)

Permanently discontinue for:

Adrenal insufficiency (grade 3 or 4); also administer high-dose systemic corticosteroids (prednisone 1 to 2 mg/kg daily or equivalent)

Colitis or diarrhea (grade 3, if in combination with ipilimumab) or colitis or diarrhea (grade 4); also administer high-dose systemic corticosteroids (prednisone 1 to 2 mg/kg daily or equivalent) followed by a corticosteroid taper

Colitis (recurrent)

Diabetes mellitus, type 1 (grade 4 hyperglycemia)

Encephalitis (immune mediated); also administer high-dose systemic corticosteroids (prednisone 1 to 2 mg/kg daily or equivalent) followed by a corticosteroid taper

Hypophysitis (grade 4); also administer high-dose systemic corticosteroids (prednisone 1 mg/kg daily or equivalent)

Pneumonitis (grade 3 or 4); also administer high-dose systemic corticosteroids (prednisone 1 to 2 mg/kg daily or equivalent) followed by a corticosteroid taper

Rash (grade 4), or confirmed Stevens-Johnson syndrome or toxic epidermal necrolysis; also administer high-dose systemic corticosteroids (prednisone 1 to 2 mg/kg daily or equivalent)

Any toxicity requiring corticosteroid dose of prednisone ≥10 mg/day (or equivalent) for longer than 12 weeks.

Other adverse reactions that are life-threatening or grade 4, severe or grade 3 adverse reactions that recur, or persistent grade 2 or 3 treatment-related toxicity lasts beyond 12 weeks.

Infusion-related reaction:

Mild or moderate reaction: Interrupt or slow the infusion rate

Severe or life-threatening reaction: Discontinue

Thyroid disorder (hyperthyroidism or hypothyroidism):

There are no recommended dosage modifications. Initiate antithyroid therapy for hyperthyroidism; administer thyroid hormone replacement therapy for hypothyroidism.

3 mg/kg IV over 60 minutes every 2 weeks
Duration of therapy: Continue therapy until disease progression or unacceptable toxicity occurs.

Use: For the treatment of patients with classical Hodgkin lymphoma (cHL) that has relapsed or progressed after autologous hematopoietic stem cell transplantation (HSCT) and post-transplantation brentuximab vedotin

Safety and efficacy have not been established in patients younger than 18 years.

Consult WARNINGS section for additional precautions.

Administration Advice:
-Administer IV over 60 minutes.
-Use sterile, non-pyrogenic, low protein binding in-line filter with a 0.2 to 1.2 micrometer pore.
-Flush IV line after infusion.
-When this drug is administered in combination with ipilimumab, infuse this drug first followed by ipilimumab on the same day. Use separate infusion bags and filters for each infusion.
-When this drug is administered in combination with ipilimumab, if this drug is withheld, ipilimumab should also be withheld.

Reconstitution/preparation techniques:
-Dilute the drug with either normal saline or 5% dextrose to a concentration of 1 to 10 mg/mL.
-Invert to mix; do not shake.

Storage requirements:
-Refrigerate; protect from light; store in original package until use.
-After preparation, keep at room temperature for no more than 4 hours or in the refrigerator for no more than 24 hours, include infusion time.
-Do not freeze.

IV compatibility:
-Do not coadminister other drugs through the same line.

Monitoring:
-Hepatic: Liver function tests prior to initiating therapy and periodically thereafter
-Renal: Serum creatinine prior to initiating therapy and periodically thereafter
-Endocrine: Thyroid function prior to initiating therapy and periodically thereafter

Patient Education:
-Inform patients about the risk of immune-mediated reactions that may occur and lead to disruption or discontinuation of therapy and corticosteroid treatment.
-Advise females of reproductive age to use effective contraception during treatment and for at least 5 months after the last dose.
-Advise women against breastfeeding while taking this drug.
-Inform patients about the importance of having regular blood work and lab tests done while taking this drug.