Nivolumab

Nivolumab is a prescription drug indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving nivolumab.

• Nivolumab is also indicated for the treatment of patients with advanced renal cell carcinoma, classical Hodgkin lymphoma, squamous cell carcinoma of the head and neck and urothelial carcinoma.
• Nivolumab is available under the following different brand names: Opdivo.

Intravenous solution

• 40 mg/4 ml (10 mg/ml)
• 100 mg/10 ml (10 mg/ml)
• Further dilution required before administration

Dosing Considerations – Should be Given as Follows:

Safety and efficacy have not been established for pediatric use. Adult dosages only:

Melanoma

• Single-agent
• Indicated as a single agent for BRAF V600 wild-type or BRAF V600 mutation-positive unresectable or metastatic melanoma
• 240 mg intravenous every 2 weeks infused over 1 hour
• Continue until disease progression or unacceptable toxicity
• Combination with ipilimumab
• Indicated in combination with ipilimumab for the treatment of patients with BRAF unresectable or metastatic melanoma
• 1 mg/kg intravenous infused over 1 hour, followed by ipilimumab (3 mg/kg intravenous infused over 90 min) administer on the same day every 3 weeks for 4 doses
• Subsequent doses of nivolumab as a single agent are 240 mg intravenous every 2 weeks infused over 1 hour until disease progression or unacceptable toxicity

Non-Small Cell Lung Cancer

• Indicated for metastatic non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy
• Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving nivolumab
• 240 mg intravenous every 2 weeks infused over 1 hour
• Continue until disease progression or unacceptable toxicity

Renal Cell Carcinoma

• Indicated for patients with advanced renal cell carcinoma (RCC) who have received prior anti-angiogenic therapy
• 240 mg intravenous every 2 weeks infused over 1 hour
• Continue until disease progression or unacceptable toxicity

Hodgkin Lymphoma

• Indicated for classical Hodgkin lymphoma (cHL) that has relapsed or progressed after autologous hematopoietic stem cell transplantation (HSCT) and post-transplantation brentuximab vedotin
• 3 mg/kg intravenous infused over 1 hour every 2 weeks until disease progression or unacceptable toxicity

Head and Neck Cancer

• Indicated for recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) with disease progression on or after a platinum-based therapy
• 3 mg/kg intravenously every 2 weeks infused over 1 hour
• Continue until disease progression or unacceptable toxicity

Urothelial Carcinoma

• Indicated for locally advanced or metastatic urothelial carcinoma in patients who have disease progression during or following platinum-containing chemotherapy, or who have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy
• 240 mg intravenously every 2 weeks infused over 1 hour
• Continue until disease progression or unacceptable toxicity

Dosage Modifications

• Infusion reactions: interrupt or slow infusion rate with mild or moderate reactions; discontinue if severe or life-threatening infusion reactions occur
• Hypothyroidism or hyperthyroidism: no recommended dose modifications
• Renal impairment: no dosage modifications are required
• Mild hepatic impairment: no dosage modifications required
• Moderate or severe hepatic impairment: not studied
• Note: When administered in combination with ipilimumab, if nivolumab is withheld, ipilimumab should also be withheld

Withhold for any of the following

• Grade 2 pneumonitis
• Grade 2 diarrhea or colitis
• Grade 3 diarrhea or colitis (single-agent nivolumab)
• Grade 2 or 3 hypophysitis
• Grade 2 adrenal insufficiency
• Grade 3 hyperglycemia
• Encephalitis, new-onset moderate or severe neurologic signs or symptoms
• Grade 3 rash or suspected Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN)
• AST or ALT over 3-5 times the upper limit of normal (ULN) or total bilirubin over 1.5-3 times ULN
• Serum creatinine over 1.5-6 times ULN or over 1.5 times baseline
• Any other severe or grade 3 treatment-related adverse reaction
• May resume treatment for patients whose adverse reactions recover to grade 0-1

Permanently discontinue for any of the following:

• Any life-threatening or grade 4 adverse reactions
• Grade 3 or 4 pneumonitis
• Grade 3 diarrhea or colitis (nivolumab in combination with ipilimumab)
• Grade 4 diarrhea or colitis
• Grade 4 hypophysitis
• Grade 3 or 4 adrenal insufficiency
• Grade 4 hyperglycemia
• Immune-mediated encephalitis
• Grade 4 rash or confirmed SJS or TEN
• AST or ALT over 5 times upper limit of normal (ULN) or total bilirubin over 3 times ULN
• Serum creatinine over 6 times ULN
• Any severe or grade 3 treatment-related adverse reaction that recurs
• Inability to reduce corticosteroid dose to up to 10 mg/day of prednisone or equivalent within 12 weeks
• Persistent grade 2 or 3 treatment-related adverse reactions that do not recover to grade 0-1 within 12 weeks after the last dose

Dosing Considerations

Melanoma

• Indications for melanoma (as a single agent for BRAF V600 mutation-positive or in combination with ipilimumab) were approved under accelerated approval based on tumor response rate and durability of response; continued approval may be contingent upon verification and description of clinical benefit in the confirmatory trials
• Information on FDA-approved tests for detection of PD-L1 expression in non-small-cell lung cancer (NSCLC) is available at: http://www.fda.gov/CompanionDiagnostics
• Classical Hodgkin lymphoma (cHL)
• Indication for cHL approved under accelerated approval based on overall response rate
• Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials

Urothelial carcinoma

• Indication for urothelial carcinoma was approved under accelerated approval based on tumor response rate and duration of response
• Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials

Pediatric:

• 2.5 mg-10 mg/kg/day orally or 20-300 mg/m2/day orally divided every 6-8 hours

Physiologic Replacement

Adult:

• 0.5-0.75 mg/kg/day orally divided every 8 hours or 25-35 mg/day
• 0.25-0.35 mg/kg intramuscularly each day

Pediatric:

• 0.5-0.75 mg/kg/day orally or 20-25 mg/sq.meter/day orally divided every 8 hours

Common Side effects of Nivolumab include:

• increased AST
• low blood sodium level
• increased alkaline phosphatase
• rash
• severe itching
• cough
• upper respiratory tract infection
• high blood potassium levels
• increased ALT
• abnormal heart rhythm
• inflammation of the iris of the eye
• fatigue
• low white blood cell count
• difficulty breathing
• musculoskeletal pain
• nausea
• anemia
• constipation
• increased creatinine
• increased lipase
• increased amylase
• high blood calcium level
• low blood magnesium level
• vomiting
• weakness
• diarrhea
• swelling
• fever
• abdominal pain
• increased thyroid-stimulating hormone
• low blood platelet count
• chest pain
• joint pain
• decreased appetite and weight
• pneumonia
• pain
• fatigue
• musculoskeletal pain
• cough
• reddening of the skin
• loss of skin pigmentation
• increased bilirubin
• headache/migraine
• redness and swelling of hands and feet
• low blood calcium level
• increased triglycerides
• increased cholesterol
• nasal congestion
• hypothyroidism/thyroiditis
• back pain
• bone pain
• musculoskeletal chest pain
• musculoskeletal discomfort
• muscle pain
• neck pain
• extremity pain
• acne
• scaling and peeling rash
• rash with small red bumps
• rash with the flat red area covered with small pumps
• excessive physical sensitivity of the skin
• loss of sensitivity of the skin
• burning and numbness in hands or feet
• abnormal sense of touch
• tumor-associated fever
• peripheral motor neuropathy
• peripheral sensory neuropathy
• burning and numbness on both sides of the body
• severe itching
• joint pain
• thyroid disorders
• low blood platelet count
• high blood sugar (hyperglycemia)
• inflamed mouth
• numbness in hands and feet
• bronchitis, upper respiratory tract infection
• infusion-related reactions
• immune disorders
• Guillain-Barre syndrome
• dizziness
• numbness and tingling in extremities
• erythema multiforme, loss of pigmentation, psoriasis

This document does not contain all possible side effects and others may occur. Check with your physician for additional information about side effects.

If your doctor has directed you to use this medication, your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor, health care provider, or pharmacist first.

• Nivolumab has no known severe interactions with other drugs.
• Nivolumab has no known serious interactions with other drugs.
• Nivolumab has no known moderate interactions with other drugs.
• Nivolumab has no known mild interactions with other drugs.

This information does not contain all possible interactions or adverse effects. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share this information with your doctor and pharmacist. Check with your health care professional or doctor for additional medical advice, or if you have health questions, concerns, or for more information about this medicine.

Warnings

• This medication contains nivolumab. Do not take it if you are allergic to nivolumab or any ingredients contained in this drug.
• Keep out of reach of children
• In case of overdose, get medical help or contact a Poison Control Center immediately

Contraindications

• Documented hypersensitivity
• Systemic fungal infection

Effects of Drug Abuse

• No information available

Short-Term Effects

• See "What Are Side Effects Associated with Using Nivolumab?"

Long-Term Effects

• Risk of osteoporosis, myopathy, delayed wound healing
• See "What Are Side Effects Associated with Using Nivolumab?"

Cautions

• Short-acting agent
• Cirrhosis, ocular herpes simplex, high blood pressure (hypertension), diverticulitis, hypothyroidism, myasthenia gravis, peptic ulcer disease, osteoporosis, ulcerative colitis, psychotic tendencies, untreated systemic infections, renal insufficiency, and pregnancy
• Hydroxylated to active compound hydronivolumab
• When used to treat adrenocortical insufficiency may need to use additional mineralocorticoid
• Not indicated for intravenous use
• Diabetes mellitus, thromboembolic disorders
• Long-term treatment: Risk of osteoporosis, myopathy, delayed wound healing
• Patients receiving corticosteroids should avoid chickenpox or measles-infected persons if unvaccinated
• Latent tuberculosis may be reactivated
• Monitor patients with positive tuberculin test
• Some suggestions of slightly increase cleft palate risk if corticosteroids are used in pregnancy, but not fully substantiated

Pregnancy and Lactation

• Based on its mechanism of action and data from animal studies, nivolumab can cause fetal harm during pregnancy when administered to a pregnant woman
• Advise females of reproductive potential to use effective contraception during treatment and for at least 5 months following the last dose
• In animal reproduction studies, administration to cynomolgus monkeys from the onset of organogenesis through delivery resulted in increased abortion and premature infant death
• Human IgG4 is known to cross the placental barrier and nivolumab is an IgG4
• Therefore, nivolumab has the potential to be transmitted from the mother to the developing fetus
• The effects of nivolumab are likely to be greater during the second and third trimesters of pregnancy
• There are no available human data informing the drug-associated risk
• It is unknown if nivolumab is distributed in human breast milk; it is advised to discontinue breastfeeding during treatment