Nivolumab-Hyaluronidase

Nivolumab-Hyaluronidase is a combination medication used for the treatment of:

• Renal cell carcinoma (RCC)
• Melanoma
• Non-small cell lung cancer (NSCLC)
• Squamous Cell Carcinoma of Head & Neck Carcinoma (SCCHN)
• Urothelial carcinoma
• Colorectal cancer (CRC)
• Hepatocellular carcinoma (HCC)
• Esophageal cancer
• Gastric cancer, gastroesophageal junction (GEJ) cancer, and esophageal adenocarcinoma

Nivolumab-Hyaluronidase is available under the following different brand names: Opdivo Qvantig, Nivolumab-Hyaluronidase-nvhy

Common side effects of Nivolumab-Hyaluronidase include:

• pain in muscles, bones, and joints 
• low thyroid hormone levels
• feeling tired 
• itchy skin 
• cough
• rash 
• abdominal pain
• numbness, pain, tingling, or burning in the hands and feet 
• mouth sores 
• weakness  
• upper respiratory tract infection
• fever
• headache
• vomiting
• urinary tract infection
• rash  
• cough
• shortness of breath
• itchy skin 
• constipation
• diarrhea 
• decreased appetite
• nausea 
• back pain
• redness, pain, swelling, or blisters on the palms of your hands or soles of the feet

Serious side effects of Nivolumab-Hyaluronidase include:

• lung problems such as new or worsening cough, shortness of breath, chest pain
• intestinal problems such as diarrhea (loose stools) or more bowel movements than usual, stools that are black, tarry, sticky, or have blood or mucus, and severe stomach-area (abdomen) pain or tenderness
• liver problems such as yellowing of the skin or the whites of your eyes, dark urine (tea-colored), severe nausea or vomiting, bleeding or bruising more easily than normal, and pain on the right side of the stomach area (abdomen)
• hormone gland problems such as headaches that will not go away or unusual headaches, urinating more often than usual, hair loss, eye sensitivity to light, eye problems, rapid heartbeat, increased sweating, extreme tiredness, weight gain or weight loss, feeling cold, constipation, voice gets deeper, dizziness or fainting, changes in mood or behavior, such as decreased, sex drive, irritability, or forgetfulness, feeling more hungry or thirsty than usual
• kidney problems such as a decrease in the amount of urine, swelling in your ankles, and blood in your urine loss of appetite
• skin problems such as rash, itching, skin blistering or peeling, painful sores or ulcers in the mouth or the nose, throat, or genital area, fever or flu-like symptoms, and swollen lymph nodes
• immune system problem symptoms such as chest pain, irregular heartbeat, shortness of breath or swelling of ankles, confusion, sleepiness, memory problems, changes in mood or behavior, stiff neck, balance problems, tingling or numbness of the arms or legs, double vision, blurry vision, sensitivity to light, eye pain, changes in eyesight, persistent or severe muscle pain or weakness, muscle cramps, low red blood cells, bruising
• rejection of a transplanted organ or tissue
• graft-versus-host-disease

Rare side effects of Nivolumab-Hyaluronidase include:

• none 

Seek medical care or call 911 at once if you have the following serious side effects:

• Severe headache, confusion, slurred speech, arm or leg weakness, trouble walking, coordination loss, unsteady, very stiff muscles, high fever, profuse sweating, or tremors.
• Serious eye symptoms such as sudden vision loss, blurred vision, tunnel vision, eye pain or swelling, or seeing halos around lights.
• Serious heart symptoms include fast, irregular, or pounding heartbeats; fluttering in the chest; shortness of breath; sudden dizziness, lightheadedness, or passing out.

This is not a complete list of side effects and other serious side effects or health problems that may occur because of the use of this drug. Call your doctor for medical advice about serious side effects or adverse reactions. You may report side effects or health problems to FDA at 1-800-FDA-1088.

Adult dosage

Solution for SC injection

• 5-mL single-dose vial: 600 mg/10,000 units (120 mg/2000 units per mL)

RCC

Adult dosage

• Single-agent therapy after prior treatment
  • Limitation of use: Not indicated in combination with ipilimumab for RCC
  • Also indicated for the treatment of advanced RCC in adults who have received prior antiangiogenic therapy
  • 600 mg nivolumab/10,000 units hyaluronidase SC every 2 weeks, or
  • 1200 mg nivolumab/20,000 units hyaluronidase SC every 4 weeks
  • Continue until disease progression or unacceptable toxicity
• First-line therapy with cabozantinib
  • 600 mg nivolumab/10,000 units hyaluronidase SC every 2 weeks, or
  • 1200 mg nivolumab/20,000 units hyaluronidase SC every 4 weeks
  • Continue until disease progression, unacceptable toxicity, or up to 2 years plus
  • Cabometyx (cabozantinib) 40 mg orally daily until disease progression or unacceptable toxicity

Melanoma

Adult dosage

Unresectable or metastatic melanoma

• Limitation of use: Not indicated in combination with ipilimumab for unresectable or metastatic melanoma
• 600 mg nivolumab/10,000 units hyaluronidase SC every 2 weeks, or
• 1200 mg nivolumab/20,000 units hyaluronidase SC every 4 weeks
• Continue until disease progression or unacceptable toxicity

Adjuvant therapy

• 600 mg nivolumab/10,000 units hyaluronidase SC every 2 weeks, OR
• 1200 mg nivolumab/20,000 units hyaluronidase SC every 4 weeks
• Continue until disease recurrence or unacceptable toxicity for up to 1 year

NSCLC

Adult dosage

Neoadjuvant therapy with platinum-doublet chemotherapy

• 900 mg nivolumab/15,000 units hyaluronidase SC every 3 weeks for 3 cycles plus
• Platinum-doublet chemotherapy (on the same day) every 3 weeks
• Neoadjuvant and adjuvant therapy with platinum-doublet chemotherapy
• Neoadjuvant therapy
  • 900 mg nivolumab/15,000 units hyaluronidase SC every 3 weeks until disease progression or unacceptable toxicity for up to 4 cycles plus
  • Platinum-doublet chemotherapy (on the same day) every 3 weeks
• Adjuvant therapy
  • 1200 mg nivolumab/20,000 units hyaluronidase SC every 4 weeks as monotherapy following neoadjuvant therapy and surgery
  • Continue until disease progression, recurrence, or unacceptable toxicity for up to 13 cycles (up to 1 year)

Metastatic NSCLC

• Limitation of use: Not indicated in combination with ipilimumab for metastatic NSCLC
• 600 mg nivolumab/10,000 units hyaluronidase SC every 2 weeks, or
• 1200 mg nivolumab/20,000 units hyaluronidase SC every 4 weeks
• Continue until disease progression or unacceptable toxicity

SCCHN

Adult dosage

• 600 mg nivolumab/10,000 units hyaluronidase SC every 2 weeks, or
• 1200 mg nivolumab/20,000 units hyaluronidase SC every 4 weeks
• Continue until disease progression or unacceptable toxicity

Urothelial Carcinoma

Adult dosage

• Adjuvant therapy
• 600 mg nivolumab/10,000 units hyaluronidase SC every 2 weeks, OR
• 1200 mg nivolumab/20,000 units hyaluronidase SC every 4 weeks
• Continue until disease recurrence or unacceptable toxicity for up to 1 year
• Locally advanced/unresectable or metastatic urothelial carcinoma
• First-line therapy with cisplatin and gemcitabine
  • 900 mg nivolumab/15,000 units hyaluronidase SC every 3 weeks for up to 6 cycles plus cisplatin and gemcitabine (on same day) every 3 weeks
  • Single-agent therapy: 600 mg nivolumab/10,000 units hyaluronidase SC every 2 weeks or 1200 mg nivolumab/20,000 units hyaluronidase SC every 4 weeks following 6 cycles of combination therapy with cisplatin and gemcitabine; continue until disease progression, unacceptable toxicity, or up to 2 years from the first dose
• Single-agent therapy following disease progression
  • 600 mg nivolumab/10,000 units hyaluronidase SC every 2 weeks, or
  • 1200 mg nivolumab/20,000 units hyaluronidase SC every 4 weeks
  • Continue until disease progression or unacceptable toxicity

CRC

Adult dosage

Limitation of use: Not indicated in combination with ipilimumab for microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic CRC

• 600 mg nivolumab/10,000 units hyaluronidase SC every 2 weeks, or
• 1200 mg nivolumab/20,000 units hyaluronidase SC every 4 weeks
• Continue until disease progression or unacceptable toxicity

HCC

Adult dosage

Limitation of use: Not indicated in combination with ipilimumab for HCC

• 600 mg nivolumab/10,000 units hyaluronidase SC every 2 weeks, or
• 1200 mg nivolumab/20,000 units hyaluronidase SC every 4 weeks
• Continue until disease progression or unacceptable toxicity

Esophageal Cancer

Adult dosage

Adjuvant therapy

• 600 mg nivolumab/10,000 units hyaluronidase SC every 2 weeks, or
• 1200 mg nivolumab/20,000 units hyaluronidase SC every 4 weeks
• Continue until disease recurrence or unacceptable toxicity for up to 1 year

ESCC

Adult dosage

Single-agent therapy after prior treatment

• 600 mg nivolumab/10,000 units hyaluronidase SC every 2 weeks, OR
• 1200 mg nivolumab/20,000 units hyaluronidase SC every 4 weeks
• Continue until disease progression or unacceptable toxicity

First-line therapy with fluoropyrimidine- and platinum-containing chemotherapy

• Limitation of use: Not indicated in combination with ipilimumab for unresectable advanced or metastatic ESCC
• 600 mg nivolumab/10,000 units hyaluronidase SC every 2 weeks, OR
• 1200 mg nivolumab/20,000 units hyaluronidase SC every 4 weeks
• Continue until disease progression, unacceptable toxicity, or up to 2 years PLUS
• Fluoropyrimidine- and platinum-containing chemotherapy until disease progression or unacceptable toxicity

Gastric Cancer, GEJ Cancer, and Esophageal Adenocarcinoma

Adult dosage

• 600 mg nivolumab/10,000 units hyaluronidase SC plus fluoropyrimidine-and platinum-containing chemotherapy every 2 weeks, or
• 900 mg nivolumab/15,000 units hyaluronidase SC plus fluoropyrimidine-and platinum-containing chemotherapy every 3 weeks
• Continue Nivolumab-Hyaluronidase until disease progression, unacceptable toxicity, or up to 2 years
• Continue chemotherapy until disease progression or unacceptable toxicity

Dosage Considerations – Should be Given as Follows: 

• See “Dosages”

If your medical doctor is using this medicine to treat your pain, 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-Hyaluronidase has no noted severe interactions with any other drugs
• Nivolumab-Hyaluronidase has no noted serious interactions with any other drugs
• Nivolumab-Hyaluronidase has no noted moderate interactions with any other drugs
• Nivolumab-Hyaluronidase has no noted minor interactions with any other drugs

This information does not contain all possible interactions or adverse effects. Visit the RxList Drug Interaction Checker for any drug interactions. Therefore, before using this product, tell your doctor or pharmacist about 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 healthcare professional or doctor for additional medical advice, health questions, or concerns.

Contraindications

• None

Effects of drug abuse

• None

Short-Term Effects

• See “What Are Side Effects Associated with Using Nivolumab-Hyaluronidase?”

Long-Term Effects

• See “What Are Side Effects Associated with Using Nivolumab-Hyaluronidase?”

Cautions

• Immune-mediated adverse reactions
  • Severe and fatal immune-mediated reactions reported
  • Can occur in any organ system or tissue at any time after starting therapy, including after therapy discontinuation
  • Monitor for symptoms and signs of clinical manifestations of underlying immune-mediated adverse reactions
  • For suspected reactions, initiate appropriate workup to exclude alternative etiologies (.eg, infection)
  • Institute medical management promptly; consult specialists as appropriate or permanently discontinue depending on the severity
  • Administer systemic corticosteroids (.eg, prednisone 1-2 mg/kg/day or equivalent) until improvement to Grade less than1, then taper corticosteroids over at least 1 month
  • Other systemic immunosuppressants may be required if reactions are not controlled with corticosteroids
• Pneumonitis
  • Immune-mediated pneumonitis can occur
  • Incidence of pneumonitis is higher following prior thoracic radiation
• Colitis
  • Immune-mediated colitis can occur
  • Cytomegalovirus (CMV) infection/reactivation reported with corticosteroid-refractory immune-mediated colitis
  • For corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies
• Hepatitis and hepatotoxicity
  • Immune-mediated hepatitis can occur
  • Evaluate liver function tests before initiation and periodically during therapy incidence of hepatotoxicity is higher with nivolumab IV and cabozantinib combination therapy compared with nivolumab alone
  • Consider more frequent LFT monitoring for Nivolumab-Hyaluronidase and cabozantinib combination therapy
• Endocrinopathies
  • Immune-mediated adrenal insufficiency, hypophysitis, thyroiditis, hyperthyroidism, and hypothyroidism reported
  • Initiate symptomatic treatment (.eg, hormone replacement, anti-thyroid agent) as clinically indicated
  • Evaluate thyroid function before initiation and periodically during therapy
• Type 1 diabetes mellitus
  • Immune-mediated type 1 diabetes mellitus may occur; may present with diabetic ketoacidosis
  • Monitor for hyperglycemia or other signs and symptoms of diabetes
  • Initiate treatment with insulin as clinically indicated
• Nephritis
  • Immune-mediated nephritis with renal dysfunction can occur
  • Evaluate renal function before initiation and periodically during therapy
• Dermatologic reactions
  • Immune-mediated rash or dermatitis can occur
  • Exfoliative dermatitis reactions may include Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), or Drug Rash with Eosinophilia and Systemic Symptoms (DRESS).
  • Treat mild-to-moderate non-exfoliative rashes with topical emollients and/or topical corticosteroids
• Complications of allogeneic hematopoietic stem cell transplantation (HSCT)
  • Fatal and other serious complications can occur in patients who receive allogeneic HSCT before or after being treated with a PD-1-blocking antibody
  • Transplant-related complications include hyperacute graft-versus-host-disease (GVHD), acute GVHD, chronic GVHD, hepatic veno-occlusive disease (VOD) after reduced-intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause)
  • These complications may occur despite intervening therapy between PD-1 blockade and allogeneic HSCT
  • Follow patients closely for evidence of transplant-related complications and intervene promptly; consider benefits versus risks of treatment with a PD-1 blocking antibody before or after an allogeneic HSCT
• Combination therapy with a thalidomide analog and dexamethasone
  • Nivolumab is not recommended in combination with a thalidomide analog and dexamethasone
  • Increased mortality was reported in patients with multiple myeloma who received nivolumab IV in combination with a thalidomide analog and dexamethasone
• Embryo-fetal toxicity
  • Fetal harm may occur if used during pregnancy
  • Advise pregnant patients of potential risk to the fetus
  • Effective contraception is recommended during and after therapy in females of reproductive potential

Pregnancy and Lactation

May cause fetal harm when administered during pregnancy, based on its mechanism of action and data from animal studies

Fetal exposure may increase the risk of developing immune-mediated disorders or altering the normal immune response

No available human data informing drug-associated risk

Advise pregnant patients of potential risk to the fetus

Contraception

• Females of reproductive potential
• Verify pregnancy status before initiating therapy
• Recommend use of effective contraception during therapy and for 5 months after the last dose

Lactation

• No data available on the presence of nivolumab or hyaluronidase in human milk, effects on breastfed children, or on milk production. 
• Due to potential for adverse reactions in breastfed children, advise patients to avoid breastfeeding during therapy and for 5 months after the last dose