Nivolumab and hyaluronidase (human recombinant)
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Endoglycosidase, Programmed Death Receptor-1 Blocking Antibody
Dosing in kidney impairment
Immune-Mediated Adverse Reactions : o Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, including the following: immune-mediated pneumonitis, immune-mediated colitis, immune-mediated hepatitis and hepatotoxicity, immune-mediated endocrinopathies, immune-mediated dermatologic adverse reactions, and immune-mediated nephritis and renal dysfunction. o Monitor for early identification and management.
Immune-Mediated Endocrinopathies Adrenal Insufficiency OPDIVO QVANTIG can cause primary or secondary adrenal insufficiency. For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold OPDIVO QVANTIG depending on severity [see Dosage and Administration ] .
Adrenal insufficiency occurred in 2% (5/247) of patients receiving OPDIVO QVANTIG, including Grade 3 (0.8%) and Grade 2 (1.2%) adverse reactions. Adrenal insufficiency led to permanent discontinuation of OPDIVO QVANTIG in 0.4% of patients and withholding of OPDIVO QVANTIG in 0.4% of patients. Systemic corticosteroids were required in 100% (5/5) of patients with adrenal insufficiency.
Adrenal insufficiency resolved in 20% of the 5 patients. Intravenous Nivolumab with Cabozantinib Adrenal insufficiency occurred in 4.7% (15/320) of patients with RCC who received intravenous nivolumab with cabozantinib, including Grade 3 (2.2%) and Grade 2 (1.9%) adverse reactions. Adrenal insufficiency led to permanent discontinuation of intravenous nivolumab and cabozantinib in 0.9% and withholding of intravenous nivolumab and cabozantinib in 2.8% of patients with RCC.
Approximately 80% (12/15) of patients with adrenal insufficiency received hormone replacement therapy, including systemic corticosteroids. Adrenal insufficiency resolved in 27% (n=4) of the 15 patients. Of the 9 patients in whom intravenous nivolumab with cabozantinib was withheld for adrenal insufficiency, 6 reinstated treatment after symptom improvement; of these, all (n=6) received hormone replacement therapy and 2 had recurrence of adrenal insufficiency.
Initiate treatment with insulin as clinically indicated. Withhold OPDIVO QVANTIG depending on severity [see Dosage and Administration ] . Grade 3 diabetes occurred in 0.4% (1/247) of patients receiving OPDIVO QVANTIG. No patients with diabetes required systemic corticosteroids. Diabetes did not resolve in this patient. Immune-Mediated Nephritis with Renal Dysfunction OPDIVO QVANTIG can cause immune-mediated nephritis, which is defined as requiring use of steroids and no clear alternate etiology.
| † Dosing recommendations for monotherapy or monotherapy following intravenous nivolumab and ipilimumab combination therapy. | ||
| Indication | Recommended OPDIVO QVANTIG Dosage | Duration of Therapy |
| Advanced renal cell carcinoma† | 600 mg nivolumab and 10,000 units hyaluronidase every 2 weeksor1,200 mg nivolumab and 20,000 units hyaluronidase every 4 weeks | Until disease progression or unacceptable toxicity |
| Metastatic non-small cell lung cancer | ||
| Squamous cell carcinoma of the head and neck | ||
| Locally advanced or metastatic urothelial carcinoma | ||
| Hepatocellular carcinoma previously treated with sorafenib† | ||
| Esophageal squamous cell carcinoma | ||
| Unresectable or metastatic melanoma† | Adult patients and pediatric patients age 12 years and older and weighing 40 kg or greater:600 mg nivolumab and 10,000 units hyaluronidase every 2 weeksor1,200 mg nivolumab and 20,000 units hyaluronidase every 4 weeks | Until disease progression or unacceptable toxicity |
| Pediatric patients age 12 years and older and weighing 30 kg or greater but less than 40 kg:300 mg nivolumab and 5,000 units hyaluronidase every 2 weeksor600 mg nivolumab and 10,000 units hyaluronidase every 4 weeks | ||
| Adjuvant treatment of melanoma | Adult patients and pediatric patients age 12 years and older and weighing 40 kg or greater:600 mg nivolumab and 10,000 units hyaluronidase every 2 weeksor1,200 mg nivolumab and 20,000 units hyaluronidase every 4 weeks | Until disease recurrence or unacceptable toxicity for up to 1 year |
| Pediatric patients age 12 years and older and weighing 30 kg or greater but less than 40 kg:300 mg nivolumab and 5,000 units hyaluronidase every 2 weeksor600 mg nivolumab and 10,000 units hyaluronidase every 4 weeks | ||
| Unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) colorectal cancer† | Adult patients and pediatric patients age 12 years and older and weighing 40 kg or greater:600 mg nivolumab and 10,000 units hyaluronidase every 2 weeksor1,200 mg nivolumab and 20,000 units hyaluronidase every 4 weeks | Until disease progression or unacceptable toxicity, or up to 2 years |
| Pediatric patients age 12 years and older and weighing 30 kg or greater but less than 40 kg:300 mg nivolumab and 5,000 units hyaluronidase every 2 weeksor600 mg nivolumab and 10,000 units hyaluronidase every 4 weeks | ||
| Microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer that has progressed following prior treatment for metastatic disease† | Adult patients and pediatric patients age 12 years and older and weighing 40 kg or greater:600 mg nivolumab and 10,000 units hyaluronidase every 2 weeksor1,200 mg nivolumab and 20,000 units hyaluronidase every 4 weeks | Until disease progression or unacceptable toxicity |
| Pediatric patients age 12 years and older and weighing 30 kg or greater but less than 40 kg:300 mg nivolumab and 5,000 units hyaluronidase every 2 weeksor600 mg nivolumab and 10,000 units hyaluronidase every 4 weeks | ||
| First-line unresectable or metastatic hepatocellular carcinoma† | 600 mg nivolumab and 10,000 units hyaluronidase every 2 weeksor1,200 mg nivolumab and 20,000 units hyaluronidase every 4 weeks | Until disease progression or unacceptable toxicity, or up to 2 years |
| Adjuvant treatment of urothelial carcinoma | 600 mg nivolumab and 10,000 units hyaluronidase every 2 weeksor1,200 mg nivolumab and 20,000 units hyaluronidase every 4 weeks | Until disease recurrence or unacceptable toxicity for up to 1 year |
| Adjuvant treatment of resected esophageal or gastroesophageal junction cancer | ||
| Indication | Recommended OPDIVO QVANTIG Dosage | Duration of Therapy |
| Advanced renal cell carcinoma | 600 mg nivolumab and 10,000 units hyaluronidase every 2 weeksor1,200 mg nivolumab and 20,000 units hyaluronidase every 4 weeksAdminister OPDIVO QVANTIG in combination with cabozantinib 40 mg orally once daily without food | OPDIVO QVANTIG: Until disease progression, unacceptable toxicity, or up to 2 years Cabozantinib: Until disease progression or unacceptable toxicity |
| Neoadjuvant treatment of resectable non-small cell lung cancer | 900 mg nivolumab and 15,000 units hyaluronidase with platinum-doublet chemotherapy on the same day every 3 weeks | In combination with platinum-doublet chemotherapy for 3 cycles |
| Neoadjuvant and adjuvant treatment of resectable non-small cell lung cancer | Neoadjuvant: 900 mg nivolumab and 15,000 units hyaluronidase with platinum-doublet chemotherapy on the same day every 3 weeks | Neoadjuvant: in combination with platinum-doublet chemotherapy until disease progression or unacceptable toxicity, for up to 4 cycles |
| Adjuvant: 1,200 mg nivolumab and 20,000 units hyaluronidase every 4 weeks | Adjuvant: following neoadjuvant therapy and surgery, administer as a single agent until disease progression, recurrence, or unacceptable toxicity, for up to 13 cycles (up to 1 year) | |
| First-line unresectable or metastatic urothelial carcinoma | 900 mg nivolumab and 15,000 units hyaluronidase every 3 weeks Administer OPDIVO QVANTIG in combination with cisplatin and gemcitabine on the same day every 3 weeks | In combination with cisplatin and gemcitabine for up to 6 cycles |
| 600 mg nivolumab and 10,000 units hyaluronidase every 2 weeksor1,200 mg nivolumab and 20,000 units hyaluronidase every 4 weeks | After completing up to 6 cycles of combination therapy, administer as single agent until disease progression, unacceptable toxicity, or up to 2 years from first dose | |
| Esophageal squamous cell carcinoma | 600 mg nivolumab and 10,000 units hyaluronidase every 2 weeksor1,200 mg nivolumab and 20,000 units hyaluronidase every 4 weeksAdminister OPDIVO QVANTIG in combination with fluoropyrimidine- and platinum-containing chemotherapy | Until disease progression, unacceptable toxicity, or up to 2 years |
| Chemotherapy: Until disease progression or unacceptable toxicity | ||
| Gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma | 600 mg nivolumab and 10,000 units hyaluronidase with fluoropyrimidine- and platinum-containing chemotherapy every 2 weeksor900 mg nivolumab and 15,000 units hyaluronidase with fluoropyrimidine- and platinum-containing chemotherapy every 3 weeks | OPDIVO QVANTIG: Until disease progression, unacceptable toxicity, or up to 2 years Chemotherapy: Until disease progression or unacceptable toxicity |
| a Resume in patients with complete or partial resolution (Grade 0 to 1) after corticosteroid taper. Permanently discontinue if no complete or partial resolution within 12 weeks of last dose or inability to reduce prednisone to 10 mg per day (or equivalent) or less within 12 weeks of initiating steroids. b If AST and ALT are less than or equal to ULN at baseline, withhold or permanently discontinue OPDIVO QVANTIG based on recommendations for hepatitis with no liver involvement. c Depending on clinical severity, consider withholding for Grade 2 endocrinopathy until symptom improvement with hormone replacement. Resume once acute symptoms have resolved. ALT = alanine aminotransferase, AST = aspartate aminotransferase, DRESS = Drug Rash with Eosinophilia and Systemic Symptoms, SJS = Stevens-Johnson Syndrome, TEN = toxic epidermal necrolysis, ULN = upper limit of normal | ||
| Adverse Reaction | Severity | Dosage Modification |
| Immune-Mediated Adverse Reactions [see Warnings and Precautions (5.1)] | ||
| Pneumonitis | Grade 2 | Withholda |
| Grade 3 or 4 | Permanently discontinue | |
| Colitis For colitis in patients treated with combination therapy with ipilimumab, see Table 4. | Grade 2 or 3 | Withholda |
| Grade 4 | Permanently discontinue | |
| Hepatitis with no tumor involvement of the liver For liver enzyme elevations in patients treated with combination therapy with cabozantinib, see Table 4. | AST/ALT increases to >3 and ≤8 times ULN or Total bilirubin increases to >1.5 and ≤3 times ULN. | Withholda |
| AST or ALT increases to >8 times ULN or Total bilirubin increases to >3 times ULN. | Permanently discontinue | |
| Hepatitis with tumor involvement of the liverb | Baseline AST/ALT is >1 and ≤3 times ULN and increases to >5 and ≤10 times ULNorBaseline AST/ALT is >3 and ≤5 times ULN and increases to >8 and ≤10 times ULN. | Withholda |
| AST/ALT increases to >10 times ULN or Total bilirubin increases to >3 times ULN. | Permanently discontinue | |
| Endocrinopathiesc | Grade 3 or 4 | Withhold until clinically stable or permanently discontinue depending on severity |
| Nephritis with Renal Dysfunction | Grade 2 or 3 increased blood creatinine | Withholda |
| Grade 4 increased blood creatinine | Permanently discontinue | |
| Exfoliative Dermatologic Conditions | Suspected SJS, TEN, or DRESS | Withhold |
| Confirmed SJS, TEN, or DRESS | Permanently discontinue | |
| Myocarditis | Grades 2, 3, or 4 | Permanently discontinue |
| Neurological Toxicities | Grade 2 | Withholda |
| Grade 3 or 4 | Permanently discontinue | |
Dosing in liver impairment
| a Consider corticosteroid therapy for hepatic adverse reactions if OPDIVO QVANTIG is withheld or discontinued when administered in combination with cabozantinib. b After recovery, rechallenge with one or both of OPDIVO QVANTIG and cabozantinib may be considered. If rechallenging with cabozantinib with or without OPDIVO QVANTIG, refer to cabozantinib Prescribing Information. | |||
| Treatment | Adverse Reaction | Severity | Dosage Modification |
| OPDIVO QVANTIG in combination with cabozantinib | Liver enzyme elevations | ALT or AST >3 times ULN but ≤10 times ULN with concurrent total bilirubin <2 times ULN | Withholda both OPDIVO QVANTIG and cabozantinib until adverse reactions recoverb to Grades 0-1 |
| ALT or AST >10 times ULN or >3 times ULN with concurrent total bilirubin ≥2 times ULN | Permanently discontinuea both OPDIVO QVANTIG and cabozantinib | ||
Preparation and administration
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Your numbers for nivolumab and hyaluronidase (human recombinant). Take vial strength, diluent, and limits from the label below.
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Important Dosage and Administration Information OPDIVO QVANTIG has different dosage and administration instructions than intravenously administered nivolumab products [see Dosage and Administration ]. OPDIVO QVANTIG is for subcutaneous use only in the abdomen or thigh. Do not administer intravenously. OPDIVO QVANTIG is to be administered by a healthcare professional only.
Adult patients currently receiving intravenous nivolumab as a single agent, or in combination with chemotherapy or cabozantinib, may switch to subcutaneous OPDIVO QVANTIG at their next scheduled dose.
Preparation and Administration To prevent medication errors, check the vial labels to ensure that the drug being prepared and administered is OPDIVO QVANTIG for subcutaneous use and NOT intravenous nivolumab. Do NOT administer OPDIVO QVANTIG intravenously. OPDIVO QVANTIG should be administered by a healthcare professional.
Each OPDIVO QVANTIG vial is for one-time use only. It is a ready-to-use solution for injection. It should not be diluted. Visually inspect for particulate matter and discoloration prior to administration. OPDIVO QVANTIG is a clear to opalescent, colorless to yellow solution. Discard if the solution is discolored or contains extraneous particulate matter other than a few translucent-to-white particles.
Do not shake. Preparation No incompatibilities were observed between OPDIVO QVANTIG and polypropylene and polycarbonate syringes, or between OPDIVO QVANTIG and polyethylene, polyurethane, polyvinyl chloride, and fluorinated ethylene propylene subcutaneous administration sets. A syringe and a transfer needle are needed to withdraw OPDIVO QVANTIG solution from the vial.
OPDIVO QVANTIG may be injected subcutaneously using a 23G to 25G (3/8 to 5/8 inch) hypodermic injection needle or subcutaneous administration set (eg., winged/butterfly). Calculate the appropriate number of vials of OPDIVO QVANTIG (300 mg/5,000 units and/or 600 mg/10,000 units) needed based on the prescribed dose. Allow vial(s) to reach room temperature 20°C to 25°C (68°F to 77°F) before withdrawing dose.
300 mg nivolumab and 5,000 units hyaluronidase ∘ Withdraw 2.5 mL from the 300 mg/5,000 units vial of OPDIVO QVANTIG into the syringe.
600 mg nivolumab and 10,000 units hyaluronidase ∘ Withdraw 5 mL from the 600 mg/10,000 units vial of OPDIVO QVANTIG into the syringe.
900 mg nivolumab and 15,000 units hyaluronidase ∘ Withdraw 5 mL from the 600 mg/10,000 units vial and 2.5 mL from the 300 mg/5,000 units vial of OPDIVO QVANTIG into a single syringe for a total volume of 7.5 mL .
1,200 mg nivolumab and 20,000 units hyaluronidase ∘ Withdraw 5 mL from each vial of 600 mg/10,000 units OPDIVO QVANTIG into a single syringe for a total volume of 10 mL . Select the appropriate syringe label provided in the carton that matches the prescribed dose and apply to the prepared syringe. Discard partially used or empty vials of OPDIVO QVANTIG.
If the dose is not to be used immediately, attach a tip cap to the syringe prior to storage. To avoid clogging of the hypodermic injection needle, attach a 23G to 25G (3/8 to 5/8 inch) hypodermic injection needle to the syringe immediately prior to administration. Storage in Syringe Once withdrawn into the syringe, OPDIVO QVANTIG should be used immediately.
If not used immediately, store the syringe:
In the refrigerator at 2°C to 8°C (36°F to 46°F), protected from light for up to 72 hours ; do not freeze, or
At room temperature 20°C to 25°C (68°F to 77°F) for up to 8 hours. Storage at room temperature for this duration does not require protection from light.
Discard if storage time exceeds these limits.
If stored in the refrigerator, allow the solution to come to room temperature before administration. Administration
Administer the full contents of the syringe into the subcutaneous tissue of 1 of the 4 quadrants of the abdomen, or thigh over a period of 3 to 5 minutes.
Alternate injection sites across the 4 quadrants of the abdomen or thighs for successive injections. Do not inject into areas where the skin is tender, red, or bruised, or areas where there are scars or moles. If the administration of OPDIVO QVANTIG is interrupted, continue administering at the same site, or at an alternate site.
During treatment with OPDIVO QVANTIG, do not administer other subcutaneous medications at the same site used for OPDIVO QVANTIG.
Contraindications
None. • None. (4)
Pregnancy and lactation
Pregnancy
8.1 Pregnancy Risk Summary Based on data from animal studies and its mechanism of action [see Clinical Pharmacology (12.1) ] , OPDIVO QVANTIG can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of nivolumab to cynomolgus monkeys from the onset of organogenesis through delivery resulted in increased abortion and premature infant death (see Data) . Human IgG4 is known to cross the placental barrier and nivolumab is an immunoglobulin G4 (IgG4); therefore, nivolumab has the potential to be transmitted from the mother to the developing fetus.
The effects of OPDIVO QVANTIG are likely to be greater during the second and third trimesters of pregnancy. There are no available data on OPDIVO QVANTIG use in pregnant women to evaluate a drug-associated risk. Advise pregnant women of the potential risk to a fetus. The background risk in the U.S. general population of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies. Data Animal Data OPDIVO QVANTIG for subcutaneous injection contains nivolumab and hyaluronidase [see Description (11) ] . Nivolumab A central function of the PD-1/PD-L1 pathway is to preserve pregnancy by maintaining maternal immune tolerance to the fetus.
Blockade of PD-L1 signaling has been shown in murine models of pregnancy to disrupt tolerance to the fetus and to increase fetal loss. The effects of nivolumab on prenatal and postnatal development were evaluated in monkeys that received nivolumab intravenously twice weekly from the onset of organogenesis through delivery, at exposure levels of between 4 and 15 times higher than those observed at the clinical dose of 600 mg once every 2 weeks, 900 mg once every 3 weeks, or 1,200 mg once every 4 weeks (based on AUC). Nivolumab administration resulted in a non-dose-related increase in spontaneous abortion and increased neonatal death.
Based on its mechanism of action, fetal exposure to nivolumab may increase the risk of developing immune-mediated disorders or altering the normal immune response, and immune-mediated disorders have been reported in PD-1 knockout mice. In surviving infants (18 of 32 compared to 11 of 16 vehicle-exposed infants) of cynomolgus monkeys treated with nivolumab, there were no apparent malformations and no effects on neurobehavioral, immunological, or clinical pathology parameters throughout the 6-month postnatal period. Hyaluronidase In an embryo-fetal development study, mice were dosed daily by subcutaneous injection during the period of organogenesis with hyaluronidase…
For breastfeeding, also see LactMed (National Library of Medicine), which summarizes milk levels and infant effects.
Supply and cost
Drug shortage status
Recalls (last 24 months)
Therapeutic equivalence (Orange Book)
Price ladder
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