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Generic Name
Nivolumab
Brand Names
Opdivo QVANTIG, Opdualag, Opdivo
FDA approval date: December 22, 2014
Classification: Endoglycosidase
Form: Injection
What is Opdivo QVANTIG (Nivolumab)?
OPDIVO QVANTIG is a combination of nivolumab, a programmed death receptor-1 -blocking antibody, and hyaluronidase, an endoglycosidase, indicated for the treatment of: Renal Cell Carcinoma adult patients with intermediate or poor risk advanced RCC, as a first-line treatment following combination treatment with intravenous nivolumab and ipilimumab.
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Brand Information
OPDIVO QVANTIG (nivolumab and hyaluronidase-nvhy)
1DOSAGE FORMS AND STRENGTHS
Injection: 300 mg nivolumab and 5,000 units hyaluronidase per 2.5 mL (120 mg/2,000 units per mL), as a clear to opalescent, colorless to yellow solution in a single-dose vial.
Injection: 600 mg nivolumab and 10,000 units hyaluronidase per 5 mL (120 mg/2,000 units per mL), as a clear to opalescent, colorless to yellow solution in a single-dose vial.
2CONTRAINDICATIONS
None.
3ADVERSE REACTIONS
The following clinically significant adverse reactions are described elsewhere in the labeling.
- Severe and Fatal Immune-Mediated Adverse Reactions
- Complications of Allogeneic HSCT
3.1Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The data in WARNINGS AND PRECAUTIONS reflect exposure to OPDIVO QVANTIG as a single agent in 247 patients enrolled in CHECKMATE-67T, with additional data from intravenous nivolumab single-agent (1994 patients), and from intravenous nivolumab in combination with cabozantinib (320 patients) for select adverse reactions.
3.1.1Advanced Renal Cell Carcinoma
CHECKMATE-67T was a multicenter, randomized, open-label study in adult patients with advanced or metastatic RCC. Patients received OPDIVO QVANTIG dose of 1,200 mg of nivolumab and 20,000 units of hyaluronidase subcutaneously every 4 weeks (n=247) or 3 mg/kg of nivolumab intravenously every 2 weeks (n=245). Among patients who received OPDIVO QVANTIG, 52% were exposed for 6 months or longer and 20% were exposed for greater than 1 year.
Serious adverse reactions occurred in 28% of patients who received OPDIVO QVANTIG. Serious adverse reactions in >1% of patients included pleural effusion (1.6%), pneumonitis (1.6%), hyperglycemia (1.2%), hyperkalemia (1.2%), hemorrhage (1.2%) and diarrhea (1.2%). Fatal adverse reactions occurred in 3 patients (1.2%) who received OPDIVO QVANTIG and included myocarditis, myositis, and colitis complications.
Permanent discontinuation of OPDIVO QVANTIG due to an adverse reaction occurred in 10% of patients. The most common adverse reaction which resulted in permanent discontinuation was pneumonitis (2%).
Dosage interruptions of OPDIVO QVANTIG due to an adverse reaction occurred in 34% of patients. Adverse reactions which required dosage interruption in >2% of patients included COVID-19 (4.5%), increased blood creatinine (2.8%), anemia, diarrhea, and fatigue (2.4% each).
The most common adverse reactions (≥10%) were musculoskeletal pain, fatigue, pruritus, rash, hypothyroidism, diarrhea, cough, and abdominal pain.
Tables 5 and 6 summarize adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-67T.
Clinically important adverse reactions in <5% of patients who received OPDIVO QVANTIG include:
Cardiac: myocarditis
Respiratory, thoracic, and mediastinal: pneumonitis, dyspnea
Endocrine: adrenal insufficiency, hyperthyroidism, thyroiditis
Gastrointestinal: colitis, pancreatitis
Hepatobiliary: hepatitis
Nervous system: peripheral neuropathy
Skin and subcutaneous tissue: psoriasis, erythema
Musculoskeletal and connective tissue: arthritis
Blood and lymphatic system: eosinophilia
Eye disorders: uveitis
Immune system: hypersensitivity
3.1.2Adverse Reactions in Patients Treated with Intravenous Nivolumab
The safety of OPDIVO QVANTIG for its approved indications
3.1.2.1First-line Renal Cell Carcinoma
CHECKMATE-214
The safety of intravenous nivolumab with ipilimumab was evaluated in CHECKMATE-214, a randomized open-label trial in 1082 patients with previously untreated advanced RCC; patients received intravenous nivolumab 3 mg/kg over 60 minutes with ipilimumab 1 mg/kg intravenously every 3 weeks for 4 doses followed by intravenous nivolumab as a single agent at a dose of 3 mg/kg by intravenous infusion every 2 weeks (n=547) or sunitinib 50 mg orally daily for the first 4 weeks of a 6-week cycle (n=535)
Serious adverse reactions occurred in 59% of patients receiving intravenous nivolumab and ipilimumab. Study therapy was discontinued for adverse reactions in 31% of intravenous nivolumab and ipilimumab patients. Fifty-four percent (54%) of patients receiving intravenous nivolumab and ipilimumab had a dose interruption for an adverse reaction.
The most frequent serious adverse reactions reported in ≥2% of patients treated with intravenous nivolumab and ipilimumab were diarrhea, pyrexia, pneumonia, pneumonitis, hypophysitis, acute kidney injury, dyspnea, adrenal insufficiency, and colitis; in patients treated with sunitinib, they were pneumonia, pleural effusion, and dyspnea. The most common adverse reactions (reported in ≥20% of patients) were fatigue, rash, diarrhea, musculoskeletal pain, pruritus, nausea, cough, pyrexia, arthralgia, and decreased appetite. The most common laboratory abnormalities which have worsened compared to baseline in ≥30% of intravenous nivolumab and ipilimumab-treated patients include increased lipase, anemia, increased creatinine, increased ALT, increased AST, hyponatremia, increased amylase, and lymphopenia.
Tables 7 and 8 summarize adverse reactions and laboratory abnormalities, respectively, that occurred in >15% of intravenous nivolumab and ipilimumab‑treated patients in CHECKMATE-214.
In addition, among patients with TSH ≤ ULN at baseline, a lower proportion of patients experienced a treatment-emergent elevation of TSH > ULN in the intravenous nivolumab and ipilimumab group compared to the sunitinib group (31% and 61%, respectively).
CHECKMATE-9ER
The safety of intravenous nivolumab with cabozantinib was evaluated in CHECKMATE-9ER, a randomized, open-label study in patients with previously untreated advanced RCC. Patients received intravenous nivolumab 240 mg over 30 minutes every 2 weeks with cabozantinib 40 mg orally once daily (n=320) or sunitinib 50 mg daily, administered orally for 4 weeks on treatment followed by 2 weeks off (n=320)
Serious adverse reactions occurred in 48% of patients receiving intravenous nivolumab and cabozantinib. The most frequent (≥2%) serious adverse reactions were diarrhea, pneumonia, pneumonitis, pulmonary embolism, urinary tract infection, and hyponatremia. Fatal intestinal perforations occurred in 3 (0.9%) patients.
Adverse reactions leading to discontinuation of either intravenous nivolumab or cabozantinib occurred in 20% of patients: 7% intravenous nivolumab only, 8% cabozantinib only, and 6% both drugs due to same adverse reaction at the same time. Adverse reaction leading to dose interruption or reduction of either intravenous nivolumab or cabozantinib occurred in 83% of patients: 3% intravenous nivolumab only, 46% cabozantinib only, and 21% both drugs due to same adverse reaction at the same time, and 6% both drugs sequentially.
The most common adverse reactions reported in ≥20% of patients treated with intravenous nivolumab and cabozantinib were diarrhea, fatigue, hepatotoxicity, palmar-plantar erythrodysesthesia syndrome, stomatitis, rash, hypertension, hypothyroidism, musculoskeletal pain, decreased appetite, nausea, dysgeusia, abdominal pain, cough, and upper respiratory tract infection.
Tables 9 and 10 summarize adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-9ER.
3.1.2.2Previously Treated Renal Cell Carcinoma
CHECKMATE-025
The safety of intravenous nivolumab was evaluated in CHECKMATE-025, a randomized open-label trial in 803 patients with advanced RCC who had experienced disease progression during or after at least one anti-angiogenic treatment regimen received intravenous nivolumab 3 mg/kg over 60 minutes by intravenous infusion every 2 weeks (n=406) or everolimus 10 mg daily (n=397)
Rate of death on treatment or within 30 days of the last dose was 4.7% on the intravenous nivolumab arm. Serious adverse reactions occurred in 47% of patients receiving intravenous nivolumab. Study therapy was discontinued for adverse reactions in 16% of intravenous nivolumab patients. Forty-four percent (44%) of patients receiving intravenous nivolumab had a dose interruption for an adverse reaction.
The most frequent serious adverse reactions in at least 2% of patients were: acute kidney injury, pleural effusion, pneumonia, diarrhea, and hypercalcemia. The most common adverse reactions (≥20%) were fatigue, cough, nausea, rash, dyspnea, diarrhea, constipation, decreased appetite, back pain, and arthralgia. The most common laboratory abnormalities which have worsened compared to baseline in ≥30% of patients include increased creatinine, lymphopenia, anemia, increased AST, increased alkaline phosphatase, hyponatremia, increased triglycerides, and hyperkalemia. In addition, among patients with TSH < ULN at baseline, a greater proportion of patients experienced a treatment-emergent elevation of TSH > ULN in the intravenous nivolumab group compared to the everolimus group (26% and 14%, respectively).
Tables 11 and 12 summarize adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-025.
Other clinically important adverse reactions in CHECKMATE-025 were:
General Disorders and Administration Site Conditions: peripheral edema/edema
Gastrointestinal Disorders: abdominal pain/discomfort
Musculoskeletal and Connective Tissue Disorders: extremity pain, musculoskeletal pain
Nervous System Disorders: headache/migraine, peripheral neuropathy
Investigations: weight decreased
Skin Disorders: palmar-plantar erythrodysesthesia
3.1.3Unresectable or Metastatic Melanoma
Previously Treated Metastatic Melanoma
CHECKMATE-037
The safety of intravenous nivolumab was evaluated in CHECKMATE-037, a randomized, open-label trial in 370 patients with unresectable or metastatic melanoma
The population characteristics in the intravenous nivolumab group and the chemotherapy group were similar: 66% male, median age 59.5 years, 98% White, baseline Eastern Cooperative Oncology Group (ECOG) performance status 0 (59%) or 1 (41%), 74% with M1c stage disease, 73% with cutaneous melanoma, 11% with mucosal melanoma, 73% received two or more prior therapies for advanced or metastatic disease, and 18% had brain metastasis. There were more patients in the intravenous nivolumab group with elevated lactate dehydrogenase (LDH) at baseline (51% vs. 38%).
Serious adverse reactions occurred in 41% of patients receiving intravenous nivolumab. Intravenous nivolumab was discontinued for adverse reactions in 9% of patients. Twenty-six percent of patients receiving intravenous nivolumab had a dose interruption for an adverse reaction. Grade 3 and 4 adverse reactions occurred in 42% of patients receiving intravenous nivolumab. The most frequent Grade 3 and 4 adverse reactions reported in 2% to <5% of patients receiving intravenous nivolumab were abdominal pain, hyponatremia, increased aspartate aminotransferase, and increased lipase. The most common adverse reaction (reported in ≥20% of patients) was rash.
Tables 13 and 14 summarize the adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-037.
Clinically important adverse reactions in <10% of patients who received intravenous nivolumab were:
Cardiac Disorders: ventricular arrhythmia
Eye Disorders: iridocyclitis
General Disorders and Administration Site Conditions: infusion-related reactions
Investigations: increased amylase, increased lipase
Nervous System Disorders: dizziness, peripheral and sensory neuropathy
Skin and Subcutaneous Tissue Disorders: exfoliative dermatitis, erythema multiforme, vitiligo, psoriasis
3.1.3.1Previously Untreated Metastatic Melanoma
CHECKMATE-066
The safety of intravenous nivolumab was also evaluated in CHECKMATE-066, a randomized, double-blind, active‑controlled trial in 411 previously untreated patients with BRAF V600 wild-type unresectable or metastatic melanoma
The trial population characteristics in the intravenous nivolumab group and dacarbazine group: 59% male, median age 65 years, 99.5% White, 61% with M1c stage disease, 74% with cutaneous melanoma, 11% with mucosal melanoma, 4% with brain metastasis, and 37% with elevated LDH at baseline. There were more patients in the intravenous nivolumab group with ECOG performance status 0 (71% vs. 59%).
Serious adverse reactions occurred in 36% of patients receiving intravenous nivolumab. Adverse reactions led to permanent discontinuation of intravenous nivolumab in 7% of patients and dose interruption in 26% of patients; no single type of adverse reaction accounted for the majority of intravenous nivolumab discontinuations. Grade 3 and 4 adverse reactions occurred in 41% of patients receiving intravenous nivolumab.
The most frequent Grade 3 and 4 adverse reactions reported in ≥2% of patients receiving intravenous nivolumab were increased gamma-glutamyl transferase (3.9%) and diarrhea (3.4%). The most common adverse reactions (reported in ≥20% of patients and at a higher incidence than in the dacarbazine arm) were fatigue, musculoskeletal pain, rash, and pruritus.
Tables 15 and 16 summarize selected adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-066.
Clinically important adverse reactions in <10% of patients who received intravenous nivolumab were:
Nervous System Disorders: peripheral neuropathy
CHECKMATE-067
The safety of intravenous nivolumab, administered with ipilimumab or as a single agent, was evaluated in CHECKMATE-067, a randomized (1:1:1), double-blind trial in 937 patients with previously untreated, unresectable or metastatic melanoma
Patients were randomized to receive:
- Intravenous nivolumab 1 mg/kg over 60 minutes with ipilimumab 3 mg/kg by intravenous infusion every 3 weeks for 4 doses followed by intravenous nivolumab as a single agent at a dose of 3 mg/kg by intravenous infusion over 60 minutes every 2 weeks (nivolumab and ipilimumab arm; n=313), or
- Intravenous nivolumab 3 mg/kg by intravenous infusion over 60 minutes every 2 weeks (nivolumab arm; n=313), or
- Ipilimumab 3 mg/kg by intravenous infusion every 3 weeks for up to 4 doses (ipilimumab arm; n=311).
The median duration of exposure to intravenous nivolumab was 2.8 months (range: 1 day to 36.4 months) for the intravenous nivolumab and ipilimumab arm and 6.6 months (range: 1 day to 36.0 months) for the intravenous nivolumab arm. In the intravenous nivolumab and ipilimumab arm, 39% were exposed to intravenous nivolumab for ≥6 months and 30% exposed for >1 year. In the intravenous nivolumab arm, 53% were exposed for ≥6 months and 40% for >1 year.
The population characteristics were: 65% male, median age 61 years, 97% White, baseline ECOG performance status 0 (73%) or 1 (27%), 93% with American Joint Committee on Cancer (AJCC) Stage IV disease, 58% with M1c stage disease; 36% with elevated LDH at baseline, 4% with a history of brain metastasis, and 22% had received adjuvant therapy.
Serious adverse reactions (74% and 44%), adverse reactions leading to permanent discontinuation (47% and 18%) or to dosing delays (58% and 36%), and Grade 3 or 4 adverse reactions (72% and 51%) all occurred more frequently in the intravenous nivolumab and ipilimumab arm relative to the intravenous nivolumab arm.
The most frequent (≥10%) serious adverse reactions in the intravenous nivolumab and ipilimumab arm and the intravenous nivolumab arm, respectively, were diarrhea (13% and 2.2%), colitis (10% and 1.9%), and pyrexia (10% and 1%). The most frequent adverse reactions leading to discontinuation of both drugs in the intravenous nivolumab and ipilimumab arm and of intravenous nivolumab in the intravenous nivolumab arm, respectively, were colitis (10% and 0.6%), diarrhea (8% and 2.2%), increased ALT (4.8% and 1%), increased AST (4.5% and 0.6%), and pneumonitis (1.9% and 0.3%).
The most common (≥20%) adverse reactions in the intravenous nivolumab and ipilimumab arm were fatigue, diarrhea, rash, nausea, pyrexia, pruritus, musculoskeletal pain, vomiting, decreased appetite, cough, headache, dyspnea, upper respiratory tract infection, arthralgia, and increased transaminases. The most common (≥20%) adverse reactions in the intravenous nivolumab arm were fatigue, rash, musculoskeletal pain, diarrhea, nausea, cough, pruritus, upper respiratory tract infection, decreased appetite, headache, constipation, arthralgia, and vomiting.
Tables 17 and 18 summarize the incidence of adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-067.
Clinically important adverse reactions in <10% of patients who received intravenous nivolumab with ipilimumab or intravenous nivolumab as a single agent were:
Gastrointestinal Disorders: stomatitis, intestinal perforation
Skin and Subcutaneous Tissue Disorders: vitiligo
Musculoskeletal and Connective Tissue Disorders: myopathy, Sjogren’s syndrome, spondyloarthropathy, myositis (including polymyositis)
Nervous System Disorders: neuritis, peroneal nerve palsy
3.1.4Adjuvant Treatment of Melanoma
CHECKMATE-76K
The safety of intravenous nivolumab as a single agent was evaluated in CHECKMATE-76K, a randomized (2:1), double-blind trial in 788 patients with completely resected Stage IIB/C melanoma who received intravenous nivolumab 480 mg by intravenous infusion over 30 minutes every 4 weeks (n=524) or placebo by intravenous infusion over 30 minutes every 4 weeks (n=264) for up to 1 year
Serious adverse reactions occurred in 18% of patients treated with intravenous nivolumab. A fatal adverse reaction occurred in 1 (0.2%) patient (heart failure and acute kidney injury). Permanent discontinuation of intravenous nivolumab due to an adverse reaction occurred in 17% of patients. Adverse reactions which resulted in permanent discontinuation of intravenous nivolumab in >1% of patients included diarrhea (1.1%), arthralgia (1.7%), and rash (1.7%).
Dosage interruptions of intravenous nivolumab due to an adverse reaction occurred in 25% of patients. Adverse reactions which required dosage interruption in >1% of patients included COVID-19 infection, infusion related reaction, diarrhea, arthralgia, and increased ALT.
The most common adverse reactions (reported in ≥20% of patients) were fatigue, musculoskeletal pain, rash, diarrhea, and pruritus.
Tables 19 and 20 summarize the adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-76K.
CHECKMATE-238
The safety of intravenous nivolumab as a single agent was evaluated in CHECKMATE-238, a randomized (1:1), double-blind trial in 905 patients with completely resected Stage IIIB/C or Stage IV melanoma received intravenous nivolumab 3 mg/kg by intravenous infusion over 60 minutes every 2 weeks (n=452) or ipilimumab 10 mg/kg by intravenous infusion every 3 weeks for 4 doses then every 12 weeks beginning at Week 24 for up to 1 year (n=453)
Serious adverse reactions occurred in 18% of intravenous nivolumab-treated patients. Study therapy was discontinued for adverse reactions in 9% of intravenous nivolumab-treated patients and 42% of ipilimumab-treated patients. Twenty-eight percent of intravenous nivolumab-treated patients had at least one omitted dose for an adverse reaction. Grade 3 or 4 adverse reactions occurred in 25% of intravenous nivolumab-treated patients.
The most frequent Grade 3 and 4 adverse reactions reported in ≥2% of intravenous nivolumab-treated patients were diarrhea and increased lipase and amylase. The most common adverse reactions (at least 20%) were fatigue, diarrhea, rash, musculoskeletal pain, pruritus, headache, nausea, upper respiratory infection, and abdominal pain. The most common immune-mediated adverse reactions were rash (16%), diarrhea/colitis (6%), and hepatitis (3%).
Tables 21 and 22 summarize the adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-238.
3.1.5Non-Small Cell Lung Cancer
Neoadjuvant Treatment of Resectable (Tumors ≥4 cm or Node Positive) Non-Small Cell Lung Cancer
CHECKMATE-816
The safety of intravenous nivolumab in combination with platinum-doublet chemotherapy was evaluated in CHECKMATE-816, a randomized, open-label, multicenter trial in patients with resectable NSCLC
The median age of patients who received intravenous nivolumab in combination with platinum-doublet chemotherapy or platinum-doublet chemotherapy was 65 years (range: 34 – 84); 72% male; 47% White, 50% Asian, and 2% Black/African American.
Serious adverse reactions occurred in 30% of patients who were treated with intravenous nivolumab in combination with platinum-doublet chemotherapy. Serious adverse reactions in >2% included pneumonia and vomiting. No fatal adverse reactions occurred in patients who received intravenous nivolumab in combination with platinum-doublet chemotherapy.
Study therapy with intravenous nivolumab in combination with platinum-doublet chemotherapy was permanently discontinued for adverse reactions in 10% of patients and 30% had at least one treatment withheld for an adverse reaction. The most common adverse reactions (≥1%) resulting in permanent discontinuation of intravenous nivolumab in combination with platinum-doublet chemotherapy were anaphylactic reaction (1.7%), acute kidney injury (1.1%), rash (1.1%), and fatigue (1.1%).
The most common (>20%) adverse reactions were nausea, constipation, fatigue, decreased appetite, and rash. The most common Grade 3 or 4 laboratory abnormalities (≥2%) were neutropenia, hyperglycemia, leukopenia, lymphopenia, increased amylase, anemia, thrombocytopenia, and hyponatremia.
Tables 23 and 24 summarize selected adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-816.
3.1.5.1Neoadjuvant and Adjuvant Treatment of Resectable (Tumors ≥4 cm or Node Positive) Non-Small Cell Lung Cancer
CHECKMATE-77T
The safety of intravenous nivolumab in combination with neoadjuvant platinum-doublet chemotherapy followed by surgery and continued adjuvant treatment with intravenous nivolumab as a single agent after surgery was evaluated in CHECKMATE-77T, a randomized, double-blind, multicenter trial in patients with previously untreated resectable Stage IIA (>4 cm) to IIIB (T3N2 or T4N2) NSCLC (per the AJCC Cancer Staging Manual 8th Edition)
The study population characteristics were: median age 66 years (range: 35 - 86); 71% male; 72% White, 25% Asian, 1.7% Black/African American, and 1.5% other race; and 6% Hispanic or Latino.
Adverse reactions occurring in patients with resectable NSCLC receiving intravenous nivolumab in combination with platinum-doublet chemotherapy, given as neoadjuvant treatment and followed as a single agent adjuvant treatment after surgery, were generally similar to those occurring in patients in other clinical trials across tumor types receiving intravenous nivolumab in combination with chemotherapy.
Neoadjuvant Phase of CHECKMATE-77T
A total of 228 patients received at least 1 dose of intravenous nivolumab in combination with platinum-doublet chemotherapy as neoadjuvant treatment and 230 patients received at least 1 dose of placebo in combination with platinum-doublet chemotherapy as neoadjuvant treatment.
Serious adverse reactions occurred in 21% of patients who received intravenous nivolumab in combination with platinum-doublet chemotherapy as neoadjuvant treatment; the most frequent (≥2%) serious adverse reactions was pneumonia. Fatal adverse reactions occurred in 2.2% of patients, due to cerebrovascular accident, COVID-19 infection, hemoptysis, pneumonia, and pneumonitis (0.4% each).
Permanent discontinuation of any study drug due to an adverse reaction occurred in 13% of patients who received intravenous nivolumab in combination with platinum-doublet chemotherapy as neoadjuvant treatment; the most frequent (≥1%) adverse reaction that led to permanent discontinuation of any study drug was peripheral sensory neuropathy (2.2%).
Of the 228 intravenous nivolumab-treated patients and 230 placebo-treated patients who received neoadjuvant treatment, 5.3% (n=12) and 3.5% (n=8), respectively, did not receive surgery due to adverse reactions. The adverse reactions that led to cancellation of surgery in intravenous nivolumab-treated patients were cerebrovascular accident, pneumonia, and colitis/diarrhea (2 patients each) and acute coronary syndrome, myocarditis, hemoptysis, pneumonitis, COVID-19, and myositis (1 patient each).
Of the 178 intravenous nivolumab-treated patients who received surgery, 4.5% (n=8) experienced delay of surgery (surgery more than 6 weeks from last neoadjuvant treatment) due to adverse reactions. Of the 178 placebo-treated patients who received surgery, 3.9% (n=7) experienced delay of surgery due to adverse reactions.
Of the 178 intravenous nivolumab-treated patients who received surgery, 7% (n=13) did not receive adjuvant treatment due to adverse reactions. Of the 178 placebo-treated patients who received surgery, 2.8% (n=5) did not receive adjuvant treatment due to adverse reactions.
Adjuvant Phase of CHECKMATE-77T
A total of 142 patients in the intravenous nivolumab arm and 152 patients in the placebo arm received at least 1 dose of adjuvant treatment.
Of the patients who received single agent intravenous nivolumab as adjuvant treatment, 22% experienced serious adverse reactions; the most frequent serious adverse reaction was pneumonitis/ILD (2.8%). One fatal adverse reaction due to COVID-19 occurred. Permanent discontinuation of adjuvant intravenous nivolumab due to an adverse reaction occurred in 14% of patients; the most frequent (≥1%) adverse reactions that led to permanent discontinuation of adjuvant intravenous nivolumab were pneumonitis (4.2%) and diarrhea (1.4%).
Second-line Treatment of Metastatic NSCLC
CHECKMATE-017 and CHECKMATE-057
The safety of intravenous nivolumab was evaluated in CHECKMATE-017, a randomized open-label, multicenter trial in patients with metastatic squamous NSCLC and progression on or after one prior platinum doublet-based chemotherapy regimen and in CHECKMATE-057, a randomized, open-label, multicenter trial in patients with metastatic non-squamous NSCLC and progression on or after one prior platinum doublet-based chemotherapy regimen
Across both trials, the median age of intravenous nivolumab-treated patients was 61 years (range: 37 to 85); 38% were ≥65 years of age, 61% were male, and 91% were White. Ten percent of patients had brain metastases and ECOG performance status was 0 (26%) or 1 (74%).
In CHECKMATE-057, in the intravenous nivolumab arm, seven deaths were due to infection including one case of
The most frequent serious adverse reactions reported in ≥2% of patients receiving intravenous nivolumab were pneumonia, pulmonary embolism, dyspnea, pyrexia, pleural effusion, pneumonitis, and respiratory failure. Across both trials, the most common adverse reactions (≥20%) were fatigue, musculoskeletal pain, cough, dyspnea, and decreased appetite.
Tables 25 and 26 summarize selected adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-057.
Other clinically important adverse reactions observed in intravenous nivolumab-treated patients and which occurred at a similar incidence in docetaxel-treated patients and not listed elsewhere in section 6 include: fatigue/asthenia (48% all Grades, 5% Grade 3-4), musculoskeletal pain (33% all Grades), pleural effusion (4.5% all Grades), pulmonary embolism (3.3% all Grades).
3.1.6Squamous Cell Carcinoma of the Head and Neck
CHECKMATE-141
The safety of intravenous nivolumab was evaluated in CHECKMATE-141, a randomized, active-controlled, open-label, multicenter trial in patients with recurrent or metastatic SCCHN with progression during or within 6 months of receiving prior platinum-based therapy
The median age of all randomized patients was 60 years (range: 28 to 83); 28% of patients in the intravenous nivolumab group were ≥65 years of age and 37% in the comparator group were ≥65 years of age, 83% were male and 83% were White, 12% were Asian, and 4% were Black. Baseline ECOG performance status was 0 (20%) or 1 (78%), 45% of patients received only one prior line of systemic therapy, the remaining 55% of patients had two or more prior lines of therapy, and 90% had prior radiation therapy.
Serious adverse reactions occurred in 49% of patients receiving intravenous nivolumab. Intravenous nivolumab was discontinued in 14% of patients and was delayed in 24% of patients for an adverse reaction. Adverse reactions and laboratory abnormalities occurring in patients with SCCHN were generally similar to those occurring in patients with melanoma and NSCLC.
The most frequent serious adverse reactions reported in ≥2% of patients receiving intravenous nivolumab were pneumonia, dyspnea, respiratory failure, respiratory tract infection, and sepsis. The most common adverse reactions occurring in ≥10% of intravenous nivolumab-treated patients and at a higher incidence than investigator’s choice were cough and dyspnea. The most common laboratory abnormalities occurring in ≥10% of intravenous nivolumab-treated patients and at a higher incidence than investigator’s choice were increased alkaline phosphatase, increased amylase, hypercalcemia, hyperkalemia, and increased TSH.
3.1.7Urothelial Carcinoma
Adjuvant Treatment of Urothelial Carcinoma (UC)
CHECKMATE-274
The safety of intravenous nivolumab was evaluated in CHECKMATE-274, a randomized, double‑blind, multicenter trial of adjuvant intravenous nivolumab versus placebo in adult patients who had undergone radical resection of UC originating in the bladder or upper urinary tract (renal pelvis or ureter) and were at high risk of recurrence
Serious adverse reactions occurred in 30% of intravenous nivolumab patients. The most frequent serious adverse reaction reported in ≥2% of patients was urinary tract infection. Fatal adverse reactions occurred in 1% of patients; these included events of pneumonitis (0.6%). Intravenous nivolumab was discontinued for adverse reactions in 18% of patients. Intravenous nivolumab was delayed for adverse reaction in 33% of patients.
The most common adverse reactions (reported in ≥20% of patients) were rash, fatigue, diarrhea, pruritus, musculoskeletal pain, and urinary tract infection.
Tables 27 and 28 summarize adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-274.
First-line Treatment of Unresectable or Metastatic UC
CHECKMATE-901
The safety of intravenous nivolumab was evaluated in CHECKMATE-901, a randomized, open-label trial in cisplatin-eligible patients with unresectable or metastatic UC
Among patients who received intravenous nivolumab with chemotherapy, the median duration of intravenous nivolumab exposure was 7.4 months (range: 0.03 to 47.9 months). Serious adverse reactions occurred in 48% of patients receiving intravenous nivolumab in combination with chemotherapy. The most frequent serious adverse reactions reported in ≥2% of patients who received intravenous nivolumab with chemotherapy were urinary tract infection (4.9%), acute kidney injury (4.3%), anemia (3%), pulmonary embolism (2.6%), sepsis (2.3%), and platelet count decreased (2.3%). The most common adverse reactions (reported in ≥20% of patients) were nausea, fatigue, musculoskeletal pain, constipation, decreased appetite, rash, vomiting, and peripheral neuropathy.
Fatal adverse reactions occurred in 3.6% of patients who received intravenous nivolumab in combination with chemotherapy; these included sepsis (1%).
Intravenous nivolumab and/or chemotherapy were discontinued in 30% of patients and were delayed in 67% of patients for an adverse reaction.
Tables 29 and 30 summarize the adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-901.
Previously Treated Advanced or Metastatic UC
CHECKMATE-275
The safety of intravenous nivolumab was evaluated in CHECKMATE-275, a single arm trial in which 270 patients with locally advanced or metastatic UC had disease progression during or following platinum-containing chemotherapy or had disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy
Fourteen patients (5.2%) died from causes other than disease progression. This includes 4 patients (1.5%) who died from pneumonitis or cardiovascular failure which was attributed to treatment with intravenous nivolumab. Serious adverse reactions occurred in 54% of patients. Intravenous nivolumab was discontinued for adverse reactions in 17% of patients.
The most frequent serious adverse reactions reported in ≥2% of patients were urinary tract infection, sepsis, diarrhea, small intestine obstruction, and general physical health deterioration. The most common adverse reactions (reported in ≥20% of patients) were fatigue, musculoskeletal pain, nausea, and decreased appetite.
Tables 31 and 32 summarize adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-275.
3.1.8Esophageal Cancer
Adjuvant Treatment of Resected Esophageal or Gastroesophageal Junction Cancer
CHECKMATE-577
The safety of intravenous nivolumab was evaluated in CHECKMATE-577, a randomized, placebo-controlled, double-blinded, multicenter trial in 792 treated patients with completely resected (negative margins) esophageal or gastroesophageal junction cancer who had residual pathologic disease following chemoradiotherapy (CRT)
Serious adverse reactions occurred in 33% of patients receiving intravenous nivolumab. A serious adverse reaction reported in ≥2% of patients who received intravenous nivolumab was pneumonitis. A fatal adverse reaction of myocardial infarction occurred in one patient who received intravenous nivolumab.
Intravenous nivolumab was discontinued in 12% of patients and was delayed in 28% of patients for an adverse reaction.
Tables 41 and 42 summarize the adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-577.
First-line Treatment of Unresectable Advanced or Metastatic ESCC
CHECKMATE‑648
The safety of intravenous nivolumab in combination with chemotherapy or in combination with ipilimumab was evaluated in CHECKMATE‑648, a randomized, active-controlled, multicenter, open-label trial in patients with previously untreated unresectable advanced, recurrent or metastatic ESCC
- intravenous nivolumab 240 mg on days 1 and 15, 5-FU (fluorouracil) 800 mg/m
- intravenous nivolumab 3 mg/kg every 2 weeks in combination with ipilimumab 1 mg/kg every 6 weeks.
- 5-FU (fluorouracil) 800 mg/m
Among patients who received intravenous nivolumab with chemotherapy, the median duration of exposure was 5.7 months (range: 0.1 to 30.6 months). Among patients who received intravenous nivolumab and ipilimumab, the median duration of exposure was 2.8 months (range: 0 to 24 months).
Serious adverse reactions occurred in 62% of patients receiving intravenous nivolumab in combination with chemotherapy and in 69% of patients receiving intravenous nivolumab in combination with ipilimumab. The most frequent serious adverse reactions reported in ≥2% of patients who received intravenous nivolumab with chemotherapy were pneumonia (11%), dysphagia (7%), esophageal stenosis (2.9%), acute kidney injury (2.9%), and pyrexia (2.3%). The most frequent serious adverse reactions reported in ≥2% of patients who received intravenous nivolumab with ipilimumab were pneumonia (10%), pyrexia (4.3%), pneumonitis (4%), aspiration pneumonia (3.7%), dysphagia (3.7%), hepatic function abnormal (2.8%), decreased appetite (2.8%), adrenal insufficiency (2.5%), and dehydration (2.5%).
Fatal adverse reactions occurred in 5 (1.6%) patients who received intravenous nivolumab in combination with chemotherapy; these included pneumonitis, pneumatosis intestinalis, pneumonia, and acute kidney injury and in 5 (1.6%) patients who received intravenous nivolumab in combination with ipilimumab; these included pneumonitis, interstitial lung disease, pulmonary embolism, and acute respiratory distress syndrome.
Intravenous nivolumab and/or chemotherapy were discontinued in 39% of patients and were delayed in 71% of patients for an adverse reaction. Intravenous nivolumab and/or ipilimumab were discontinued in 23% of patients and were delayed in 46% of patients for an adverse reaction.
The most common adverse reactions reported in ≥20% of patients treated with intravenous nivolumab in combination with chemotherapy were nausea, decreased appetite, fatigue, constipation, stomatitis, diarrhea, and vomiting. The most common adverse reactions reported in ≥20% of patients treated with intravenous nivolumab in combination with ipilimumab were rash, fatigue, pyrexia, nausea, diarrhea, and constipation.
Tables 43 and 44 summarize the adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-648.
Previously-Treated Unresectable Advanced, Recurrent or Metastatic Esophageal Squamous Cell Carcinoma (ESCC)
ATTRACTION-3
The safety of intravenous nivolumab was evaluated in ATTRACTION-3, a randomized, active-controlled, open‑label, multicenter trial in 209 patients with unresectable advanced, recurrent or metastatic ESCC refractory or intolerant to at least one fluoropyrimidine- and platinum‑based chemotherapy
Serious adverse reactions occurred in 38% of patients receiving intravenous nivolumab. Serious adverse reactions reported in ≥2% of patients who received intravenous nivolumab were pneumonia, esophageal fistula, interstitial lung disease and pyrexia. The following fatal adverse reactions occurred in patients who received intravenous nivolumab: interstitial lung disease or pneumonitis (1.4%), pneumonia (1.0%), septic shock (0.5%), esophageal fistula (0.5%), gastrointestinal hemorrhage (0.5%), pulmonary embolism (0.5%), and sudden death (0.5%).
Intravenous nivolumab was discontinued in 13% of patients and was delayed in 27% of patients for an adverse reaction.
Tables 45 and 46 summarize the adverse reactions and laboratory abnormalities, respectively, in ATTRACTION-3.
3.1.9Gastric Cancer, Gastroesophageal Junction Cancer, and Esophageal Adenocarcinoma
CHECKMATE-649
The safety of intravenous nivolumab in combination with chemotherapy was evaluated in CHECKMATE-649, a randomized, multicenter, open-label trial in patients with previously untreated advanced or metastatic gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma
- intravenous nivolumab 240 mg in combination with mFOLFOX6 (fluorouracil, leucovorin and oxaliplatin) every 2 weeks or mFOLFOX6 every 2 weeks.
- intravenous nivolumab 360 mg in combination with CapeOX (capecitabine and oxaliplatin) every 3 weeks or CapeOX every 3 weeks.
Patients were treated with intravenous nivolumab in combination with chemotherapy or chemotherapy until disease progression, unacceptable toxicity, or up to 2 years. The median duration of exposure was 6.8 months (range: 0 to 33.5 months) in intravenous nivolumab and chemotherapy-treated patients. Among patients who received intravenous nivolumab and chemotherapy, 54% were exposed for >6 months and 28% were exposed for >1 year.
Fatal adverse reactions occurred in 16 (2.0%) patients who were treated with intravenous nivolumab in combination with chemotherapy; these included pneumonitis (4 patients), febrile neutropenia (2 patients), stroke (2 patients), gastrointestinal toxicity, intestinal mucositis, septic shock, pneumonia, infection, gastrointestinal bleeding, mesenteric vessel thrombosis, and disseminated intravascular coagulation. Serious adverse reactions occurred in 52% of patients treated with intravenous nivolumab in combination with chemotherapy. Intravenous nivolumab and/or chemotherapy were discontinued in 44% of patients and at least one dose was withheld in 76% of patients due to an adverse reaction.
The most frequent serious adverse reactions reported in ≥2% of patients treated with intravenous nivolumab in combination with chemotherapy were vomiting (3.7%), pneumonia (3.6%), anemia (3.6%), pyrexia (2.8%), diarrhea (2.7%), febrile neutropenia (2.6%), and pneumonitis (2.4%). The most common adverse reactions reported in ≥20% of patients treated with intravenous nivolumab in combination with chemotherapy were peripheral neuropathy, nausea, fatigue, diarrhea, vomiting, decreased appetite, abdominal pain, constipation, and musculoskeletal pain.
Tables 47 and 48 summarize the adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-649.
3.2Postmarketing Experience
The following adverse reactions have been identified during post-approval use of intravenous nivolumab. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Eye: Vogt-Koyanagi-Harada (VKH) syndrome
Complications of Intravenous Nivolumab Treatment After Allogeneic HSCT: Treatment refractory, severe acute and chronic GVHD
Blood and lymphatic system disorders: Hemophagocytic lymphohistiocytosis (HLH) (including fatal cases), autoimmune hemolytic anemia (including fatal cases)
4DESCRIPTION
OPDIVO QVANTIG is a fixed-combination drug product containing nivolumab and hyaluronidase (human recombinant).
Nivolumab is a programmed death receptor-1 (PD-1) blocking antibody. Nivolumab is an IgG4 kappa immunoglobulin that has a calculated molecular mass of 146 kDa. It is expressed in a recombinant Chinese Hamster Ovary (CHO) cell line.
Hyaluronidase (human recombinant) is an endoglycosidase used to increase the dispersion and absorption of co-administered drugs when administered subcutaneously. Hyaluronidase (human recombinant) is a glycosylated single-chain protein produced by CHO cells containing a DNA plasmid encoding for a soluble fragment of human hyaluronidase (PH20). Hyaluronidase (human recombinant) has a molecular weight of approximately 61 kDa.
OPDIVO QVANTIG (nivolumab and hyaluronidase-nvhy) injection is a sterile, preservative-free, clear to opalescent, colorless to yellow solution that may contain a few translucent-to-white particles, supplied in a single-dose vial for subcutaneous use.
Each 2.5 mL single-dose vial contains 300 mg of nivolumab and 5,000 units of hyaluronidase (human recombinant), and the inactive ingredients: histidine (3.88 mg), histidine hydrochloride monohydrate (5.25 mg), methionine (1.87 mg), pentetic acid (0.049 mg), polysorbate 80 (1.25 mg), sucrose (214 mg), and Water for Injection, USP. The pH is 5.5 to 6.5.
Each 5 mL single-dose vial contains 600 mg of nivolumab and 10,000 units of hyaluronidase (human recombinant), and the inactive ingredients: histidine (7.75 mg), histidine hydrochloride monohydrate (10.5 mg), methionine (3.73 mg), pentetic acid (0.0985 mg), polysorbate 80 (2.5 mg), sucrose (428 mg), and Water for Injection, USP. The pH is 5.5 to 6.5.
5HOW SUPPLIED/STORAGE AND HANDLING
OPDIVO QVANTIG™ (nivolumab and hyaluronidase-nvhy) injection is a sterile, preservative-free, clear to opalescent and colorless to yellow solution for subcutaneous use. It is supplied as an individually packaged single-dose vial as follows:
Store OPDIVO QVANTIG vials in a refrigerator at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light.
Do not freeze or shake.
6PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Immune-Mediated Adverse Reactions
Inform patients of the risk of immune-mediated adverse reactions that may require corticosteroid treatment and withholding or discontinuation of OPDIVO QVANTIG, including:
- Pneumonitis: Advise patients to contact their healthcare provider immediately for any new or worsening cough, chest pain, or shortness of breath
- Colitis: Advise patients to contact their healthcare provider immediately for diarrhea or severe abdominal pain
- Hepatitis: Advise patients to contact their healthcare provider immediately for jaundice, severe nausea or vomiting, pain on the right side of abdomen, lethargy, or easy bruising or bleeding
- Endocrinopathies: Advise patients to contact their healthcare provider immediately for signs or symptoms of hypophysitis, adrenal insufficiency, hypothyroidism, hyperthyroidism, and diabetes mellitus
- Nephritis and Renal Dysfunction: Advise patients to contact their healthcare provider immediately for signs or symptoms of nephritis including decreased urine output, blood in urine, swelling in ankles, loss of appetite, and any other symptoms of renal dysfunction
- Skin Adverse Reactions: Advise patients to contact their healthcare provider immediately for rash
- Other immune-mediated adverse reactions:
Complications of Allogeneic HSCT
- Advise patients of potential risk of post-transplant complications
Embryo-Fetal Toxicity
- Advise females of reproductive potential of the potential risk to a fetus and to inform their healthcare provider of a known or suspected pregnancy
- Advise females of reproductive potential to use effective contraception during treatment with OPDIVO QVANTIG and for 5 months following the last dose
Lactation
- Advise women not to breastfeed during treatment with OPDIVO QVANTIG and for 5 months after the last dose
Manufactured by:
Bristol-Myers Squibb Company
U.S. License No. 1713
Halozyme Therapeutics, Inc.
U.S. License No. 2187
7OPDIVO QVANTIG™ 300 mg and 5,000 units/2.5 mL Representative Packaging
Rx Only
OPDIVO QVANTIG™
300 mg and 5,000 units/2.5 mL
Single-dose vial;
Bristol Myers Squibb
8OPDIVO QVANTIGTMmg and 10,000 units/5 mL Representative Packaging
Rx Only
OPDIVO QVANTIG™
600 mg and 10,000 units/5 mL
Single-dose vial;
Bristol Myers Squibb