Allopathy
Prescription Required
DCGI (Drugs Controller General of India)
Schedule H
Nivolumab is an antineoplastic agent belonging to the pharmacological class of Programmed Death-Ligand 1 (PD-L1) inhibitors.
The FDA approves Nivolumab for treating melanoma, non small-cell lung cancer, renal cell cancer, bladder cancer, head and neck cancer, and Hodgkin lymphoma.
Nivolumab is administered intravenously, achieving systemic absorption. It undergoes distribution throughout the body, primarily in the blood. Metabolism occurs in tissues with unclear details. Elimination involves clearance through the reticuloendothelial system, with a half-life of around 25 days.
The most common side effects of Nivolumab include fatigue, nausea, decreased appetite, constipation, cough, and shortness of breath.
Nivolumab is available as an injectable solution.
The molecule is available in India, the United States, the United Kingdom, Germany, Japan, Australia, Canada, France, and Italy.
Nivolumab is an antineoplastic agent belonging to the pharmacological class of programmed death-ligand 1 (PD-L1) inhibitors.
Nivolumab, a human immunoglobulin G4 (IgG4) monoclonal antibody, activates the immune response to tumour cells by binding to the harmful immunoregulatory protein programmed death-1 (PD-1) receptor. Tumour cells expressing PD-L1 and PD-L2 inhibit T-cell action by binding to the PD-1 receptor. Nivolumab prevents this inhibition, restoring a patient's tumor-specific T-cell response.
Steady-state for Nivolumab is reached after 12 weeks of monotherapy.
Nivolumab is available as an injectable solution.
Injectable solutions: To be administered parenterally, as applicable.
As prescribed by the physician, take the medication with or without meals.
- Non-small cell lung cancer
- Kidney cancer
- Head and neck cancer
- Melanoma
- Hodgkin’s disease
- Liver cancer
- Non-small cell lung cancer: By focusing on the PD-L1 pathways, Nivolumab effectively treats non-small cell lung cancer (NSCLC) by boosting the immune system's ability to identify and destroy cancer cells. It is a PD-L1 inhibitor that helps patients with advanced or metastatic NSCLC that is mainly brought on by cigarette smoking by improving overall survival, progression-free survival, and therapeutic outcomes.
- Melanoma: Melanoma, a common type of skin cancer that develops from melanocytes, which produce pigment. Nivolumab targets the PD-L1 pathway in melanoma, improving treatment outcomes and overall survival by strengthening the immune system's ability to combat cancer cells.
- Treatment of Hepatocellular carcinoma: Hepatocellular carcinoma (HCC) is an effective treatment for primary liver cancer produced by hepatocytes treated with Nivolumab. Its effectiveness is due to its ability to interfere with the immune system's PD-L1-mediated suppression, which permits a focused anti-cancer response. With the potential to prolong life and enhance patient quality of life, targeted immunotherapy offers a promising approach to managing HCC.
- Head and neck cancer: Cancer of the mouth, nose, sinuses, or throat is categorized as head and neck cancer. Cancer cells cannot increase after injecting Nivolumab; instead, they are killed or stopped from growing. Consult a doctor about the advantages and hazards of taking this potent and highly toxic drug. When receiving this medication, you should abstain from smoking and alcohol. One should also keep hydrated by drinking lots of water.
- Liver Cancer: Hepatocytes, which are the cells that make up the liver, are the cells that can develop cancer. In its early stages, cancer may not show any signs at all, but when it progresses to later stages, it may cause symptoms including weight loss, vomiting, stomach discomfort, and yellowing skin. By killing cancer cells, nivolumab stops the disease from growing and spreading to other unaffected areas. Refrain from smoking and consuming alcohol. Smoking and alcohol use might exacerbate the disease, thereby making recovery challenging.
- Hodgkin’s disease: A kind of blood cancer called lymphoma, which originates in the lymphatic system, is Hodgkin's disease. The lymphatic system aids in the immune system's ability to eliminate waste and combat infections. Nivolumab inhibits the growth and/or kills cancer cells and their ability to increase.
Nivolumab is indicated in the following conditions:
- Adjuvant treatment for melanoma in patients aged ≥12 years with wholly resected Stage IIB, Stage IIC, Stage III, or Stage IV disease.
- Single-agent or in combination with ipilimumab for unresectable or metastatic melanoma in pediatric and adults patients aged ≥12 years.
- Neoadjuvant treatment in combination with the platinum-doublet chemotherapy for resectable non-small cell lung cancer (NSCLC).
- Monotherapy for metastatic NSCLC with progression after platinum-based chemotherapy.
- As a first-line treatment of metastatic non-small cell lung cancer (NSCLC) when combined with ipilimumab.Also in the treatment of metastatic or recurrent NSCLC in the adults when combined with ipilimumab and platinum-doublet chemotherapy.
- First-line treatment for unresectable malignant pleural mesothelioma when combined with ipilimumab.
- Combination with cabozantinib for first-line advanced renal cell carcinoma (RCC) treatment.
- Intermediate or poor-risk, previously untreated advanced RCC.
- As a single agent for advanced RCC in those patients who received prior antiangiogenic therapy.
- Relapsed or progressed classical Hodgkin lymphoma (cHL).
- Recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) until the disease progression on or after platinum-based therapy.
- Locally advanced or metastatic urothelial carcinoma (UC) with disease progression during or following the platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.
- Adjuvant treatment of urothelial carcinoma (UC) in patients at high risk of recurrence after radical resection.
- Single-agent or in combination with ipilimumab for microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (CRC) that progressed after fluoropyrimidine, oxaliplatin and irinotecan treatment.
- Combination with ipilimumab for hepatocellular carcinoma (HCC) in those patients previously treated with sorafenib.
- Unresectable advanced, recurrent, or metastatic oesophagal squamous cell carcinoma (ESCC) previously treated with fluoropyrimidine- and platinum-based chemotherapy.
- As a first-line treatment of unresectable advanced or metastatic ESCC when combined with fluoropyrimidine- and platinum-based chemotherapy or ipilimumab.
- Completely resected oesophagal or gastroesophageal junction cancer with residual pathologic disease after neoadjuvant chemoradiotherapy.
- Combination with fluoropyrimidine- and platinum-containing chemotherapy is indicated for advanced or metastatic gastric cancer, gastroesophageal junction cancer, and oesophagal adenocarcinoma.
Parenterally: Administer Nivolumab exclusively via intravenous (IV) infusion for 30-60 minutes, using an IV line equipped with a sterile, nonpyrogenic, low protein-binding inline filter (pore size of 0.2-1.2 microns). Inspect the drug for particulate matter and discolouration, ensuring it is clear to opalescent and colourless to the pale-yellow solution. Before administering, dilute vials comprise of 10 mg per mL with NaCl 0.9% solution or glucose 5% solution to provide a solution containing approximately 1-10 mg/mL. Do not shake. Ensure that, for adult and pediatric patients (<40 kg), the total infusion volume does not exceed 4 mL/kg of body weight. Avoid coadministering other drugs through the same IV line. When combined with ipilimumab, infuse Nivolumab first over 30 minutes, followed by ipilimumab over 30 minutes on the same day, utilizing separate infusion bags and filters for each. If administering chemotherapy on the same day, administer Nivolumab before chemotherapy. Flush the IV line at the end of the infusion.
The dosage and duration of treatment should be as per the treating physician's clinical judgment.
Nivolumab is available as an injectable solution.
Dose Adjustment in Adult Patients:
Locally advanced urothelial carcinoma, Advanced renal cell carcinoma, Locally advanced non-small cell lung carcinoma, Metastatic non-small cell lung carcinoma, Metastatic melanoma, Metastatic squamous cell carcinoma of the head and neck, Refractory classical Hodgkin lymphoma, Metastatic urothelial carcinoma, Relapsed classical Hodgkin lymphoma, Locally advanced squamous cell carcinoma of the head and neck
Administer 3 mg/kg by infusion over 60 minutes every two weeks. Continued until disease progression or the toxicity became unacceptable.
Metastatic colorectal cancer
240 mg administered every two weeks by infusion for 60 minutes. Continued until the illness worsened or the toxicity became unacceptable.
Hepatocellular carcinoma
240 mg administered every two weeks by infusion for 60 minutes. Continued until the illness worsened or the toxicity became unacceptable.
Metastatic melanoma
1 mg/kg, administered by infusion over 60 minutes, four times a week for a total of four doses, in combination with ipilimumab. After that, use 3 mg/kg as monotherapy for 60 minutes every two weeks. Continued until unacceptable toxicity or the advancement of the illness.
While undergoing Nivolumab treatment, it is crucial to refrain from consuming antioxidant-rich foods like berries and spinach for added health benefits. Integrate fibre-rich options into your diet, including beans, whole grains, peas, lentils, nuts, and seeds, as they contribute to improved digestion.
The dietary restriction should be individualized as per patient requirements.
- Immune-Mediated Adverse Reactions: Severe or fatal immune-mediated reactions impacting diverse organ systems, such as pneumonitis, colitis, hepatitis, hepatotoxicity, endocrinopathies, dermatologic adverse reactions, nephritis, and renal dysfunction, may occur. Diligent monitoring for early identification is imperative. Regular assessment of liver enzymes, creatinine, and thyroid function at baseline and throughout treatment is advised. Adjustments in treatment involving withholding or permanent discontinuation should be implemented based on the severity and type of the reaction.
- Infusion-Related Reactions: Infusion-related reactions may occur during or after administration of nivolumab. These reactions can range in severity. In the event of such reactions, consider interrupting the infusion, slowing the infusion rate, or permanently discontinuing nivolumab based on the severity of the reaction. Close monitoring and appropriate medical management are essential to mitigate potential risks associated with infusion-related reactions.
- Hepatotoxicity: When used in combination with cabozantinib, there is an increased risk of hepatic toxicity, including higher frequencies of Grades 3 and 4 ALT and AST elevations compared to the use of the drug alone. Monitor liver enzymes before starting treatment and regularly throughout. Consider more frequent monitoring of liver enzymes compared to when the drugs are administered as single agent. In the case of elevated liver enzymes, interrupt the combination with cabozantinib and consider administering corticosteroids.
- Fatal and severe complications may occur in patients receiving allogeneic hematopoietic stem cell transplantation (HSCT) before or after PD-1/PD-L1 blocking antibody treatment.
- It is advisable to avoid using a PD-1 or PD-L1 blocking antibody in combination with a thalidomide analogue plus dexamethasone for treating multiple myeloma outside controlled clinical trials.
- Interrupt, slow the infusion rate, or permanently discontinue Nivolumab, depending on the severity of infusion-related reactions.
- When combining with ipilimumab, consult the prescribing information for additional risk details relevant to the combined treatment.
- In clinical trials involving multiple myeloma patients, the introduction of a PD-1 blocking antibody to a thalidomide analogue plus dexamethasone led to elevated mortality rates.
Alcohol Warning
Breast Feeding Warning
Pregnancy Warning
Food Warning
The adverse reactions related to Nivolumab can be categorized as:
- Common Adverse Effects: Rash, pruritus, cough, upper respiratory tract infection, and peripheral oedema
- Less Common Adverse Effects: Complications of allogeneic hematopoietic stem cell transplantation, infusion-related reactions, and embryo-fetal toxicity.
- Rare Adverse Effects: Immune-mediated pneumonitis, colitis, hepatitis, endocrinopathies, dermatologic adverse reactions, nephritis, and renal dysfunction.
Reports on Postmarketing
Vogt-Koyanagi-Harada (VKH) syndrome; diseases of the eyes
Treatment-related side effects following allogeneic hematopoietic stem cell transplantation include severe acute and chronic graft versus host disease (GVHD) and treatment resistance.
pyrexia
Acute backache
A general decline in physical health
Discomfort in the abdomen
Pneumonia
Anemia
Pathology of hemophagocytic lymphohistiocytosis (HLH)
Autoimmune hemolytic anemia
The clinically relevant drug interactions of Nivolumab are briefly summarized here.
Nivolumab may increase the risk of side effects, such as tiredness, nausea, vomiting, diarrhoea, and musculoskeletal discomfort, when combined with several chemotherapeutic drugs, such as Fluoropyrimidine, Platinum-Doublet, and Platinum-Containing.
Hepatic toxicity may be more likely when nivolumab and cabozantinib, a tyrosine kinase inhibitor, are used together.
Reduced immunosuppressive treatment effects might be fatal.
- Pregnancy
Pregnancy Category D (FDA): Use in cases where no safer medication is available, and life is in danger. Positive evidence of prenatal risk in humans.
If given to a pregnant woman, there may be fetal damage according to its method of action and findings from animal studies.
There is no human data available to determine the risk linked with drugs.
Animal data
In investigations on animal reproduction, giving nivolumab to cynomolgus monkeys from the beginning of organogenesis until delivery caused a rise in abortions and the early death of babies.
Nivolumab is an immunoglobulin G4 (IgG4), and since human IgG4 is known to penetrate the placental barrier, there is a chance that the mother might pass Nivolumab to the growing fetus.
Nivolumab's effects are probably noticeable in the second and third trimesters of pregnancy.
Contraception
Potential fertile females: Before starting therapy, establish the pregnancy status; use effective contraception while taking nivolumab; and for at least 5 months following the last dose of therapy
- Nursing Mothers
There is no information available on nivolumab's presence in human milk, its effects on nursing children, or its impact on milk production. Recommend that women refrain from breastfeeding throughout therapy and for five months following the final dose of Nivolumab due to the potential of severe adverse effects in the breastfed infant.
- Pediatric Use
Nivolumab's safety and efficacy have been established in pediatric patients more than 12 years of age for the following indications: unresectable or metastatic melanoma as a single agent and in combination with ipilimumab; adjuvant treatment of wholly resected Stage IIB, Stage IIC, Stage III, or Stage IV melanoma as a single agent and in combination with ipilimumab; and MSI-H or dMMR mCRC that has progressed after treatment with a oxaliplatin, fluoropyrimidine, and irinotecan. Sufficient and well-conducted trials in adults with melanoma, MSI-H, or dMMR mCRC, as well as extra pharmacokinetic information in pediatric patients, support the use of nivolumab.
Exposure of pediatric patients to nivolumab The age range of 12 years and above is similar to that of adults. In pediatric patients, the melanoma and MSI-H or dMMR mCRC courses are equivalent to those of adults, allowing for the extrapolation of safety and effectiveness.
Pediatric patients with melanoma, MSI-H, or dMMR mCRC who are less than 12 years old may not benefit from Nivolumab due to safety and efficacy concerns.
Pediatric patients with squamous cell carcinoma of the head and neck, malignant pleural mesothelioma, advanced renal cell carcinoma, urothelial carcinoma, hepatocellular carcinoma, oesophagal cancer, gastric cancer, gastroesophageal cancer, oesophagal adenocarcinoma have not had the safety and efficacy of nivolumab established.
Dose Adjustment in Kidney Impairment Patients:
Mild to Severe: No need to change the dosage.
Dose Adjustment in Hepatic Impairment Patients:
Mild or moderate: It is not advised to change the dosage.
Severe: Unstudied
There is no information available regarding Nivolumab overdose.
In the event of a Nivolumab overdose, patients should start receiving the proper symptomatic treatment and be continuously observed for indications of adverse reactions.
Pharmacodynamic
Nivolumab prevents T-cells from receiving signals that suppress PD-1.6. Because it is taken every two to four weeks, its duration of effect is long.6. Patients should be informed about the possibility of immunological-mediated side effects, infusion-related side effects, allogenic hematopoietic stem cell transplant problems, and embryo-fetal damage.
Pharmacokinetics
When the pharmacokinetics of nivolumab were extensively investigated, it was shown that exposure increased in a dose-proportionate manner between 0.1 and 10 mg/kg. Comparability between 30- and 60-minute infusions was demonstrated by the effect of infusion time on expected exposure. The systemic accumulation was 3.7 times higher with a dosage of 3 mg per kg every two weeks, reaching steady-state concentrations by the end of 12 weeks. The distribution was identified with a Vd of 6.8 L (monotherapy) and 7.92 L (combined with ipilimumab). At 8.2 mL/h (53.9%), the geometric mean steady-state clearance was reached, showing a time-dependent decline in clearance. The half-lives were 24.8 days and 25 days when combined with ipilimumab.
Distribution: When ipilimumab was added, the volume of distribution (Vd) increased to 7.92 L from 6.8 L in monotherapy.
Elimination: A steady-state clearance (CLss) of 8.2 mL/h (53.9%) was reached after nivolumab clearance (CL) showed a time-dependent decrease. It is believed that this decrease is not clinically significant. Clearance did not deteriorate with time in individuals with fully resected melanoma, in contrast to metastatic melanoma, highlighting its population-specific heterogeneity. Nivolumab's half-life was 24.8 days when paired with ipilimumab and 25 days when used alone.
- Guo L, Zhang H, Chen B. Nivolumab as Programmed Death-1 (PD-1) Inhibitor for Targeted Immunotherapy in Tumor. J Cancer. 2017 Feb 10;8(3):410-416. doi: 10.7150/jca.17144. PMID: 28261342; PMCID: PMC5332892.
- Tanizaki J, Yonemori K, Akiyoshi K, Minami H, Ueda H, Takiguchi Y, Miura Y, Segawa Y, Takahashi S, Iwamoto Y, Kidera Y, Fukuoka K, Ito A, Chiba Y, Sakai K, Nishio K, Nakagawa K, Hayashi H. Open-label phase II study of the efficacy of nivolumab for cancer of unknown primary. Ann Oncol. 2022 Feb;33(2):216-226. doi: 10.1016/j.annonc.2021.11.009. Epub 2021 Nov 26. PMID: 34843940.
- Almohideb M. Safety and efficacy of nivolumab compared with other regimens in patients with melanoma: A network meta-analysis. Medicine (Baltimore). 2022 Sep 2;101(35):e29390. doi: 10.1097/MD.0000000000029390. PMID: 36107612; PMCID: PMC9439759.
- Owen DH, Benner B, Wei L, Sukrithan V, Goyal A, Zhou Y, Pilcher C, Suffren SA, Christenson G, Curtis N, Jukich M, Schwarz E, Savardekar H, Norman R, Ferguson S, Kleiber B, Wesolowski R, Carson WE, Otterson GA, Verschraegen CF, Shah MH, Konda B. A Phase II Clinical Trial of Nivolumab and Temozolomide for Neuroendocrine Neoplasms. Clin Cancer Res. 2023 Feb 16;29(4):731-741. doi: 10.1158/1078-0432.CCR-22-1552. PMID: 36255391; PMCID: PMC9932582.
- https://www.ncbi.nlm.nih.gov/books/NBK567801/
- https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/125554s112lbl.pdf
- https://www.ncbi.nlm.nih.gov/books/NBK548206/
- https://www.ema.europa.eu/en/documents/product-information/opdivo-epar-product-information_en.pdf
