Yervoy (ipilimumab)

Dosage reduction is not recommended for adverse reactions. In general, withhold ipilimumab for severe (grade 3) immune-mediated adverse reactions.

Permanently discontinue ipilimumab therapy in patients experiencing life-threatening (grade 4) immune-mediated adverse reactions; recurrent severe (grade 3) immune-mediated reactions that require systemic immunosuppressive treatment; persistent moderate (grade 2) or severe (grade 3) reactions (excluding endocrinopathy) lasting 12 weeks or longer after the last ipilimumab dose; or an inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks of initiating steroids.

When ipilimumab is administered in combination with nivolumab, withhold or permanently discontinue both ipilimumab and nivolumab for toxicity.

Ipilimumab is available as a 5-mg/mL, preservative-free, injection concentrate in single-use vials containing 50 or 200 mg of the drug.

Ipilimumab is administered by IV infusion. Dilution of the concentrate is required prior to administration. Administer diluted ipilimumab through an IV line containing an inline, sterile, nonpyrogenic, low-protein-binding filter. Flush the IV line with 0.9% sodium chloride or 5% dextrose injection after each dose.

When administered in combination with nivolumab, infuse nivolumab first followed by ipilimumab on the same day.

When administered with nivolumab and platinum-doublet chemotherapy, infuse nivolumab first followed by ipilimumab, and then platinum-doublet chemotherapy on the same day. Use separate infusion bags and filters for each infusion. Do not co-administer other drugs through the same IV line.

Store ipilimumab injection concentrate at 2-8degreesC. Do not shake or freeze; protect from light by storing in the original carton until time of use.

The diluted solution may be refrigerated (2-8degreesC) or stored at controlled room temperature (20-25degreesC) for no more than 24 hours from the time of preparation to the time of infusion. Discard any partially used vials, including unused diluted solution.

No dosing information is available for this tab.

Other than use in combination with nivolumab and antineoplastic chemotherapy, no formal drug interaction studies have been performed to date.

There are no contraindication interactions for this drug.

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Igg Antibodies And Derivatives/Efgartigimod-Alfa

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: The neonatal Fc receptor (FcRn) prevents catabolism and mediates recycling of IgG and albumin, which leads to their long persistence in the body.(1,2) Efgartigimod-alfa binds to FcRn and may decrease systemic exposure of other ligands of FcRn, like immunoglobulins and IgG-based antibodies.(3)

CLINICAL EFFECTS: The effectiveness of medicines that bind to FcRn may be decreased.(3)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of efgartigimod-alfa states that efgartigimod-alfa should not be combined with long-term use of FcRn-binding medications. If the medication is essential for the patient, efgartigimod-alfa should be discontinued.(3)

DISCUSSION: Clinical drug interaction studies with efgartigimod-alfa have not been performed. Efgartigimod-alfa may decrease concentrations of compounds that bind to the human FcRn.(3)

Igg Antibodies And Derivatives/Nipocalimab-Aahu

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: The neonatal Fc receptor (FcRn) prevents catabolism and mediates recycling of IgG and albumin, which leads to their long persistence in the body.(1,2) Nipocalimab-aahu binds to FcRn and may decrease systemic exposure of other ligands of FcRn, like immunoglobulins and IgG-based antibodies.(3)

CLINICAL EFFECTS: The effectiveness of medicines that bind to FcRn may be decreased.(3)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of nipocalimab-aahu states that nipocalimab-aahu should not be combined with long-term use of FcRn-binding medications. If the medication is essential for the patient, nipocalimab-aahu should be discontinued.(3)

DISCUSSION: Clinical drug interaction studies with nipocalimab-aahu have not been performed. Nipocalimab-aahu may decrease concentrations of compounds that bind to the human FcRn.(3)

Moderate Interaction: Assess the risk to the patient and take action as needed.

Igg Antibodies And Derivatives/Rozanolixizumab-Noli

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The neonatal Fc receptor (FcRn) prevents catabolism and mediates recycling of IgG and albumin, which leads to their long persistence in the body.(1,2) Rozanolixizumab-noli binds to FcRn and may decrease systemic exposure of other ligands of FcRn, like immunoglobulins and IgG-based antibodies.(3)

CLINICAL EFFECTS: The effectiveness of medications that bind to FcRn may be decreased.(3)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of rozanolixizumab-noli states that concurrent use with medications that bind to the human neonatal Fc receptor (FcRn) should be closely monitored for reduced effectiveness of these medications. If long-term use of such medications is essential for the patient, consider discontinuing rozanolixizumab-noli and use alternative therapies.(3)

DISCUSSION: Clinical drug interaction studies with rozanolixizumab-noli have not been performed. Rozanolixizumab-noli may decrease concentrations of compounds that bind to the human FcRn.(3)

Immune Checkpoint Inhibitors/Proton Pump Inhibitors

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The mechanism of this interaction has not been fully investigated. Proposed mechanisms include: 1. Proton pump inhibitor (PPI)-induced changes of the microbiota (dysbiosis) causing resistance to immune checkpoint inhibitors, 2. Co-administration of PPIs with corticosteroids or non steroidal anti-inflammatory drugs (NSAIDs) and immune checkpoint inhibitors resulting in poorer prognosis.(1)

CLINICAL EFFECTS: PPIs may decrease the therapeutic effects of immune checkpoint inhibitors. Several observational studies have shown a reduction in progression free survival (PFS), overall survival (OS), and tumor response in patients on concurrent treatment with immune checkpoint inhibitors and PPIs.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Concurrent use of immune checkpoint inhibitors and PPIs should be approached with caution. Manufacturers of immune checkpoint inhibitors do not provide recommendations on the concurrent use of PPIs. Primary literature on the concurrent use of these agents include recommendations to evaluate the risks and benefits of PPI use and consideration of alternative therapy when possible such as histamine H2-receptor antagonists (H2RAs) or antacids.(1-3)

DISCUSSION: A meta analysis of 23 studies evaluating the impact of acid suppressing therapy on the efficacy of immune checkpoint inhibitors found coadministration of a PPI decreased PFS (HR 1.34 [95% confidence interval (CI), 1.13 to 1.58]) and OS (HR 1.43 [95% CI, 1.21 to 1.69]) compared with patients not treated with PPIs. Furthermore, the meta analysis identified that H2RAs did not affect OS. These results were consistent across cancer types.(1) In another meta analysis of 22 studies (5 prospective and 17 retrospective, n=16,072) evaluating the impact of concomitant medications on survival outcomes in patients treated with systemic therapy for advanced unresectable or metastatic renal cell carcinoma, concomitant use of PPIs (n=3959) was significantly associated with worse OS in patients treated with immune checkpoint inhibitors (HR 1.22, P=0.01).(4) A retrospective analysis of 635 patients treated with immune checkpoint inhibitors found PPI use was associated with significantly decreased OS (9 vs 26.5 months), PFS (3.5 vs. 8 months), and tumor response (61% vs. 72%).(5) Analysis of retrospective data from clinical trials of atezolizumab for urothelial carcinoma and non-small-cell lung cancer, among patients using a PPI within 30 days before or after therapy initiation, OS was significantly worse for patients randomized to treatment with atezolizumab than for patients randomized to chemotherapy.(6,7) A retrospective study of 381 patients treated with immune checkpoint inhibitors found use of acid-suppression therapy (n=168 PPIs, n=37 potassium competitive acid blocker, n=13 H2RAs) was associated with significantly shorter PFS and OS (2.9 vs. 6.2 months and 12.3 vs. 24 months, respectively) compared with patients who did not use acid-suppression therapy. However, when stratified by concomitant use of corticosteroids or NSAIDs, use of acid-suppression therapy was not associated with worse progression-free or overall survival.(8) In a retrospective cohort study of patients with advanced non-small-cell lung cancer treated with pembrolizumab, exposure to PPIs was associated with worse OS (HR, 1.13; 95% CI, 1.10-1.17).(9) Analysis of US and Japanese adverse drug event reporting system databases found administration of immune checkpoint inhibitors and PPIs was associated with an increased risk of adverse events including acute kidney injury (10) and congenital, familial and genetic disorders.(11) In a meta analysis of 14 observational studies, the risk of immune checkpoint inhibitor related AKI (ICI-AKI) in cancer patients concurrently using PPIs was found to be significantly higher (pooled OR of 1.84 [95% CI 1.16-2.90]) in comparison to the overall incidence of AKI from all-causes (1.57 [95% CI 1.02-2.40]).(12) In contrast to these findings, other studies have not found a negative effect on PFS or OS when patients are co-administered PPIs and immune checkpoint inhibitors. In a retrospective study of 159 patients treated with ipilimumab, coadministration of PPIs was associated with increased odds of experiencing a partial or complete response to ipilimumab (OR 3.73 [95% CI, 1.26 to 11.04]).(13) In another retrospective study of 233 patients who received nivolumab or pembrolizumab, use of PPI had no effect on OS (HR 1.2 [95% CI, 0.8-1.9]) or PFS (HR 1.1 [95% CI, 0.8 to 1.5]).(14) A nested case-control study of patients (n=38,930) with cancer who were new PPI or immune checkpoint inhibitor users and had no history of AKI before cohort entry, found the risk of AKI in patients treated with both PPIs and immune checkpoint inhibitors was not higher than then additional or multiplication of the risks in those who were treated with PPIs or immune checkpoint inhibitors alone. The study reinforces the association between PPIs and immune checkpoint inhibitors use and the increased risk of AKI and the need for careful monitoring and evaluation of kidney function when treated with both medicines.(15)

*None.

• Lactation

• Guillain-barre syndrome
• Pregnancy

• Hyperthyroidism
• Hypothyroidism
• Kidney disease with reduction in glomerular filtration rate (GFr)
• Myasthenia gravis

The most common adverse reactions (>=20%) with ipilimumab as a single agent are fatigue, diarrhea, pruritus, rash, nausea, and headache.

The most common adverse reactions (>=20%) with ipilimumab in combination with nivolumab are fatigue, diarrhea, rash, pruritus, nausea, musculoskeletal pain, pyrexia, cough, decreased appetite, vomiting, abdominal pain, dyspnea, upper respiratory tract infection, arthralgia, headache, hypothyroidism, constipation, decreased weight, and dizziness.

The most common adverse reactions (>=20%) with ipilimumab in combination with nivolumab and platinum doublet chemotherapy are fatigue, musculoskeletal pain, nausea, diarrhea, rash, decreased appetite, constipation, and pruritus.

More Frequent

• Colitis
• Lymphopenia

Less Frequent

• Abnormal hepatic function tests
• Anemia
• Enterocolitis
• Hepatitis
• Hypercortisolism
• Hyperthyroidism
• Hypothyroidism
• Ileus
• Pituitary insufficiency

Rare or Very Rare

• Acute respiratory distress syndrome
• Adrenocortical insufficiency
• Aplastic anemia
• Autoimmune hemolytic anemia
• Autoimmune hepatitis
• Cytomegalovirus colitis
• DRESS syndrome
• Duodenitis
• Encephalitis
• Erythema multiforme
• Esophagitis
• Gastrointestinal perforation
• Gastrointestinal ulcer
• Giant cell arteritis
• Graft-versus-host disease
• Guillain-barre syndrome
• Hashimoto thyroiditis
• Hearing loss
• Hemophagocytic lymphohistiocytosis
• Hepatic failure
• Histiocytic necrotizing lymphadenitis
• Hypersensitivity angiitis
• Hypersensitivity drug reaction
• Hypersensitivity pneumonitis
• Hypophysitis
• Interstitial nephritis
• Interstitial pneumonitis
• Intestinal perforation
• Iritis
• Meningitis
• Multiple organ failure
• Muscle weakness
• Myasthenia gravis
• Myelitis
• Myocarditis
• Myositis
• Nephritis
• Orbital myositis
• Organ transplant rejection
• Pancreatitis
• Pericarditis
• Peripheral motor neuropathy
• Polymyalgia rheumatica
• Polymyositis
• Posterior reversible encephalopathy syndrome
• Renal failure
• Retinal detachment
• Rhabdomyolysis
• Sarcoidosis
• Scleritis
• Sepsis
• Stevens-johnson syndrome
• Toxic epidermal necrolysis
• Uveitis
• Vasculitis
• Vision impairment
• Vogt-koyanagi-harada disease

More Frequent

• Acute abdominal pain
• Anorexia
• Arthralgia
• Constipation
• Cough
• Diarrhea
• Dizziness
• Dyspnea
• Fatigue
• Fever
• Headache disorder
• Myalgia
• Nausea
• Pruritus of skin
• Skin rash
• Upper respiratory infection
• Weight loss

Less Frequent

• Elevated serum amylase
• Elevated serum lipase
• Hypocalcemia
• Hypogonadotropic hypogonadism
• Hypokalemia
• Hyponatremia
• Increased alkaline phosphatase
• Insomnia
• Myopathy
• Pneumonia
• Skin inflammation
• Urticaria
• Vomiting

Rare or Very Rare

• Arthritis
• Blepharitis
• Blurred vision
• Conjunctivitis
• Eosinophilia
• Hypoesthesia
• Paresthesia
• Peripheral sensory neuropathy
• Psoriasis
• Reduced visual acuity

No enhanced messaging available.

The safety and effectiveness of ipilimumab have been established in pediatric patients 12 years of age and older for the following indications: as a single agent and in combination with nivolumab for unresectable or metastatic melanoma; in combination with nivolumab for the treatment of microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR ) unresectable and metastatic CRC; and in combination with nivolumab for MSI-H or dMMR mCRC that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.

The safety and effectiveness of ipilimumab have not been established in pediatric patients <12 years of age with unresectable or metastatic melanoma or MSI-H or dMMR mCRC.

The safety and effectiveness of ipilimumab have not been established in pediatric patients for the adjuvant treatment of melanoma or for the treatment of advanced renal cell carcinoma, hepatocellular carcinoma, metastatic non-small cell lung cancer, malignant pleural mesothelioma, or esophageal cancer.

Based on findings from animal studies and its mechanism of action, ipilimumab can cause fetal harm when administered to a pregnant woman. There is insufficient human data for ipilimumab exposure in pregnant women. In animal reproduction studies, administration of ipilimumab to cynomolgus monkeys from the onset of organogenesis through delivery resulted in higher incidences of abortion, stillbirth, premature delivery (with corresponding lower birth weight), and higher incidences of infant mortality in a dose-related manner. The effects of ipilimumab are likely to be greater during the second and third trimesters of pregnancy.

Human IgG1is known to cross the placental barrier and ipilimumab is an IgG1; therefore, ipilimumab has the potential to be transmitted from the mother to the developing fetus.

Verify pregnancy status in females of reproductive potential prior to initiating ipilimumab. Advise pregnant women of the potential risk to a fetus. Report pregnancies to the manufacturer (Bristol-Myers Squibb) at 1-844-593-7869.

There are no data on the presence of ipilimumab in human milk or its effects on the breast-fed child or milk production. In monkeys, ipilimumab was present in milk.

Because of the potential for serious adverse reactions in breastfed children, advise women not to breast-feed during treatment with ipilimumab and for 3 months following the last dose.

The manufacturer makes no specific dosage recommendations for geriatric patients.

No overall differences in safety were observed between younger patients and patients >=65 years of age with ipilimumab as monotherapy for unresectable or metastatic melanoma or in combination with nivolumab for renal cell carcinoma.

Although no overall differences in safety were observed between younger patients and patients >=65 years of age, discontinuation rates due to adverse reactions were higher in patients >=75 years of age who received combination treatment with ipilimumab and nivolumab for NSCLC, malignant pleural mesothelioma, metastatic CRC (in patients >=65 years of age), esophageal squamous cell carcinoma, and in patients who received ipilimumab in combination with nivolumab plus platinum-doublet chemotherapy.