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Ipilimumab – Uses, Dosage, Side Effects, Interaction

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Ipilimumab is a human cytotoxic T-lymphocyte antigen 4 (CTLA-4) blocking antibody used to treat metastatic or unresectable melanoma. Ipilimumab is a fully humanized IgG1 monoclonal antibody that blocks cytotoxic T lymphocyte antigen-4 (CTLA-4). Blocking CTLA-4 removes an inhibitory signal from reducing the activity of T lymphocytes. Ipilimumab was developed by Bristol-Myers Squibb and Medarex.  Ipilimumab was granted FDA approval on 25 March 2011.[rx]

Mechanism of action

Cytotoxic T-lymphocyte antigen-4 (CTLA-4) is an inhibitory molecule that competes with the stimulatory CD28 for binding to B7 on antigen presenting cells. CTLA-4 and CD28 are both presented on the surface of T-cells. Ipilimumab is a human IgG1 that binds CTLA-4, preventing the inhibition of T-cell mediated immune responses to tumors.[rx]

T lymphocytes can recognize and destroy cancer cells. However, an inhibitory mechanism interrupts this destruction. Ipilimumab turns off this inhibitory mechanism and allows the lymphocytes to continue to destroy cancer cells.[rx]

Cancer cells produce antigens, which the immune system can use to identify them. These antigens are recognized by dendritic cells that present the antigens to cytotoxic T lymphocytes (CTLs) in the lymph nodes. The CTLs recognize the cancer cells by those antigens and destroy them. However, along with the antigens, the dendritic cells present an inhibitory signal. That signal binds to a receptor, cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), on the CTL and turns off the cytotoxic reaction. This allows the cancer cells to survive.[rx]

Ipilimumab binds to CTLA-4, blocking the inhibitory signal, which allows the CTLs to destroy the cancer cells. In 2014 a study indicated that the antibody works by allowing the patients’ T cells to target a greater variety of antigens rather than by increasing the number attacking a single antigen.[rx]

or

Ipilimumab is a CTLA-4 monoclonal antibody. Two signals are necessary for full T-cell activation: major histocompatibility complexes (MHC) I and II receptors on T-cells binding to tumor-associated antigens (TAA) presented by antigen-presenting cells (APCs) as well as CD28 receptor located on the T cell binding to CD80 and CD86 (B7 ligand subtypes) on APCs. These two signals result in T-cell proliferation and cytokine release, triggering and amplifying the immune response. In response to this T-cell activation, cytotoxic T lymphocyte antigen-4 (CTLA-4) becomes upregulated, competing with CD28 for CD80 and CD86 binding on APCs. However, with a much higher affinity, it can downregulate the T cell activation, which results in a decreased immune response to TAAs.

CTLA-4 is the primary negative regulator of T-cell-mediated antitumor immune responses and therefore represents a critical checkpoint for immunity, controlling both the intensity and duration of an immune response. Ipilimumab is an anti-CTLA-4 monoclonal antibody that prevents CD80 and CD86 on APCs from binding to CTLA-4 on T cells. This blockage of CTLA-4 signaling allows T-cell activation, proliferation, and amplification of T-cell-mediated immunity, which allows the patient’s immune system to mount a better response.The drug is metabolized via the CYP450 enzyme system and has a half-life of 15.4 days.

Indications

Ipilimumab is indicated in the following cancerous conditions:

Melanoma

Renal Cell Carcinoma (RCC)

Colorectal Cancer

Hepatocellular Carcinoma

Non-Small Cell Lung Cancer (NSCLC)

Malignant Pleural Mesothelioma

Esophageal Cancer – Treatment of adult patients with unresectable advanced or metastatic esophageal squamous cell carcinoma, as first line treatment in combination with nivolumab

Use in Cancer

Ipilimumab is approved to treat:

This use is approved under FDA’s Accelerated Approval Program. As a condition of approval, a confirmatory trial(s) must show that ipilimumab provides a clinical benefit in these patients. Ipilimumab is also being studied in the treatment of other types of cancer.

Contraindications

Dosage

Strengths: 5 mg/mL

Dosing by indication is as follows:

Melanoma

  • As adjuvant treatment: 10 mg/kg/dose IV every three weeks for 4 doses, then commencing with the 24th week, the dose changes to 10 mg/kg/dose IV every 12 weeks for up to three years.
  • For metastatic or unresectable disease: 3 mg/kg/dose IV every 3 weeks for up to 4 doses; treatment must be completed within 16 weeks following the first dose. It can be used as monotherapy or with nivolumab.

Advanced Renal Cell Carcinoma

  • 1 mg/kg/dose IV every 3 weeks for up to 4 doses. In patients with previously untreated disease or who have poor risk profiles, use with nivolumab.

Metastatic Microsatellite Instability-high or Mismatch Repair-deficient Colorectal Cancer

  • 1 mg/kg/dose IV every 3 weeks for up to 4 doses. In patients with relapsing or refractory disease, use in conjunction with nivolumab.

Hepatocellular Carcinoma

  • 3 mg/kg/dose IV every 3 weeks for up to 4 doses. In patients with disease that is refractory to treatment with sorafenib or who cannot tolerate sorafenib, use with nivolumab.

Non-small Cell Cancer

  • For metastatic PD-L1-expressing disease: 1 mg/kg/dose IV every 6 weeks for up to 2 years. This is a first-line treatment, along with nivolumab, for patients without EGFR or ALK genomic tumor defects.
  • Recurring or metastatic disease: 1 mg/kg/dose IV every 6 weeks for up to 2 years. This is a first-line treatment, along with nivolumab plus two cycles of histology-based platinum-doublet chemotherapy, for patients without EGFR or ALK genomic tumor defects.

Malignant Pleural Mesothelioma

  • 1 mg/kg/dose IV every 6 weeks for up to 2 years; used with nivolumab.

If the patient’s creatinine clearance is above 15, no dose adjustment is necessary. Dosing is undefined for patients with renal disease and creatinine clearance of 15 and lower. Patients with hepatic impairment with an AST reading between 1 to 1.5 times the upper normal limit require no dose adjustment. Dosing is undefined for patients with bilirubin values over 1.5 of the upper normal limit irrespective of AST value. For pediatric dosing, refer to institutional protocols; ipilimumab is only approved for children aged 12 and older.

Ipilimumab may only be administered intravenously (IV), specifically with an IV line containing a sterile, low protein binding filter to minimize protein medication loss. It should be infused over 30 to 90 minutes. It should not be mixed or administered with any other medical products. No other specific or extra precautions are necessary.

or

Melanoma – Metastatic

UNRESECTABLE OR METASTATIC MELANOMA:

  • 3 mg/kg IV over 90 minutes every 3 weeks for a maximum of 4 doses

ADJUVANT TREATMENT OF MELANOMA:

  • 10 mg/kg IV over 90 minutes every 3 weeks for 4 doses followed by 10 mg/kg IV over 90 minutes every 12 weeks for up to 3 years
  • For the treatment of unresectable or metastatic melanoma
  • For the adjuvant treatment of cutaneous melanoma with pathologic involvement of regional lymph nodes of more than 1 mm who have undergone complete resection, including total lymphadenectomy

Renal Cell Carcinoma

  • Ipilimumab 1 mg/kg IV over 30 minutes every 3 weeks with nivolumab 3 mg/kg IV over 30 minutes on the same day for 4 doses; after completing 4 doses of the combination, administer nivolumab as a single agent until disease progression or unacceptable toxicity
  • Review the full prescribing information for nivolumab prior to initiation.
  • For intermediate or poor risk, previously untreated advanced renal cell carcinoma (RCC) in combination with nivolumab

Colorectal Cancer

  • Ipilimumab 1 mg/kg IV over 30 minutes every 3 weeks with nivolumab 3 mg/kg IV over 30 minutes on the same day; after completing 4 doses of combination therapy, administer nivolumab as a single agent until disease progression or unacceptable toxicity
  • Review the full prescribing information for nivolumab prior to initiation.
  • In combination with nivolumab for the treatment of microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (CRC) that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan

Hepatocellular Carcinoma

  • Ipilimumab 3 mg/kg IV over 30 minutes every 3 weeks with nivolumab 1 mg/kg IV over 30 minutes on the same day for 4 doses; after completing 4 doses of combination therapy, administer nivolumab as a single agent until disease progression or unacceptable toxicity
  • Review the full prescribing information for nivolumab prior to initiation.
  • In combination with nivolumab for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib

Non-Small Cell Lung Cancer

METASTATIC NON-SMALL CELL LUNG CANCER EXPRESSING PD-L1:

  • Ipilimumab 1 mg/kg IV over 30 minutes every 6 weeks with nivolumab 3 mg/kg IV over 30 minutes every 2 weeks until disease progression, unacceptable toxicity, or up to 2 years in patients without disease progression

METASTATIC OR RECURRENT NON-SMALL CELL LUNG CANCER:

  • Ipilimumab 1 mg/kg IV over 30 minutes every 6 weeks with nivolumab 360 mg IV over 30 minutes every 3 weeks until disease progression, unacceptable toxicity, or up to 2 years in patients without disease progression; this is given with histology-based platinum-doublet chemotherapy every 3 weeks for 2 cycles
  • Review the full prescribing information for nivolumab prior to initiation
  • In combination with nivolumab for the first-line treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors express PD-L1 (1% or greater) as determined by an FDA-approved test. with no EGFR or ALK genomic tumor aberrations
  • In combination with nivolumab and 2 cycles of platinum-doublet chemotherapy for the first-line treatment of adult patients with metastatic or recurrent NSCLC, with no EGFR or ALK genomic tumor aberrations

Malignant Pleural Mesothelioma

  • Ipilimumab 1 mg/kg IV over 30 minutes every 6 weeks with nivolumab 360 mg IV over 30 minutes every 3 weeks until disease progression, unacceptable toxicity, or up to 2 years in patients without disease progression
  • Review the full prescribing information for nivolumab prior to initiation.
  • For the first-line treatment of unresectable malignant pleural mesothelioma in combination with nivolumab

Pediatric Dose for

Melanoma – Metastatic

12 years and older:
UNRESECTABLE OR METASTATIC MELANOMA:

  • 3 mg/kg IV over 90 minutes every 3 weeks for a maximum of 4 doses
  • For the treatment of unresectable or metastatic melanoma in pediatric patients 12 years and older

Colorectal Cancer

12 years and older:

  • Ipilimumab 1 mg/kg IV over 30 minutes every 3 weeks with nivolumab 3 mg/kg IV over 30 minutes on the same day; after completing 4 doses of combination therapy, administer nivolumab as a single agent until disease progression or unacceptable toxicity
  • Review the full prescribing information for nivolumab prior to initiation.
  • In combination with nivolumab for the treatment of microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (CRC) that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan in pediatric patients 12 years and older

Dose Adjustments

When ipilimumab is administered in combination with nivolumab, if ipilimumab is withheld, nivolumab should also be withheld.

No dose reduction for ipilimumab is recommended:

  • Withhold for severe (Grade 3) immune-mediated adverse reactions.
  • Permanently discontinue for 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 lasting 12 weeks or longer after last dose (excluding endocrinopathy), or an inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks of initiating steroids.
  • Dose modifications for ipilimumab or ipilimumab in combination with nivolumab for adverse reactions that require management different from these general guidelines are summarized below.

IMMUNE-MEDIATED COLITIS:

  • Grade 2: Withhold therapy; resume in patients with complete or partial resolution (Grade 0 or 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.
  • Grade 3 or 4: Permanently discontinue therapy.

IMMUNE-RELATED HEPATITIS:
HEPATITIS WITH NO TUMOR INVOLVEMENT OF THE LIVER:

  • AST or ALT increases to more than 3 times and up to 5 times the upper limit of normal (ULN) OR total bilirubin increases to more than 1.5 and up to 3 x ULN: Withhold therapy; resume in patients with complete or partial resolution (Grade 0 or 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

OR
HEPATITIS WITH TUMOR INVOLVEMENT OF THE LIVER/NON-HCC:

  • AST or ALT more than 1.5 and up to 3 x ULN OR total bilirubin more than 3 x ULN: Permanently discontinue therapy.

HEPATITIS WITH TUMOR INVOLVEMENT OF THE LIVER/HCCC:

  • Baseline AST/ALT is more than 1 and up to 3 x ULN and increases to more than 5 and up to 10 x ULN OR baseline AST/ALT is more than 3 and up to 5 x ULN and increases to more than 8 and up to 10 x ULN: Withhold therapy; resume in patients with complete or partial resolution (Grade 0 or 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.
  • AST/ALT increases to more than 10 x ULN OR total bilirubin increases to more than 3 x ULN: Permanently discontinue therapy.

IMMUNE-MEDIATED EXFOLIATIVE DERMATOLOGIC CONDITIONS:

  • Suspected Stevens Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), or drug rash with eosinophilia and systemic symptoms (DRESS): Withhold therapy.
  • Confirmed SJS, TEN, or DRESS: Permanently discontinue therapy.

IMMUNE-RELATED ENDOCRINOPATHIES (Depending on severity, consider withholding for Grade 2 endocrinopathy until symptom improvement with hormone replacement; resume once acute symptoms have resolved):

  • Grade 3 or 4: Withhold therapy until stable or permanently discontinue depending on severity.

IMMUNE-RELATED PNEUMONITIS:

  • Grade 2: Withhold therapy; resume in patients with complete or partial resolution (Grade 0 or 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.
  • Grade 3 or 4: Permanently discontinue therapy.

IMMUNE-RELATED NEPHRITIS WITH RENAL DYSFUNCTION:

  • Grade 2 or 3 increased blood creatinine: Withhold therapy; resume in patients with complete or partial resolution (Grade 0 or 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.
  • Grade 3 or 4 increased blood creatinine: Permanently discontinue therapy.

IMMUNE-RELATED NEUROLOGICAL TOXICITIES:

  • Grade 2: Withhold therapy; resume in patients with complete or partial resolution (Grade 0 or 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.
  • Grade 2: Withhold therapy; resume in patients with complete or partial resolution (Grade 0 or 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.
  • Grade 3 or 4: Permanently discontinue therapy.

IMMUNE-RELATED MYOCARDITIS:

  • Grade 2, 3, or 4: Permanently discontinue therapy.

IMMUNE-RELATED OPHTHALMOLOGIC:

  • Grade 2, 3, or 4 that does not improve to Grade 1 within 2 weeks while receiving topical therapy or that requires systemic treatment: Permanently discontinue therapy.

IMMUNE-RELATED INFUSION REACTIONS:

  • Grade 1 or 2: Interrupt or slow the rate of infusion.
  • Grade 3 or 4: Permanently discontinue therapy.

Consult the manufacturer product information and/or local protocol for information on corticosteroid therapy.Administration advice:

  • This drug should be administered via an IV infusion over 90 minutes. It should not be administered as an IV push or bolus injection.
  • An in-line, sterile, non-pyrogenic, low protein binding filter must be used for IV administration.
  • A separate infusion line should be used for infusion; it should not be infused concomitantly in the same IV line with another drug.
  • The line must be flushed with sterile 0.9% sodium chloride solution for injection at the end of infusion
  • Any signs or symptoms which may indicate immune-related adverse events should be immediately reported; patients should not treat symptoms of these reactions with over-the-counter medications without consulting a health care provider.
  • Patients should be advised to use caution when driving or operating machinery until they are certain that the drug does not adversely affect them.

Side Effects

The Most Common

More common

Rare

Drug Interaction

Pregnancy and Lactation

AU TGA pregnancy category: C
US FDA pregnancy category: Not assigned

Pregnancy

Based on findings from animal studies and its mechanism of action [see Clinical Pharmacology (12.1)], YERVOY can cause fetal harm when administered to a pregnant woman. There is insufficient human data for YERVOY exposure in pregnant women. In animal reproduction
studies, administration of ipilimumab to cynomolgus monkeys from the onset of organogenesis through delivery resulted in higherincidences of abortion, stillbirth, premature delivery (with corresponding lower birth weight), and higher incidences of infant mortality in a dose-related manner (see Data). The effects of ipilimumab are likely to be greater during the second and third trimesters of pregnancy. Human IgG1 is 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. Advise pregnant women of the potential risk to a fetus. Report pregnancies to Bristol-Myers
Squibb at 1-844-593-7869. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Lactation

There are no data on the presence of YERVOY in human milk or its effects on the breastfed child or milk production. In monkeys, ipilimumab was present in milk (see Data). Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with YERVOY and for 3 months following the last dose.

Why is this medication prescribed?

Ipilimumab injection is used:

  • to treat melanoma (a type of skin cancer) in adults and children 12 years of age and older that cannot be treated with surgery or that has spread to other parts of the body. It is also used in combination with nivolumab (Opdivo) to treat melanoma in adults that cannot be treated with surgery or that has spread to other parts of the body.
  • to treat and prevent the return of a certain type of melanoma after surgery to remove it and any affected lymph nodes.
  • in combination with nivolumab to treat advanced renal cell carcinoma (RCC; a type of cancer that begins in the cells of the kidneys).
  • in combination with nivolumab to treat certain types of colorectal cancer (cancer that begins in the large intestine) in adults and children 12 years of age and older that has spread to other parts of the body and has worsened after treatment with other chemotherapy medications.
  • in combination with nivolumab to treat hepatocellular carcinoma (HCC; a type of liver cancer) in people who were previously treated with sorafenib (Nexafar).
  • in combination with nivolumab to a certain type of lung cancer (non-small cell lung cancer; NSCLC) in adults that has spread to other parts of the body.
  • in combination with nivolumab and platinum-containing chemotherapy to treat a certain type of NSCLC in adults that has returned or has spread to other parts of the body.
  • in combination with nivolumab to treat malignant pleural mesothelioma (a type of cancer that affects the inside lining of the lungs and chest cavity) in adults that cannot be removed by surgery.
  • and in combination with nivolumab to treat a certain type of esophageal cancer (cancer of the tube that connects your throat to your stomach) that has spread to other parts of the body or cannot be treated with surgery.

Ipilimumab injection is in a class of medications called monoclonal antibodies. It works by helping the body to slow or stop the growth of cancer cells.

How should this medicine be used?

Ipilimumab injection comes as a solution (liquid) to be injected intravenously (into a vein) by a doctor or nurse in a hospital or medical facility. When ipilimumab is given alone to treat and help prevent the return of melanoma, it is usually given over 90 minutes once every 3 weeks for 4 doses and then once every 12 weeks as long as your doctor recommends that you receive treatment. When ipilimumab is given alone or along with nivolumab to treat melanoma, it is usually given over 30 minutes once every 3 weeks for up to 4 doses. When ipilimumab is given with nivolumab to treat renal cell carcinoma, hepatocellular carcinoma, or colorectal cancer, it is usually given over 30 minutes once every 3 weeks for up to 4 doses. When ipilimumab is given with nivolumab to treat malignant pleural mesothelioma or esophageal cancer or with nivolumab and platinum-containing chemotherapy to treat NSCLC, it is usually given over 30 minutes once every 6 weeks for as long as your doctor recommends that you receive treatment.

Ipilimumab injection may cause serious or life-threatening reactions during an infusion. A doctor or nurse will watch you closely while you are receiving the infusion and shortly after the infusion to be sure you are not having a serious reaction to the medication. Tell your doctor or nurse immediately if you experience any of the following symptoms that may occur during the infusion: chills or shaking, itching, rash, flushing, difficulty breathing, dizziness, fever, or feeling faint.

Your doctor may slow down your infusion, delay, or stop your treatment with ipilimumab injection, or treat you with additional medications depending on your response to the medication and any side effects that you experience. Talk to your doctor about how you are feeling during your treatment.

Your doctor or pharmacist will give you the manufacturer’s patient information sheet (Medication Guide) when you begin treatment with ipilimumab and each time you refill your prescription. Read the information carefully and ask your doctor or pharmacist if you have any questions. You can also visit the Food and Drug Administration (FDA) website (http://www.fda.gov/Drugs/DrugSafety/ucm085729.htm) or the manufacturer’s website to obtain the Medication Guide. This medication may be prescribed for other uses; ask your doctor or pharmacist for more information.

What special precautions should I follow?

Before receiving ipilimumab injection,

  • tell your doctor and pharmacist if you are allergic to ipilimumab injection, any other medications, or any of the ingredients in ipilimumab injection. Ask your pharmacist or check the Medication Guide for a list of the ingredients.
  • tell your doctor and pharmacist what prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
  • tell your doctor if you have received or plan to receive a stem cell transplant that uses donor stem cells (allogeneic) or have ever had an organ transplant. Also, tell your doctor if you have or have ever had an autoimmune disease (condition in which the immune system attacks a healthy part of the body) such as Crohn’s disease (condition in which the immune system attacks the lining of the digestive tract causing pain, diarrhea, weight loss, and fever), ulcerative colitis (a condition which causes swelling and sores in the lining of the colon [large intestine] and rectum), lupus (a condition in which the immune system attacks many tissues and organs including the skin, joints, blood, and kidneys); any condition that affects your nervous system such as myasthenia gravis (a disorder of the nervous system that causes muscle weakness) or Guillain-Barré syndrome (weakness, tingling, and possible paralysis due to sudden nerve damage); thyroid problems; or liver disease.
  • tell your doctor if you are pregnant or plan to become pregnant. You will need to take a pregnancy test before you receive ipilimumab. You should use effective birth control to prevent pregnancy during your treatment with ipilimumab injection and for 3 months after your final dose. Talk to your doctor about birth control methods that will work for you. If you become pregnant while receiving ipilimumab injection, call your doctor immediately. Ipilimumab injection may harm the fetus.
  • tell your doctor if you are breastfeeding or plan to breastfeed. You should not breastfeed while receiving ipilimumab injection and for 3 months after your final dose.

References
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