Usage
Ipilimumab is prescribed for the treatment of various cancers, including:
- Unresectable or Metastatic Melanoma: In adults and children 12 years and older.
- Adjuvant Treatment of Melanoma: In patients with cutaneous melanoma with pathologic involvement of regional lymph nodes (greater than 1 mm) who have undergone complete resection, including total lymphadenectomy.
- Renal Cell Carcinoma: In combination with nivolumab for intermediate or poor risk, previously untreated advanced renal cell carcinoma.
- Microsatellite Instability-High (MSI-H) or Mismatch Repair Deficient (dMMR) Metastatic Colorectal Cancer (CRC): In combination with nivolumab for adults whose disease progressed following treatment with fluoropyrimidine, oxaliplatin, and irinotecan.
- Non-Small Cell Lung Cancer (NSCLC): In combination with nivolumab for first-line treatment of metastatic NSCLC in adults whose tumors express PD-L1 (≥1%) with no EGFR or ALK genomic tumor aberrations.
- Malignant Pleural Mesothelioma: In combination with nivolumab.
- Esophageal Squamous Cell Carcinoma: In combination with nivolumab.
Pharmacological Classification: Ipilimumab is classified as an immune checkpoint inhibitor, specifically a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) blocking antibody.
Mechanism of Action: Ipilimumab blocks the inhibitory effects of CTLA-4, a protein receptor that downregulates the immune system’s T-cell response. By inhibiting CTLA-4, ipilimumab enhances T-cell activation and proliferation, leading to an increased anti-tumor immune response.
Alternate Names
Generic Name: Ipilimumab
Brand Name: YERVOY
How It Works
Pharmacodynamics: Ipilimumab enhances the immune system’s attack on cancer cells by blocking the inhibitory signal of CTLA-4 on T-cells. This leads to increased T-cell activation, proliferation, and infiltration into tumors, resulting in tumor regression.
Pharmacokinetics:
- Absorption: Administered intravenously, achieving rapid distribution.
- Metabolism: As a monoclonal antibody, it’s not primarily metabolized by CYP enzymes but undergoes catabolism like endogenous IgG.
- Elimination: Primarily through protein catabolism, with negligible renal or hepatic excretion.
Mode of Action: Ipilimumab binds to CTLA-4, preventing its interaction with its ligands (B7-1/B7-2). This blockade removes the inhibitory signal on T cells, promoting their activation and proliferation, thus increasing the anti-tumor immune response.
Receptor Binding/Enzyme Inhibition/Neurotransmitter Modulation: Ipilimumab binds to the CTLA-4 receptor, inhibiting its function. It does not involve direct enzyme inhibition or neurotransmitter modulation.
Elimination Pathways: Primarily through protein catabolism.
Dosage
Standard Dosage
Adults:
- Melanoma (Monotherapy): 3 mg/kg intravenously over 90 minutes every 3 weeks for a total of 4 doses. All doses must be administered within 16 weeks of the first dose.
- Melanoma (Adjuvant): 10 mg/kg intravenously over 90 minutes every 3 weeks for 4 doses, followed by 10 mg/kg every 12 weeks for up to 3 years or until disease recurrence or unacceptable toxicity.
- Renal Cell Carcinoma (with Nivolumab): 1 mg/kg intravenously over 30 minutes immediately following nivolumab on the same day, repeated every 3 weeks for up to 4 doses.
- MSI-H/dMMR Metastatic CRC (with Nivolumab): 1 mg/kg intravenously over 30 minutes immediately following nivolumab on the same day, repeated every 3 weeks for up to 4 doses.
- NSCLC (with Nivolumab): 1 mg/kg intravenously every 6 weeks in combination with nivolumab 360 mg every 3 weeks. Continue until disease progression, unacceptable toxicity, or up to 2 years.
- Malignant Pleural Mesothelioma (with Nivolumab): 1 mg/kg intravenously every 6 weeks in combination with nivolumab 360 mg every 3 weeks, for up to 24 months.
- Esophageal Squamous Cell Carcinoma (with Nivolumab): 1 mg/kg intravenously every 6 weeks in combination with nivolumab (either 3 mg/kg every 2 weeks or 360 mg every 3 weeks). Treatment is recommended until disease progression, unacceptable toxicity, or up to 24 months.
Children:
- Melanoma (Monotherapy, age 12 and older): 3 mg/kg intravenously every 3 weeks for a maximum of 4 doses.
- Melanoma (with Nivolumab, age 12 and older): 3 mg/kg every 3 weeks with nivolumab 1 mg/kg, for a maximum of 4 doses.
- MSI-H/dMMR mCRC (with Nivolumab, age 12 and older): 1 mg/kg IV every 3 weeks plus nivolumab (dosing according to nivolumab guidelines).
Special Cases:
- Elderly Patients: No dose adjustment required.
- Patients with Renal Impairment: Caution in severe renal impairment; no data available for dose adjustment.
- Patients with Hepatic Dysfunction: Caution; limited data available.
- Patients with Comorbid Conditions: Individualized assessment and management of immune-related adverse events is crucial.
Clinical Use Cases
Ipilimumab’s clinical use focuses on cancer treatment, and it is not typically used in settings like intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations like status epilepticus or cardiac arrest.
Dosage Adjustments
Dosage adjustments or interruptions are primarily based on the severity of immune-related adverse events. For specific guidance on dosage adjustments for various adverse reactions, refer to the product monograph.
Side Effects
Common Side Effects:
Fatigue, diarrhea, rash, pruritus, nausea, vomiting, decreased appetite, abdominal pain, fever, headache, and injection site reactions.
Rare but Serious Side Effects:
- Immune-mediated adverse reactions: Enterocolitis, hepatitis, dermatitis (including Stevens-Johnson syndrome and toxic epidermal necrolysis), neuropathy, endocrinopathy (including hypophysitis, thyroiditis, adrenal insufficiency, type 1 diabetes mellitus), pneumonitis, nephritis, myocarditis, uveitis, and other inflammatory disorders affecting various organ systems. These can be severe or life-threatening and may require systemic corticosteroids and other immunosuppressants.
Long-Term Effects:
Chronic complications can occur due to irreversible damage from severe immune-related adverse events.
Adverse Drug Reactions (ADR):
Clinically significant ADRs include severe immune-mediated reactions requiring prompt intervention with corticosteroids and other immunosuppressive therapy.
Contraindications
- Hypersensitivity to ipilimumab.
- Active, life-threatening autoimmune disease.
- Organ transplantation graft where further immune activation is potentially life-threatening.
Drug Interactions
- Immunosuppressants: Concurrent use can decrease ipilimumab’s efficacy.
- Live Vaccines: Avoid concurrent use.
- CYP450 Interactions: Ipilimumab is not metabolized by CYP450 enzymes; however, co-administered drugs affecting other metabolic pathways or having overlapping toxicity profiles should be carefully considered. Consult a comprehensive drug interaction resource for a complete list of potential interactions.
Pregnancy and Breastfeeding
- Pregnancy Safety Category: Pregnancy Category C (older FDA classification). Based on its mechanism of action and animal data, ipilimumab can cause fetal harm. Use effective contraception during treatment and for 3 months after the last dose. Advise pregnant women of the potential risk to a fetus.
- Breastfeeding: It is unknown if ipilimumab is present in human milk. Discontinue breastfeeding during treatment and for 3 months after the final dose.
Drug Profile Summary
- Mechanism of Action: CTLA-4 blocking antibody; enhances T-cell activation and anti-tumor immune response.
- Side Effects: Common: Fatigue, diarrhea, rash. Serious: Immune-mediated adverse reactions affecting various organ systems.
- Contraindications: Hypersensitivity, active autoimmune disease, certain organ transplants.
- Drug Interactions: Immunosuppressants, live vaccines. Refer to comprehensive drug interaction resources for a complete list.
- Pregnancy & Breastfeeding: Contraindicated during pregnancy unless benefits outweigh risks; discontinue breastfeeding.
- Dosage: Varies by indication; refer to detailed dosage section above.
- Monitoring Parameters: Monitor for immune-related adverse events involving any organ system (e.g., enterocolitis, hepatitis, dermatitis, neuropathy, endocrinopathy, pneumonitis).
Popular Combinations
- Nivolumab (for various cancers)
Precautions
- General Precautions: Pre-screening for allergies, autoimmune conditions, hepatic/renal dysfunction, and other relevant medical history is essential.
- Specific Populations: Refer to sections on dosage, pregnancy and breastfeeding, and contraindications.
- Lifestyle Considerations: Educate patients about managing potential side effects like fatigue and gastrointestinal issues.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Ipilimumab?
A: The dosage varies depending on the indication and patient factors. See the detailed dosage section above.
Q2: What are the most serious side effects of Ipilimumab?
A: Severe immune-related adverse events such as enterocolitis, hepatitis, dermatitis, endocrinopathy, neuropathy, and pneumonitis.
Q3: Can Ipilimumab be used during pregnancy?
A: Ipilimumab can cause fetal harm and should be avoided during pregnancy unless the benefits clearly outweigh the risks.
Q4: How is Ipilimumab administered?
A: Ipilimumab is administered intravenously over 30 to 90 minutes.
Q5: How does Ipilimumab interact with other immunosuppressants?
A: Concurrent use of immunosuppressants can decrease the efficacy of ipilimumab.
Q6: What are the common side effects of Ipilimumab?
A: Fatigue, diarrhea, rash, pruritus, nausea, vomiting, decreased appetite, abdominal pain are among the common side effects.
Q7: Can Ipilimumab be used in patients with pre-existing autoimmune conditions?
A: Ipilimumab is contraindicated in patients with active, life-threatening autoimmune diseases.
Q8: What monitoring is required during Ipilimumab treatment?
A: Close monitoring for any signs or symptoms of immune-related adverse events is crucial. Regular blood tests and clinical assessments are essential to detect and manage these reactions.
Q9: What should patients be advised regarding vaccinations while receiving ipilimumab?
A: Live vaccines should be avoided during ipilimumab treatment and for a period afterwards, due to the risk of serious infections. The duration of this avoidance depends on the specific treatment regimen and should be discussed with the healthcare team.
