Usage
- Inotuzumab ozogamicin is prescribed for adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL). This includes Philadelphia chromosome-positive (Ph+) or Philadelphia chromosome-negative (Ph-) ALL. It is also used in patients who have not responded to other treatments or whose ALL has returned after treatment.
- Pharmacological Classification: Antineoplastic agent, Antibody-drug conjugate (ADC).
- Mechanism of Action: Inotuzumab ozogamacin is an antibody-drug conjugate that targets the CD22 antigen found on B-cells. The antibody component, inotuzumab, binds to CD22 on the surface of leukemia cells. This binding triggers internalization of the conjugate, releasing the cytotoxic agent calicheamicin inside the cell. Calicheamicin causes double-stranded DNA breaks, leading to cell cycle arrest and apoptosis (programmed cell death) of the leukemia cells.
Alternate Names
- No widely used alternate names exist for the generic drug Inotuzumab ozogamicin.
- Brand Name: Besponsa™
How It Works
- Pharmacodynamics: Inotuzumab ozogamicin exerts its anti-leukemic effect by binding specifically to CD22, a cell surface antigen expressed on B-lymphoblasts. Upon internalization, the cytotoxic payload calicheamicin is released, inducing DNA damage and subsequently leading to cell death. The drug is cell cycle-independent, meaning it can kill cancer cells regardless of their stage in the cell cycle.
- Pharmacokinetics: The antibody component distributes mainly in the blood, while the small molecule component, calicheamicin, has a larger volume of distribution, indicating tissue penetration. Inotuzumab ozogamicin is primarily metabolized through non-enzymatic reduction, with calicheamicin being the main compound undergoing metabolism. Elimination occurs through multiple pathways, and the terminal half-life of the drug is around 12.3 days. The pharmacokinetics of inotuzumab ozogamicin are not significantly affected by age, race, sex, or mild to moderate renal or hepatic impairment.
- Mode of Action: The antibody portion targets the CD22 receptor. The calicheamicin payload is linked to the antibody through a chemical linker. Upon cellular internalization, the linker is cleaved, releasing the cytotoxic agent calicheamicin within the cell. Calicheamicin then binds to DNA, creating double-strand breaks which disrupt cellular replication and ultimately cause cell death.
- Elimination Pathways: Inotuzumab ozogamicin is primarily metabolized through non-enzymatic reduction of calicheamicin. The elimination pathways are not fully characterized but are thought to include hepatic metabolism and renal excretion.
Dosage
Standard Dosage
Adults:
- Cycle 1: Total dose of 1.8 mg/m² per 21-day cycle, divided into three doses.
- Day 1: 0.8 mg/m² IV infusion over 1 hour.
- Day 8: 0.5 mg/m² IV infusion over 1 hour.
- Day 15: 0.5 mg/m² IV infusion over 1 hour.
- Subsequent Cycles (for patients who achieve CR/CRi): Total dose of 1.5 mg/m² per 28-day cycle, divided into three doses.
- Day 1: 0.5 mg/m² IV infusion over 1 hour.
- Day 8: 0.5 mg/m² IV infusion over 1 hour.
- Day 15: 0.5 mg/m² IV infusion over 1 hour.
- Subsequent Cycles (for patients who do not achieve CR/CRi): Total dose of 1.8 mg/m² per 28-day cycle, divided into three doses.
- Day 1: 0.8 mg/m² IV infusion over 1 hour.
- Day 8: 0.5 mg/m² IV infusion over 1 hour.
- Day 15: 0.5 mg/m² IV infusion over 1 hour.
- Patients who do not achieve CR or CRi within 3 cycles should discontinue treatment. For patients undergoing hematopoietic stem cell transplantation (HSCT), the recommended duration is 2 cycles. A third cycle may be considered for those who do not achieve CR or CRi after 2 cycles. For patients not proceeding to HSCT, a maximum of 6 cycles may be administered.
Children:
- The safety and efficacy of inotuzumab ozogamicin in children aged 0 to <18 years have not been established. No dosage recommendations can be made.
Special Cases:
- Elderly Patients: No specific dose adjustments are recommended for elderly patients. However, they should be closely monitored for adverse effects.
- Patients with Renal Impairment: No dose adjustments are needed for mild, moderate, or severe renal impairment.
- Patients with Hepatic Dysfunction: No dose adjustments are needed for mild or moderate hepatic impairment. However, close monitoring of liver function is recommended. Patients with severe hepatic impairment should not receive Inotuzumab ozogamicin.
- Patients with Comorbid Conditions: Patients with underlying medical conditions like diabetes, cardiovascular disease, infections, or bleeding disorders should be closely monitored for exacerbation of their conditions.
Clinical Use Cases
Inotuzumab ozogamicin’s clinical use is specifically for the treatment of relapsed or refractory B-cell precursor ALL in adult patients. The dosage recommendations provided in the Standard Dosage section apply to all clinical situations involving this indication. Its use is not indicated for other conditions like intubation, surgical procedures, mechanical ventilation, intensive care, or emergency situations.
Dosage Adjustments
- Dose modifications might be necessary based on hematological and non-hematological toxicities. Detailed adjustments can be found in the prescribing information. Interruptions or dose reductions might be necessary if patients experience significant myelosuppression, hepatotoxicity, or other adverse reactions.
Side Effects
Common Side Effects
- Thrombocytopenia (low platelet count)
- Neutropenia (low neutrophil count)
- Anemia (low red blood cell count)
- Leukopenia (low white blood cell count)
- Infection
- Fatigue
- Nausea
- Headache
- Fever
- Bleeding or bruising
Rare but Serious Side Effects
- Hepatotoxicity, including veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS)
- Tumor lysis syndrome
- QT prolongation
- Severe infections
- Infusion-related reactions
- Capillary leak syndrome
- Hemolytic uremic syndrome
Long-Term Effects
- Potential long-term effects include secondary malignancies, prolonged myelosuppression, and liver damage.
Adverse Drug Reactions (ADR)
- VOD/SOS, Tumor lysis syndrome, severe infections, and severe infusion-related reactions are serious ADRs requiring urgent medical attention.
Contraindications
- Hypersensitivity to inotuzumab ozogamicin or any of its components.
- Prior confirmed severe or ongoing VOD/SOS.
- Serious ongoing hepatic disease (e.g., cirrhosis, nodular regenerative hyperplasia, active hepatitis).
Drug Interactions
- Concomitant use with drugs that prolong the QT interval can increase the risk of QT prolongation and Torsades de pointes.
- Inotuzumab ozogamicin can interact with numerous medications, including some antibiotics, antifungals, antivirals, and other chemotherapy agents. Consult a comprehensive drug interaction resource or the product monograph for detailed information.
- Interactions with OTC drugs and supplements: Limited information is available. Consult a pharmacist or the product monograph for specific guidance.
- Food and Lifestyle interactions: Limited information is available. Moderate alcohol consumption is generally acceptable, but excessive alcohol should be avoided.
Pregnancy and Breastfeeding
- Pregnancy Safety Category: Inotuzumab ozogamicin can cause fetal harm. Women of childbearing potential should use effective contraception during treatment and for at least 8 months after the last dose. Men with female partners of childbearing potential should use effective contraception during treatment and for at least 5 months after the last dose.
- Fetal risks: Based on animal studies, Inotuzumab ozogamicin can cause embryo-fetal harm, including structural abnormalities and death.
- Drug excretion in breast milk: It is unknown if Inotuzumab ozogamicin is excreted in human milk. Due to the potential for serious adverse reactions in the breastfed infant, breastfeeding should be discontinued during treatment and for at least 2 months after the last dose.
Drug Profile Summary
- Mechanism of Action: ADC targeting CD22 on B-cells, causing DNA damage and cell death.
- Side Effects: Myelosuppression, hepatotoxicity, infections, fatigue, nausea, headache, fever.
- Contraindications: Hypersensitivity, history of severe VOD/SOS, serious hepatic disease.
- Drug Interactions: Drugs that prolong the QT interval; refer to detailed drug interaction resources.
- Pregnancy & Breastfeeding: Contraindicated in pregnancy; breastfeeding should be discontinued.
- Dosage: See detailed dosage section above.
- Monitoring Parameters: Complete blood counts, liver function tests, signs and symptoms of infection, bleeding, and other adverse events. Electrocardiogram (ECG) monitoring for QT prolongation may be needed.
Popular Combinations
- Inotuzumab ozogamicin is typically used as a single agent. Clinical trials are investigating its use in combination with other therapies for ALL, but no standard combination regimens have been established yet.
Precautions
- General Precautions: Assess liver function, complete blood counts, and perform a pregnancy test in women of childbearing potential before starting treatment. Monitor for signs and symptoms of VOD/SOS, myelosuppression, infections, bleeding, and infusion reactions. Premedication with a corticosteroid, antipyretic, and antihistamine is recommended before each dose.
- Specific Populations: See “Special Cases” in the Dosage section.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Inotuzumab Ozogamacin?
A: See detailed dosage guidelines provided above.
Q2: What are the most common side effects of Inotuzumab Ozogamacin?
A: Thrombocytopenia, neutropenia, anemia, infections, fatigue, nausea, headache, fever.
A: VOD/SOS, tumor lysis syndrome, severe infections, allergic reactions, QT prolongation.
Q4: Can Inotuzumab Ozogamacin be given to pregnant women?
A: No, Inotuzumab ozogamicin is contraindicated in pregnancy due to the risk of fetal harm.
Q5: What monitoring parameters should be considered for patients taking Inotuzumab Ozogamacin?
A: Complete blood counts, liver function tests, bilirubin levels, signs and symptoms of infection, bleeding, and infusion reactions.
Q6: Is Inotuzumab ozogamicin safe for patients with liver or kidney problems?
A: Patients with pre-existing liver disease, especially severe hepatic impairment should not receive Inotuzumab Ozogamacin. No dose adjustment is needed for renal impairment.
Q7: Can patients on Inotuzumab Ozogamacin receive vaccinations?
A: Live virus vaccinations are not recommended during and for a period after treatment.
Q8: How is Inotuzumab Ozogamacin administered?
A: Intravenous infusion over 1 hour. It should not be administered as an IV push or bolus.
Q9: How does inotuzumab ozogamicin differ from traditional chemotherapy?
A: It is a targeted therapy, meaning it specifically targets the CD22 antigen present on B-cells, minimizing damage to healthy cells compared to traditional chemotherapy, which can affect all rapidly dividing cells.
Q10: What should be done if a patient experiences an infusion reaction?
A: Stop the infusion immediately and provide appropriate medical management, which may include antihistamines, corticosteroids, and supportive care.
