Usage
Crizanlizumab, sold under the brand name Adakveo, is prescribed to reduce the frequency of vaso-occlusive crises (VOCs) in individuals with sickle cell disease (SCD). It is approved for use in adults and pediatric patients aged 16 years and older. Crizanlizumab is classified as a selectin blocker, specifically a P-selectin inhibitor. It works by binding to P-selectin, an adhesion molecule found on activated endothelial cells and platelets, thereby inhibiting the interaction between sickled red blood cells, leukocytes, and the endothelium. This action disrupts the cellular adhesion that contributes to vaso-occlusion, the primary cause of VOCs in SCD.
Alternate Names
Adakveo (brand name)
crizanlizumab-tmca (generic name)
How It Works
Pharmacodynamics: Crizanlizumab primarily targets P-selectin, inhibiting the interactions that lead to vaso-occlusion. This reduces the frequency of VOCs, a hallmark of SCD characterized by severe pain and potential organ damage.
Pharmacokinetics:
- Absorption: Administered intravenously, achieving rapid distribution.
- Metabolism: Presumably metabolized via catabolic pathways, similar to other immunoglobulin G (IgG) antibodies. Specific metabolic pathways and the involvement of CYP enzymes have yet to be fully elucidated.
- Elimination: Primarily eliminated through catabolic pathways with a mean terminal half-life of approximately 7.6 days in patients with SCD, which is shorter than that observed in healthy volunteers (10.6 days). The impact of renal or hepatic impairment on crizanlizumab’s pharmacokinetics remains unknown.
Mode of Action: Crizanlizumab is a humanized monoclonal antibody that selectively binds to P-selectin. By blocking P-selectin, crizanlizumab prevents the adhesion of sickled red blood cells, leukocytes, and platelets to the endothelium, mitigating vaso-occlusion and reducing VOC frequency.
Receptor Binding/Enzyme Inhibition/Neurotransmitter Modulation: Crizanlizumab’s mechanism of action involves receptor binding (P-selectin). It does not directly inhibit enzymes or modulate neurotransmitters.
Dosage
Standard Dosage
Adults: 5 mg/kg administered as an intravenous infusion over 30 minutes.
Children (16 years and older): 5 mg/kg administered as an intravenous infusion over 30 minutes. Safety and efficacy in children younger than 16 years have not been established.
Special Cases:
- Elderly Patients: No specific dosage adjustments are recommended based solely on age.
- Patients with Renal Impairment: The effect of renal impairment on crizanlizumab’s pharmacokinetics is unknown. Dose modifications may be considered based on clinical response and monitoring.
- Patients with Hepatic Dysfunction: The effect of hepatic impairment on crizanlizumab’s pharmacokinetics is unknown. Dose modifications may be considered based on clinical response and monitoring.
- Patients with Comorbid Conditions: No specific dosage adjustments are routinely recommended for comorbid conditions such as diabetes or cardiovascular disease. Individualized adjustments may be necessary based on the patient’s overall clinical picture.
Clinical Use Cases
Crizanlizumab is specifically indicated for reducing the frequency of VOCs in patients with SCD. Its use in other clinical scenarios like intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations is not established, and its efficacy in these settings has not been studied.
Dosage Adjustments
Dose modifications may be considered in patients with renal or hepatic impairment, although specific guidelines are lacking. Adjustments should be based on clinical response, tolerability, and close monitoring.
Side Effects
Common Side Effects
Nausea, arthralgia (joint pain), back pain, pyrexia (fever), and fatigue. Infusion-related reactions (e.g., fever, chills, nausea, vomiting, dizziness, itching, rash, sweating, dyspnea) can also occur.
Rare but Serious Side Effects
Severe infusion-related reactions (e.g., anaphylaxis, severe hypotension, dyspnea) require immediate medical attention.
Long-Term Effects
Limited data exist on the long-term effects of crizanlizumab. Continued monitoring is necessary to assess potential chronic complications.
Adverse Drug Reactions (ADR)
Significant ADRs primarily include severe infusion-related reactions, requiring prompt intervention and discontinuation of the infusion.
Contraindications
No absolute contraindications to crizanlizumab are listed. Caution is advised in patients with a history of hypersensitivity reactions to other monoclonal antibodies.
Drug Interactions
Crizanlizumab has demonstrated minimal clinically significant drug interactions. Hydroxyurea does not significantly impact its pharmacokinetics. Potential interactions with other selectin antagonists or drugs metabolized via the same pathways warrant consideration. Available data suggest minimal interaction potential with commonly prescribed medications, OTC drugs, or supplements.
Pregnancy and Breastfeeding
Pregnancy: Animal studies suggest potential fetal harm. Limited human data are available. Crizanlizumab should be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus.
Breastfeeding: It is unknown whether crizanlizumab is excreted in human milk. Exercise caution when administering to breastfeeding mothers.
Drug Profile Summary
- Mechanism of Action: P-selectin inhibitor, blocks cellular adhesion, reduces VOCs.
- Side Effects: Nausea, arthralgia, back pain, pyrexia, fatigue, infusion-related reactions.
- Contraindications: None listed.
- Drug Interactions: Minimal clinically significant interactions.
- Pregnancy & Breastfeeding: Potential fetal harm; caution advised during breastfeeding.
- Dosage: 5 mg/kg IV infusion every 4 weeks (following two loading doses 2 weeks apart).
- Monitoring Parameters: Monitor for infusion-related reactions, especially during the first two infusions. Evaluate for VOC frequency and severity.
Popular Combinations
Crizanlizumab can be used as monotherapy or in combination with hydroxyurea in patients whose hydroxyurea treatment is inadequate or inappropriate.
Precautions
- General Precautions: Monitor for infusion-related reactions, especially during the first two doses.
- Specific Populations: Assess the benefit-risk ratio carefully in pregnant or breastfeeding women. No age-specific precautions are specified for elderly or pediatric patients (16 years and older).
- Lifestyle Considerations: No specific lifestyle restrictions are generally required, but individualized advice based on patient’s overall health should be provided.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Crizanlizumab?
A: The recommended dose is 5 mg/kg administered as an intravenous infusion over 30 minutes, given on Week 0, Week 2, and every 4 weeks thereafter.
Q2: How does Crizanlizumab work?
A: Crizanlizumab inhibits P-selectin, reducing the adhesion of cells involved in vaso-occlusion, a critical process in SCD.
Q3: What are the common side effects of Crizanlizumab?
A: Common side effects include nausea, joint pain, back pain, fever, fatigue, and infusion-related reactions.
Q4: Can Crizanlizumab be used during pregnancy?
A: Limited human data are available. Animal data suggest a potential for fetal harm. Use only if potential benefit outweighs potential risk.
Q5: Is Crizanlizumab safe for breastfeeding mothers?
A: It is unknown whether crizanlizumab is excreted in human milk. Caution is advised.
Q6: How is Crizanlizumab administered?
A: It is administered as an intravenous infusion over 30 minutes.
Q7: Are there any contraindications to Crizanlizumab?
A: Currently, no absolute contraindications are listed.
Q8: Can Crizanlizumab be used with hydroxyurea?
A: Yes, it can be used as monotherapy or in combination with hydroxyurea.
Q9: What should patients be monitored for during Crizanlizumab therapy?
A: Patients should be monitored for infusion-related reactions, particularly during the first two infusions. Ongoing evaluation of VOC frequency and severity is also important.
Q10: How long does it take for Crizanlizumab to work?
A: Clinical trials showed a reduction in VOCs within the first year of treatment. Individual responses may vary.
