Usage
Natalizumab is prescribed for the treatment of relapsing forms of multiple sclerosis (MS), including relapsing-remitting MS (RRMS) and active secondary progressive MS (SPMS), in adults. It is also used to treat moderate to severe Crohn’s disease in adults who haven’t responded to other treatments. It is classified as a selective adhesion molecule inhibitor, specifically an integrin antagonist. Natalizumab works by binding to the α4-integrin subunit on leukocytes, preventing them from crossing the blood-brain barrier in MS and the intestinal wall in Crohn’s disease, thus reducing inflammation.
Alternate Names
The international nonproprietary name (INN) is natalizumab. A popular brand name is Tysabri®.
How It Works
Pharmacodynamics: Natalizumab binds to the α4 subunit of α4β1 and α4β7 integrins, expressed on the surface of leukocytes. This binding prevents the interaction of α4-integrins with their receptors, vascular cell adhesion molecule 1 (VCAM-1) and mucosal addressin cell adhesion molecule 1 (MAdCAM-1). In MS, by blocking the α4β1 integrin interaction with VCAM-1, natalizumab inhibits the migration of leukocytes across the blood-brain barrier, reducing inflammation in the central nervous system. In Crohn’s disease, by blocking α4β7 integrin’s interaction with MAdCAM-1, it prevents leukocyte migration into the gut tissue, reducing inflammation.
Pharmacokinetics: Natalizumab is administered intravenously. It reaches peak serum concentrations at the end of the infusion. It has a half-life of approximately 11 days. Metabolism of monoclonal antibodies like natalizumab involves catabolism into small peptides and amino acids, similar to endogenous IgG. The exact elimination pathways are not fully characterized but likely involve both renal and hepatic mechanisms, as with other IgG antibodies. Specific CYP enzyme involvement is not expected.
Dosage
Standard Dosage
Adults:
The recommended dosage for adults with MS and Crohn’s disease is 300 mg administered as an intravenous infusion over 1 hour every 4 weeks.
Children:
Natalizumab is not recommended for use in children and adolescents under 18 years of age, as safety and efficacy haven’t been established in this population.
Special Cases:
- Elderly Patients: Not recommended for use in patients over 65 due to lack of data.
- Patients with Renal Impairment: Dose adjustments are not expected to be necessary.
- Patients with Hepatic Dysfunction: Dose adjustments are not expected to be necessary.
- Patients with Comorbid Conditions: Monitor patients with pre-existing liver disease.
Clinical Use Cases
Natalizumab is not indicated for use in clinical settings like intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations such as status epilepticus or cardiac arrest. Its use is restricted to the treatment of MS and Crohn’s disease.
Side Effects
Common Side Effects:
Headache, fatigue, urinary tract infections, joint pain, upper respiratory tract infections, nausea, diarrhea, abdominal pain, vaginitis, rash, and dizziness.
Rare but Serious Side Effects:
Progressive multifocal leukoencephalopathy (PML), a serious brain infection, is a rare but potentially fatal complication. Herpes infections, other opportunistic infections, hypersensitivity reactions, including anaphylaxis, and liver injury.
Long-Term Effects:
The risk of PML increases with longer duration of treatment. Potential long-term effects include chronic infections and immune system suppression.
Contraindications
- Hypersensitivity to natalizumab.
- Active PML or a history of PML.
- Patients with significantly compromised immune systems.
Drug Interactions
Natalizumab’s interactions with other drugs haven’t been extensively studied. Caution should be exercised when co-administering with other immunosuppressants. Live vaccines are not recommended during natalizumab treatment.
Pregnancy and Breastfeeding
Natalizumab is classified as Pregnancy Category C. Animal studies show potential risks, and there are reports of neonatal anemia and thrombocytopenia with third-trimester exposure. While natalizumab does pass into breast milk, it is unlikely to be absorbed by the infant. However, due to limited data, breastfeeding while on natalizumab is generally not recommended, especially for newborns or preterm infants.
Drug Profile Summary
- Mechanism of Action: α4-integrin antagonist, inhibiting leukocyte migration.
- Side Effects: Common: Headache, fatigue, infections. Serious: PML, opportunistic infections.
- Contraindications: Hypersensitivity, active PML, immunocompromised state.
- Drug Interactions: Limited data, caution with immunosuppressants, avoid live vaccines.
- Pregnancy & Breastfeeding: Category C, potential neonatal risks; not recommended during breastfeeding.
- Dosage: 300 mg IV every 4 weeks.
- Monitoring Parameters: Neurological status, signs of infection, complete blood counts, liver function tests, and anti-JCV antibody status.
Precautions
- General Precautions: Screen for PML risk factors (prior immunosuppressant use, anti-JCV antibody status).
- Specific Populations: Monitor pregnant women closely; discourage breastfeeding; caution in the elderly.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Natalizumab?
A: The standard dose is 300 mg IV infusion every 4 weeks for adults. Not recommended for children under 18 or adults over 65.
Q2: What is the most serious side effect of Natalizumab?
A: Progressive multifocal leukoencephalopathy (PML), a potentially fatal brain infection.
Q3: How does Natalizumab work in multiple sclerosis?
A: It prevents leukocytes from crossing the blood-brain barrier, reducing inflammation in the CNS.
Q4: Can Natalizumab be used during pregnancy?
A: It’s a Pregnancy Category C drug; use only if clearly needed. Discuss risks and benefits with the patient.
Q5: Is it safe to breastfeed while taking Natalizumab?
A: Generally not recommended, especially with newborns or preterm infants.
Q6: How often should patients be monitored for PML?
A: Regularly monitor neurological status. PML risk assessments, including anti-JCV antibody testing, are typically done before treatment initiation and then periodically based on individual risk factors.
Q7: What are the common side effects of Natalizumab?
A: Headache, fatigue, urinary tract infections, and other infections are common.
Q8: Are there any contraindications to using Natalizumab?
A: Yes. Contraindications include hypersensitivity to natalizumab, active or history of PML, and severe immunodeficiency.
Q9: What is the role of anti-JCV antibody testing in Natalizumab therapy?
A: Anti-JCV antibody status is a significant risk factor for PML. Testing helps stratify risk and guide treatment decisions.
Q10: How is Natalizumab administered?
A: As an intravenous infusion over 1 hour, every 4 weeks.
