Natalizumab (Tysabri) is a humanized monoclonal antibody against the Alpha-4 subunit of integrin. It is used to treat patients with relapsing multiple sclerosis and Crohn's disease.

Natalizumab (Tysabri) Uses:

• Tysabri in Crohn disease:

  • Used in adults, inducing and maintaining clinical response and remission with moderately to severely active Crohn disease with evidence of inflammation who have had an inadequate response to, or are unable to tolerate, conventional Crohn disease therapies & inhibitors of tumor necrosis factor-alpha (TNF-alpha).

• Tysabri in relapsing Multiple Sclerosis:

  • Used as monotherapy for the treatment of patients with relapsing forms of multiple sclerosis, including clinically isolated syndrome, relapsing-remitting disease & active secondary progressive disease.
  • It increases the risk of progressive multifocal leukoencephalopathy.
  • Consider whether the expected benefit of natalizumab is sufficient to offset this risk when initiating and continuing treatment with natalizumab.
  • Canada labeling:
    • In patients, treatment of relapsing forms of multiple sclerosis who have had an inadequate response to, or are unable to tolerate, other therapies for multiple sclerosis.

Natalizumab (Tysabri) Dose in Adults

Natalizumab (Tysabri) Dose in the treatment of relapsing Multiple Sclerosis, :

• Natalizumab (Tysabri) 300 mg infused intravenously over 1 hour every four weeks.

Natalizumab (Tysabri) Dose in the treatment of Crohn disease:

• IV:
• Tysabri 300 mg infused IV over one hour every four weeks.
• Within the initial 12 weeks of therapy, discontinue if a therapeutic benefit is not observed.

• Concomitant use with corticosteroids:

  • For patients who begin treatment while on chronic oral corticosteroids, begin tapering oral steroids when the onset of natalizumab therapeutic benefit is observed.
  • Within 6 months of therapy initiation, discontinue use if the patient cannot be tapered off of oral corticosteroids.
  • Consider discontinuing therapy if additional concomitant corticosteroids are required and exceed 3 months/year (in addition to initial corticosteroid taper).

• Concomitant use with immunosuppressants (eg, azathioprine, cyclosporine, 6mercaptopurine, or methotrexate) or inhibitors of TNF-alpha:

  • • Avoid concomitant use

Use in Children:

Not indicated.

Natalizumab (Tysabri) Pregnancy Risk Category: C

• Natalizumab crosses over the placenta.
• Information on the outcome of natalizumab use during pregnancy can be found in pregnancy registries and systematic reviews. Most women stopped using it once they became pregnant.
• There was no consistent evidence that the risk of adverse outcomes, such as spontaneous abortions or birth defects, existed in all studies.
• After maternal use, newborns have experienced hemorhagic abnormalities, including anemia and thrombocytopenia in the third trimester.
• Disease-modifying therapies for multiple Sclerosis (MS) should be stopped prior to pregnancy. They are not recommended to be started during pregnancy.
• Consider other agents if you are considering having a baby with a high-risk female who is at risk for disease reactivation.
• When natalizumab was stopped, clinical rebound (new neurologic symptoms or increased lesions) was reported.
• Studies have shown that high-risk patients may avoid relapse by continuing treatment up to the point of pregnancy and then restarting their care soon after giving birth.
• It is recommended that pregnant women with high levels of disease activity continue to delay their pregnancy.
• After a discussion about the potential risks, natalizumab can be continued in pregnancy if disease-modifying treatment is required for these patients.

Natalizumab use during breastfeeding:

• Breast milk contains Natalizumab.
• A lactating woman, 11.5 months after giving birth, had her breast milk tested for natalizumab. She was currently breastfeeding her infant three times per day.
• Breast milk was tested prior to and for 50 consecutive days after maternal administration of natalizumab 300mg IV over an hour each 4 weeks.
• The breast milk concentrations in natalizumab were lower than the limit of detection 13 days after the first dose. They were stable until day 28 (second injection on day 29).
• The highest concentration of breast milk was found on the 50th day of the study.
• The steady-state concentrations of Maternal Plasma were not reached during the study period.
• A second study was done to determine the breast milk concentrations in natalizumab in breast milk of four lactating women who had been given between 9 and 55 doses prior to and during pregnancy.
• Breast milk could be sampled up to 145 days after delivery.
• Breast milk concentrations varied significantly, but were strongly correlated with the time since the last infusion.
• Based on limited data, recommendations regarding natalizumab or breastfeeding are varied.
• According to the manufacturer, when deciding whether to continue or stop breastfeeding during therapy, it is important to consider the risks to infants, the benefits to the mother and the benefits to the mother.

Natalizumab (Tysabri) Dose in Kidney Disease:

• In the manufacturer’s labeling, there are no dosage adjustments provided (has not been studied).

Natalizumab (Tysabri) Dose in Liver disease:

• In the manufacturer’s labeling, there are no dosage adjustments provided (has not been studied).
• Discontinue use with jaundice or signs/symptoms of hepatic injury

Common Side Effects of Natalizumab (Tysabri):

• Central Nervous System:

  • Headache
  • Fatigue
  • Depression

• Dermatologic:

  • Skin Rash

• Gastrointestinal:

  • Nausea
  • Gastroenteritis
  • Abdominal Distress

• Genitourinary:

  • Urinary Tract Infection

• Infection:

  • Influenza

• Neuromuscular & Skeletal:

  • Arthralgia
  • Limb Pain
  • Back Pain

• Respiratory:

  • Upper Respiratory Tract Infection
  • Lower Respiratory Tract Infection
  • Flu-Like Symptoms

• Miscellaneous:

  • Infusion Related Reaction

Less Common Side Effects Of Natalizumab (Tysabri):

• Cardiovascular:

  • Peripheral Edema
  • Chest Discomfort
  • Syncope

• Central Nervous System:

  • Vertigo
  • Dysesthesia
  • Rigors
  • Drowsiness

• Dermatologic:

  • Dermatitis
  • Pruritus
  • Urticaria
  • Thermal Injury
  • Night Sweats
  • Xeroderma

• Endocrine & Metabolic:

  • Menstrual Disease
  • Amenorrhea
  • Ovarian Cyst
  • Weight Changes

• Gastrointestinal:

  • Diarrhea
  • Tooth Infection
  • Dyspepsia
  • Abdominal Pain
  • Constipation
  • Toothache
  • Flatulence
  • Aphthous Stomatitis
  • Cholelithiasis
  • Gingival Disease

• Genitourinary:

  • Vaginal Infection
  • Vaginitis
  • Urinary Frequency
  • Dysmenorrhea
  • Urinary Incontinence

• Hematologic & Oncologic:

  • Hematoma

• Hepatic:

  • Increased Serum Transaminases

• Hypersensitivity:

  • Hypersensitivity Reaction

• Immunologic:

  • Antibody Development

• Infection:

  • Herpes Virus Infection
  • Viral Infection
  • Serious Infection

• Local:

  • Bleeding At Injection Site

• Neuromuscular & Skeletal:

  • Muscle Cramps
  • Tremor
  • Joint Swelling

• Respiratory:

  • Sinusitis
  • Cough
  • Tonsillitis
  • Pharyngolaryngeal Pain
  • Epistaxis

• Miscellaneous:

  • Limb Injury
  • Laceration

Contraindications to Natalizumab (Tysabri):

• Hypersensitivity to natalizumab and any component of the formula
• History or current status of progressive multifocal encephalopathy (PML).

Canada labeling:Additional contraindications not listed in the US labeling:

• Patients with immunocompromised conditions as a result immunosuppressant, antineoplastic therapy or immunodeficiencies (eg HIV, lymphoma, leukemia)

Warnings and precautions

• Hepatotoxicity:

  • There have been reports of hepatotoxicity and acute liver failure that requires transplantation.
  • Transaminase elevation and bilirubin elevation are signs of hepatotoxicity. They can occur as soon as 6 days after the first or multiple doses.

• Herpes infection

  • After natalizumab treatment, severe, life-threatening herpes infections (herpes meningitis or herpes encephalitis) can occur within a few months to several decades.
  • Check for symptoms and signs of meningitis or encephalitis in patients.
  • Stop using therapy if you have meningitis or herpes encephalitis.
  • Acute retinal necrosis (ARN) was also observed during natalizumab therapy.
  • This is a fulminant viral infection caused by the family herpesviruses (eg varicella-zoster, herpes simplix virus).
  • Some cases were reported in patients with CNS herpes infection (eg, herpes menacingitis, or encephalitis).
  • Blindness may be possible in severe cases.
  • After being diagnosed with ARN, you may want to discontinue natalizumab.

• Hypersensitivity/antibodies formation

  • Hypersensitivity reactions can cause serious systemic reactions, such as anaphylaxis.
  • The symptoms may include fever, flushing and rigors.
  • Reactions to natalizumab are usually associated with antibodies.
  • Antibodies may be considered for patients with hypersensitivity reactions.
  • A prolonged interruption of therapy after a single infusion of natalizumab may increase the risk of developing anti-natalizumab antibody and/or hypersensitivity reactions upon reinitiation.
  • If you experience hypersensitivity reactions, discontinue use.
  • Patients with hypersensitivity reactions shouldn't be treated again.
  • Antibody formation, which occurs in approximately 10% of patients, is associated with a decrease of natalizumab and a decrease of its efficacy.
  • Antibody testing should always be done in all patients suspected of having persistent antibodies.
  • It should also be performed for patients who resume treatment after a time of interruption in dosage.

• Immune reconstitution inflammatory syndrome, (IRIS)

  • IRIS was reported in patients who had stopped taking natalizumab because of PML.
  • Most cases occurred within days or weeks of plasma exchange, which was done to remove natalizumab.
  • IRIS is a rare condition characterized by severe inflammation following or during immune system recovery. This can lead to a decline of patient condition and even death.

• Infections

  • There may be an increased risk of infection due to the use of this medication (rare postmarketing reports).
  • Concurrent use of antineoplastics, immunosuppressants, including short-course corticosteroids or immunomodulating drugs, may also increase this risk.
  • Stop using therapy until the infection is completely gone.

• Lab test abnormalities:

  • There may be a reversible increase in circulating lymphocytes and monocytes.
  • Changes occur within 16 weeks of the last dose. However, they usually return to baseline in 16 weeks.
  • It is possible to experience mild transient drops in hemoglobin.

• Progressive multifocal Leukoencephalopathy

  • [US Boxed Warning]

  • Natalizumab can increase the risk of developing fatal, disabling, or progressive multifocal Leukoencephalopathy (PML), a complication of the JC virus.
  • The following are risk factors for PML: the length of treatment (especially >2 year), previous use of immunosuppressants (eg azathioprine or cyclophosphamide), methotrexate and mitoxantrone (mycophenolate), and presence of anti-JC viruses antibodies.
  • Check for new symptoms or signs that may be indicative of PML.
  • Stop all treatment immediately if you notice any symptoms that suggest PML.
  • An evaluation for PML should include a gadolinium enhanced MRI scan of your brain and, if necessary, analysis of CSF to determine if there is any JCV DNA.
  • Retrospective analyses using ELISA suggest that PML risk may be related to relative serum anti-JCV antibodies levels compared with a calibrator.
  • PML cases have been diagnosed based upon MRI findings & detection of JCV DNA (in the CSF) without any specific PML symptoms.
  • Patients who are immunocompromised or on chronic immunosuppressant/immunomodulatory therapy should be advised to avoid using it.
  • For early detection of PML, it is worth considering periodic monitoring using an MRI scan.
  • Anti-JCV antibody testing can be performed before or during treatment.
  • Testing should not be used for PML diagnosis and should be stopped at least two weeks after plasma exchange.
  • Patients with negative anti-JCV antibodies are still at high risk of developing PML. However, the risk is lower.
  • Patients with negative anti-JCV antibody tests should be retested regularly.
  • A baseline brain MRI scan should be done before initiating treatment in MS patients. This should also be done in Crohn disease patients.
  • Patients who had not experienced PML symptoms at the time of discontinuation have also reported PML.
  • After discontinuing therapy, patients should be closely monitored for symptoms and signs of PML for at most 6 months.

• Crohn disease:

  • Patients with Crohn disease should not take Natalizumab in combination with immunosuppressants and tumor necrosis factor inhibitors.
  • You can use aminosalicylates concurrently with natalizumab
  • Patients who are currently taking chronic oral corticosteroids should begin to taper when natalizumab's therapeutic benefits begin.
  • Stop using oral corticosteroids if the patient is unable to taper off within six months.
  • If additional corticosteroids or corticosteroid therapy is required, and exceeds 3 months/year, you should consider discontinuing treatment.

Natalizumab: Drug Interaction

Monitoring parameters:

• Symptoms of hepatotoxicity (eg, elevated serum transaminases, bilirubin).
• Hypersensitivity reactions during & for 1 hour after infusion.
• Symptoms of persistent antibody-positivity (eg, anxiety, dizziness, dyspnea, feeling cold, flushing, headache, hypertension, myalgia, nausea, pruritus, pyrexia, rigors, tachycardia, tremor, urticaria or, vomiting).
• Signs/symptoms of meningitis & encephalitis.
• Signs/symptoms of acute retinal necrosis.
• Radiographic signs of PML periodically.
• If persistent antibodies are suspected and repeated in 3 months in all patients with documented positivity on the initial test, antibody testing is recommended.
• Following a period of dosage interruption, consider antibody testing in patients that resume therapy.
• Baseline brain MRI scan.
• Obtain a gadolinium-enhanced brain MRI scan and CSF analysis for JC viral DNA, if PML is suspected.
• Evaluate for signs or symptoms of progressive multifocal leukoencephalopathy during treatment and for 6 months after discontinuation.

• Note:

  • Transient & reversible leukocytosis (excluding neutrophils) & mildly reduced hemoglobin may occur with treatment and may require ~4 months for return to baseline values after the last dose.
  • Anti-JCV antibody (prior to therapy & periodically during therapy).

How to administer Natalizumab (Tysabri)?

• If stored under refrigeration, prior to administration allow the solution to warm to room temperature.
• The diluted solution should be infused over 1 hour.
• Do not administer by IV bolus or push.
• Patients should be closely monitored for signs and symptoms of hypersensitivity during the infusion and for at least 1 hour after the infusion is complete.
• The infusion should be discontinued if a reaction occurs, and the treatment of the reaction should be instituted.
• Following infusion, flush line with NS.

Mechanism of action of Natalizumab (Tysabri):

• Natalizumab, a monoclonal anti-integrin antibody, is directed against the alpha-4 subunit.
• These molecules are essential for adhesion and migration of cells from the vasculature to inflamed tissue.
• Natalizumab inhibits integrin interaction with vascular receptors. This limits adhesion and transmigration of leukocytes.
• The effectiveness of certain disorders could be linked to the reduction in inflammatory cell populations in target tissues.
• Multiple sclerosis may be caused by a blockade of T lymphocyte movement into the central nervous systems.
• The likelihood of relapse is lower when you are treated.
• Natalizumab reduces inflammation in Crohn disease by binding to alpha-4 Integrin. This blocks adhesion and allows for migration of leukocytes within the gut.

Distribution:

• Crohn disease:
  • 2.4-8 L.
• Multiple sclerosis:
  • 3.8-7.6 L

Half-life elimination:

• Crohn disease:
  • 3-17 days.
• Multiple sclerosis:
  • 7-15 days

International Brands of Natalizumab:

• Tysabri

Natalizumab Brand Names in Pakistan:

No Brands Available in Pakistan.