Natalizumab

Multiple Sclerosis

Natalizumab is used to treat relapsing forms of multiple sclerosis (MS) in adults. This includes several specific types of the condition:

• Relapsing-remitting disease
• Active secondary progressive disease
• Clinically isolated syndrome

In patients with MS, the medication is used to help reduce the frequency of clinical relapses and delay the progression of physical disability.

Crohn's Disease

Natalizumab is also indicated for the treatment of moderate to severe Crohn's disease in adults. It is typically reserved for patients who meet the following criteria:

• Have evidence of active inflammation.
• Have had an inadequate response to conventional Crohn's disease therapies.
• Are unable to tolerate other treatments, such as tumor necrosis factor (TNF) inhibitors.

In these cases, the medication is used to induce and maintain clinical response and remission.

Mechanism of Action

Natalizumab belongs to a class of medications called monoclonal antibodies. It is designed to target and bind to specific proteins on the surface of white blood cells, which are part of the body's immune system.

In conditions like multiple sclerosis (MS) and Crohn's disease, the immune system mistakenly attacks healthy tissues. White blood cells travel through the bloodstream and cross into the central nervous system or the lining of the intestines, causing inflammation and damage.

Natalizumab works by:

• Binding to proteins: The medication attaches to alpha-4 integrin, a protein found on the surface of certain white blood cells.
• Blocking movement: By binding to these proteins, the drug prevents the immune cells from sticking to and passing through the walls of blood vessels.
• Reducing inflammation: This action keeps the inflammatory cells from reaching the brain, spinal cord, or gut, where they would otherwise cause tissue damage.

By limiting the number of immune cells that enter these areas, natalizumab helps decrease the frequency of MS relapses and can help manage symptoms of Crohn's disease when other treatments have not worked.

Common Side Effects

• Headache
• Fatigue
• Joint or muscle pain
• Nausea or diarrhea
• Stomach pain
• Respiratory infections, such as the common cold
• Urinary tract infections
• Pain in the arms or legs
• Vaginal irritation or infection
• Depression

Serious Side Effects

Contact a healthcare provider immediately if you experience any of the following serious symptoms:

• Brain Infection (PML): Progressive multifocal leukoencephalopathy is a rare brain infection that can lead to disability or death. Symptoms include changes in vision, balance, strength, or thinking that worsen over several days.
• Liver Damage: Signs include yellowing of the skin or eyes, dark urine, or severe fatigue.
• Allergic Reactions: Symptoms such as hives, swelling of the face or throat, dizziness, or difficulty breathing, often occurring during or shortly after an infusion.
• Serious Infections: Increased risk of shingles, cold sores, or infections of the brain and spinal cord, such as meningitis or encephalitis.
• Low Platelet Count: Increased risk of bruising or bleeding that does not stop.

Progressive Multifocal Leukoencephalopathy (PML)

Natalizumab increases the risk of PML, an opportunistic viral infection of the brain caused by the John Cunningham virus (JCV). This condition is often fatal or results in severe disability. Risk factors for developing PML include the presence of anti-JCV antibodies, a longer duration of treatment (especially beyond two years), and prior use of immunosuppressant medications. Healthcare providers monitor for new or worsening neurological symptoms that may indicate PML.

Restricted Access Program

Because of the risk of PML, natalizumab is only available through a restricted distribution program. Under this program, only prescribers, pharmacies, and infusion centers certified with the program can prescribe or dispense the medication. Patients must also be enrolled and comply with regular monitoring and evaluation.

Serious Allergic Reactions

Serious hypersensitivity reactions, including anaphylaxis, have occurred in patients receiving natalizumab. These reactions typically happen during the infusion or within one hour after it is completed. Symptoms may include hives, swelling of the face, dizziness, fever, rash, and low blood pressure. If a serious allergic reaction occurs, the medication is usually discontinued permanently.

Liver Injury

Natalizumab can cause clinically significant liver injury. Signs of liver damage may include yellowing of the skin or eyes (jaundice), dark urine, or elevated liver enzymes found in blood tests. This injury can occur at any time during treatment, even after the first dose. Healthcare providers typically monitor liver function and may stop treatment if signs of liver damage appear.

Infections

This medication affects the immune system and may increase the risk of developing serious infections. This includes an increased risk of herpes simplex and varicella-zoster virus infections of the central nervous system, such as meningitis and encephalitis. Other opportunistic infections may also occur. Patients are monitored for signs of infection during and after treatment.

Thrombocytopenia

Natalizumab may cause a decrease in the number of platelets in the blood (thrombocytopenia), which are necessary for clotting. This can increase the risk of bleeding. Symptoms to watch for include easy bruising, small red or purple spots on the skin, or bleeding that is difficult to stop.

Contraindications

Natalizumab should not be used by individuals who have a history of PML or those who have had a serious allergic reaction to natalizumab or any of its ingredients.

Pregnancy

There are no adequate and well-controlled studies of natalizumab in pregnant women. Research in animals has shown some evidence of harm to the fetus. This medication should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

If natalizumab is used during the third trimester of pregnancy, healthcare providers may monitor the newborn for blood-related issues. Some infants exposed to the drug late in pregnancy have experienced:

• Low levels of platelets (thrombocytopenia)
• Low red blood cell counts (anemia)

Breastfeeding

Natalizumab passes into human breast milk. It is not known if the drug has an effect on the nursing infant or on milk production. Decisions regarding breastfeeding while using this medication should be made in consultation with a healthcare provider to evaluate the risks and benefits.

Natalizumab is available as a concentrated solution for intravenous infusion. It is supplied in vials and must be diluted with a sterile saline solution before administration.

The medication is administered by a healthcare professional in a clinical setting, such as a doctor's office, infusion center, or hospital. It is not designed for self-injection or home use. Both the original reference product and biosimilar versions are available in this injectable format.

FDA Approval and Indications

Natalizumab was first approved by the U.S. Food and Drug Administration (FDA) in 2004. It is currently approved for the treatment of relapsing forms of multiple sclerosis (MS) in adults, including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease. It is also indicated for adult patients with moderately to severely active Crohn's disease who have not responded well to or cannot tolerate other treatments.

In August 2023, the FDA approved the first biosimilar version of natalizumab to treat these same conditions, providing an additional treatment option for patients.

Boxed Warning and PML Risk

The FDA has required a boxed warning for natalizumab due to the risk of progressive multifocal leukoencephalopathy (PML). PML is a rare and potentially fatal viral infection of the brain. The risk of developing PML increases with the duration of treatment, prior use of immunosuppressant medications, and the presence of antibodies against the John Cunningham (JC) virus.

REMS Safety Program

Because of the risk of PML, natalizumab is only available through a restricted distribution program called a Risk Evaluation and Mitigation Strategy (REMS). For the original brand-name version, this is known as the TOUCH Prescribing Program. Under this regulatory requirement:

• Only healthcare providers and pharmacies enrolled in the program can prescribe or distribute the drug.
• Infusion centers must be specially certified to administer the medication.
• Patients must be educated on the risks and enrolled in the program to receive treatment.

Regulatory History

Following its initial approval in 2004, natalizumab was voluntarily withdrawn from the market in 2005 after reports of PML emerged. After a thorough safety review and the development of the restricted distribution program, the FDA allowed the medication to return to the market in 2006. The FDA continues to monitor safety data and has issued several communications regarding the importance of testing for JC virus antibodies to help assess a patient's risk for PML.

Infusion Process

Natalizumab is delivered through a needle or catheter placed into a vein, usually in the arm. Each infusion session typically lasts about one hour. Because of the risk of serious side effects, the medication is only available through a restricted distribution program and must be administered in a certified healthcare setting.

Monitoring and Frequency

The standard schedule for natalizumab infusions is once every four weeks. During the infusion and for at least one hour after it is finished, healthcare providers will monitor you closely for signs of a serious allergic reaction. Symptoms that require immediate attention include:

• Hives, itching, or skin rash
• Dizziness or lightheadedness
• Swelling of the face, lips, or tongue
• Difficulty breathing or wheezing
• Chest pain or chills

If you miss an appointment for your infusion, it should be rescheduled as soon as possible. It is important to receive the medication on a regular schedule to maintain its effectiveness.