Fingolimod

Approved Uses

Fingolimod is indicated for the treatment of relapsing forms of multiple sclerosis (MS). It is used in patients who experience episodes of worsening neurological function followed by periods of recovery. Specifically, it is approved to treat:

• Clinically isolated syndrome: This is often the first episode of neurological symptoms that may lead to an MS diagnosis.
• Relapsing-remitting disease: This is the most common form of MS, characterized by clearly defined attacks followed by periods of remission.
• Active secondary progressive disease: This occurs when the disease begins to worsen more steadily, but the patient still experiences occasional relapses.

Treatment Goals

The primary goals of treatment with fingolimod include:

• Reducing the frequency of clinical relapses (flare-ups).
• Slowing the accumulation of physical disability caused by the disease.

Fingolimod is not a cure for multiple sclerosis. It is approved for use in both adults and pediatric patients who are at least 10 years old.

Mechanism of Action

Fingolimod is classified as a sphingosine 1-phosphate (S1P) receptor modulator. Its primary function is to regulate the movement of lymphocytes, which are white blood cells that play a key role in the body's immune response.

In multiple sclerosis, the immune system attacks the myelin sheath, the protective covering of the nerves. Fingolimod interferes with this process through the following mechanisms:

• Lymphocyte Retention: The medication binds to specific receptors on the surface of white blood cells. This action signals the cells to stay within the lymph nodes rather than entering the bloodstream.
• Reduced Central Nervous System Entry: Because the white blood cells are sequestered in the lymph nodes, there are fewer of them available to cross the blood-brain barrier.
• Protection of Nerve Fibers: By limiting the number of inflammatory cells that reach the brain and spinal cord, the drug helps prevent the immune-mediated attacks that lead to nerve damage and MS relapses.

It is important to note that fingolimod does not kill the white blood cells; it simply changes where they are located in the body. Once the medication is stopped, these cells eventually begin to circulate normally again.

Common Side Effects

• Headache
• Back pain
• Diarrhea
• Cough
• Pain in the arms or legs
• Stomach pain
• Flu-like symptoms

Serious Side Effects

Seek medical attention immediately if you experience any of the following serious side effects:

• Heart rhythm problems: Slow or irregular heartbeat, dizziness, or feeling faint, especially after the first dose.
• Infections: Fever, tiredness, body aches, or other signs of infection. Some infections can be life-threatening and may occur up to two months after stopping treatment.
• Vision changes: Blurred vision, a blind spot in the center of your vision, or changes in how you see colors.
• Liver problems: Nausea, vomiting, stomach pain, loss of appetite, dark urine, or yellowing of the skin or eyes.
• Breathing issues: New or worsening shortness of breath.
• Blood pressure changes: Significant increases in blood pressure may occur during treatment.
• Skin changes: New or changing moles, or sores that do not heal, which may indicate certain types of skin cancer.
• Neurological symptoms: Sudden severe headache, confusion, seizures, or sudden vision loss.

Rare Brain Conditions

Fingolimod may increase the risk of a rare and serious brain infection called progressive multifocal leukoencephalopathy (PML). Symptoms can include weakness on one side of the body, clumsiness, or changes in thinking, memory, and personality. Another rare condition, posterior reversible encephalopathy syndrome (PRES), can cause sudden severe headaches, confusion, or seizures.

Heart Rate and Rhythm Changes

Fingolimod can cause the heart rate to slow down, especially after the first dose. This effect usually starts within an hour and is most significant around six hours after taking the medication. Because of this, the first dose is typically administered in a medical setting where the heart rate and blood pressure can be monitored for at least six hours. Individuals with certain pre-existing heart conditions, such as a recent heart attack, stroke, unstable angina, or specific types of heart failure, should not take this medication.

Infections

This medication lowers the number of white blood cells in the blood, which can increase the risk of serious infections. These may include:

• Progressive Multifocal Leukoencephalopathy (PML): A rare and potentially fatal brain infection.
• Cryptococcal Meningitis: A serious fungal infection of the brain and spinal cord.
• Herpes Viral Infections: Including shingles and herpes encephalitis.

Healthcare providers usually check for immunity to chickenpox (varicella) before starting treatment, and vaccination may be required for those without immunity.

Vision Problems

Fingolimod may cause macular edema, which is swelling in the back of the eye. This can cause blurred vision or a blind spot in the center of vision. Regular eye exams are often recommended, particularly for those with diabetes or a history of eye inflammation (uveitis).

Severe Worsening of MS After Stopping

When fingolimod is discontinued, symptoms of multiple sclerosis can return and may be significantly worse than before treatment started or during treatment. This severe increase in disability usually occurs within 12 weeks after stopping the medication.

Liver and Lung Function

The medication may cause liver injury or elevations in liver enzymes. It can also lead to a decrease in lung function. Periodic blood tests and breathing tests may be used to monitor these areas during treatment.

Pregnancy and Fetal Risk

Fingolimod may cause harm to an unborn baby. Effective contraception should be used during treatment and for at least two months after the last dose is taken. If a person becomes pregnant while taking the drug, they should notify their healthcare provider immediately.

Skin Cancer Risk

There is an increased risk of developing skin cancers, such as basal cell carcinoma and melanoma, while taking this medication. Regular skin examinations and protection from sunlight are recommended.

Posterior Reversible Encephalopathy Syndrome (PRES)

In rare cases, a serious brain condition called PRES may occur. Symptoms can include sudden severe headache, confusion, seizures, or vision loss. This requires immediate medical attention.

Pregnancy

Fingolimod can cause harm to a developing fetus. Research in animals has shown that the medication may lead to birth defects or pregnancy loss. Because of these risks, women who are able to become pregnant should use effective contraception while taking fingolimod and for at least two months after the last dose.

If pregnancy occurs during treatment or within two months after stopping fingolimod, a healthcare provider should be contacted immediately. There is a pregnancy registry available to monitor the health of both the mother and the baby for those exposed to the drug during pregnancy.

Breastfeeding

It is currently unknown whether fingolimod passes into human breast milk. However, studies in animals have shown that the drug is excreted in milk. Due to the potential for serious adverse reactions in a nursing infant, breastfeeding is generally not recommended during treatment with fingolimod. Discuss the risks and benefits with a healthcare professional to determine the best course of action.

Dosage Forms

Fingolimod is available in the following form:

• Oral Capsule: This medication is administered by mouth.

The capsules are designed to be swallowed whole and can be taken with or without food. They are typically supplied in blister packs or bottles to protect the medication from moisture.

FDA Approval and Indications

Fingolimod was the first oral disease-modifying therapy approved by the FDA for the treatment of relapsing forms of multiple sclerosis (MS). It is currently indicated for adults and pediatric patients 10 years of age and older with clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease.

Safety Communications and Monitoring

The FDA requires specific safety protocols for patients starting this medication. Because the first dose can cause a significant decrease in heart rate, patients must be monitored by a healthcare provider for at least six hours after the initial dose. This monitoring includes pulse and blood pressure checks, as well as an electrocardiogram (ECG) before and after the observation period.

In 2018, the FDA issued a safety communication warning that multiple sclerosis symptoms can become significantly worse after stopping fingolimod. This rebound effect can lead to severe disability compared to the patient's condition before or during treatment.

Risk Evaluation and Mitigation Strategy (REMS)

To ensure the benefits of the drug outweigh its risks, the FDA has implemented a Risk Evaluation and Mitigation Strategy (REMS). This program focuses on informing healthcare providers and patients about serious risks, including:

• Bradyarrhythmia: Slow or abnormal heart rhythms, especially after the first dose.
• Infections: Increased risk of serious infections, including progressive multifocal leukoencephalopathy (PML), a rare brain infection.
• Liver Injury: Potential for significant liver damage, identified as a safety signal in FDA adverse event reporting.
• Macular Edema: A vision-threatening condition involving swelling in the retina.

Risk of Worsening Symptoms

It is important not to stop taking fingolimod without consulting a healthcare provider. When the medication is discontinued, MS symptoms may return. Some patients experience a severe worsening of their condition, sometimes referred to as a rebound effect, which can lead to a higher level of disability than was present before treatment started.

Timing of Withdrawal Effects

Severe exacerbations of MS typically occur within 12 weeks after the last dose of fingolimod is taken, but they have been reported as late as 24 weeks after stopping the medication. In many reported cases, patients did not return to the level of function they had before the symptoms worsened.

Restarting the Medication

If fingolimod treatment is interrupted for more than two weeks, the initial starting procedure must usually be repeated. This includes the six-hour heart rate monitoring required for the very first dose, as the risk of a slow heart rate (bradycardia) returns after the drug has been out of the system for that length of time.