Fingolimod

Usage

Fingolimod is prescribed for the treatment of relapsing forms of multiple sclerosis (MS) in adults and children aged 10 years and older. This includes clinically isolated syndrome, relapsing-remitting MS, and active secondary progressive MS. It’s classified as a disease-modifying therapy (DMT), specifically a sphingosine 1-phosphate (S1P) receptor modulator. Fingolimod works by preventing lymphocytes (a type of white blood cell) from leaving the lymph nodes. This reduces the number of lymphocytes in the blood that can attack the central nervous system, thus decreasing inflammation and MS relapses.

Alternate Names

Fingolimod hydrochloride is the chemical name. Gilenya is a common brand name.

How It Works

Pharmacodynamics: Fingolimod is a prodrug, meaning it is inactive until metabolized in the body. It is phosphorylated by sphingosine kinase 2 to its active metabolite, fingolimod-phosphate. Fingolimod-phosphate acts as a functional antagonist of S1P receptors, specifically S1P1 receptors found on lymphocytes. This prevents lymphocytes from egressing from lymphoid tissues, reducing their circulation in the blood and their infiltration into the central nervous system.

Pharmacokinetics: Fingolimod is readily absorbed after oral administration, reaching peak plasma concentration within 1 to 4 hours. It undergoes extensive metabolism, primarily via phosphorylation to fingolimod-phosphate. It’s also metabolized through other pathways including CYP450 enzymes. The drug and its metabolites are eliminated slowly, primarily via hepatic metabolism, with a terminal elimination half-life of approximately 6 to 9 days. Excretion of fingolimod is predominantly via feces.

Mode of Action: Fingolimod-phosphate binds to S1P1 receptors on lymphocytes, internalizing these receptors. This internalization renders the lymphocytes insensitive to the S1P gradient, effectively trapping them in the lymph nodes and preventing their migration to sites of inflammation in the central nervous system.

Elimination pathways: Primarily hepatic metabolism and biliary/fecal excretion.

Dosage

Standard Dosage

Adults:

0.5 mg orally once daily.

Children (10 years and older):

• ≤ 40 kg: 0.25 mg orally once daily.

• 40 kg: 0.5 mg orally once daily.

Pediatric patients who start on 0.25 mg and subsequently reach a stable weight above 40 kg should switch to the 0.5 mg dose. Repeat the first-dose monitoring procedure upon switching to the higher dose.

Special Cases:

• Elderly Patients: No dosage adjustment is generally necessary. However, careful monitoring is advisable due to potential age-related decline in organ function.
• Patients with Renal Impairment: No dosage adjustment is generally necessary.
• Patients with Hepatic Dysfunction: Close monitoring is recommended in patients with severe hepatic impairment. Dosage adjustments are usually not required for mild or moderate hepatic dysfunction.
• Patients with Comorbid Conditions: Individualized assessment and dosage adjustments may be needed based on specific conditions, such as diabetes or cardiovascular disease.

Clinical Use Cases

Fingolimod is specifically indicated for relapsing forms of multiple sclerosis. Its use in clinical settings like intubation, surgical procedures, mechanical ventilation, ICU, or emergency situations is not relevant.

Dosage Adjustments

Dosage adjustments should be considered for patients with severe hepatic impairment, based on individual response and tolerability. Monitor for adverse events and adjust dosage accordingly.

Side Effects

Common Side Effects

Headache, influenza, cough, diarrhea, back pain, elevated liver enzymes, dizziness, fatigue, rash.

Rare but Serious Side Effects

Bradycardia (especially after the first dose), macular edema, infections (including herpes zoster and PML), hepatic dysfunction, hypertension, skin cancer, lymphoma.

Long-Term Effects

Increased risk of skin cancer and lymphoma.

Adverse Drug Reactions (ADR)

Serious infections, including PML, bradycardia, macular edema, hepatotoxicity.

Contraindications

• Hypersensitivity to fingolimod
• Recent (within 6 months) myocardial infarction, unstable angina, stroke, TIA, decompensated heart failure, or Class III/IV heart failure.
• Mobitz type II second-degree or third-degree atrioventricular block or sick sinus syndrome (unless patient has a functioning pacemaker).
• Baseline QTc interval ≥ 500 ms.
• Immunodeficiency syndrome
• Increased risk of opportunistic infections (including those receiving immunosuppressive therapies).
• Active chronic infections (e.g., hepatitis, tuberculosis).
• Pregnancy and women of childbearing potential not using effective contraception.

Drug Interactions

Fingolimod interacts with various medications, including:

• Drugs that slow heart rate (e.g., beta-blockers, calcium channel blockers, digoxin).
• Certain antiarrhythmic drugs (e.g., amiodarone, disopyramide).
• Immunosuppressants (e.g., natalizumab, rituximab).
• CYP450 enzyme inducers and inhibitors.

Consult a drug interaction database for a comprehensive list of potential interactions.

Pregnancy and Breastfeeding

Fingolimod is contraindicated during pregnancy and in women of childbearing potential not using effective contraception. It’s recommended to stop fingolimod at least two months before planning a pregnancy. Fingolimod should be avoided during breastfeeding due to the potential for serious adverse reactions in nursing infants.

Drug Profile Summary

• Mechanism of Action: S1P receptor modulator that sequesters lymphocytes in lymphoid tissues, reducing lymphocyte migration to the CNS.
• Side Effects: Common: headache, influenza, cough, diarrhea. Serious: bradycardia, macular edema, infections.
• Contraindications: Pregnancy, immunodeficiency, recent cardiac events, certain arrhythmias, active infections.
• Drug Interactions: Bradycardia-inducing drugs, immunosuppressants, CYP450 modulators.
• Pregnancy & Breastfeeding: Contraindicated in pregnancy and breastfeeding.
• Dosage: Adults: 0.5 mg once daily. Children (≥10 years): 0.25 mg (≤40 kg) or 0.5 mg (>40 kg) once daily.
• Monitoring Parameters: Heart rate (especially after the first dose), blood pressure, liver function tests, complete blood count, ophthalmological exams.

Popular Combinations

Fingolimod is generally used as monotherapy. Combining it with other DMTs is usually not recommended due to the increased risk of adverse events, especially infections.

Precautions

• First-dose monitoring for bradycardia is essential.
• Monitor for infections, macular edema, hepatic dysfunction, hypertension, and skin changes.
• Contraception is crucial for women of childbearing potential.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Fingolimod?

A: Adults: 0.5 mg orally once daily. Children (≥10 years): 0.25 mg (≤40 kg) or 0.5 mg (>40 kg) once daily.

Q2: What is the mechanism of action of Fingolimod?

A: Fingolimod acts by modulating sphingosine 1-phosphate (S1P) receptors, specifically S1P1, leading to the sequestration of lymphocytes in lymphoid tissue and reducing their migration to the central nervous system.

Q3: What are the most common side effects?

A: Headache, influenza, cough, diarrhea, back pain, and elevated liver enzymes.

Q4: What are the serious side effects of Fingolimod?

A: Bradycardia (especially after the first dose), macular edema, serious infections (including progressive multifocal leukoencephalopathy), hepatic dysfunction, and skin malignancies.

Q5: Can Fingolimod be used during pregnancy or breastfeeding?

A: No, Fingolimod is contraindicated in pregnancy and should be avoided while breastfeeding.

Q6: What are the main drug interactions with Fingolimod?

A: Drugs that slow heart rate (e.g., beta-blockers), some antiarrhythmic medications (e.g., amiodarone), and other immunosuppressants.

Q7: What precautions are necessary when initiating Fingolimod therapy?

A: First-dose cardiac monitoring for at least 6 hours, pre-treatment evaluation including ECG and ophthalmologic exam, and patient education regarding potential side effects.

Q8: How long does it take for Fingolimod to be eliminated from the body?

A: Fingolimod has a long elimination half-life of about 6-9 days. The effects may persist for up to 8 weeks after discontinuation.

Q9: What monitoring is recommended during Fingolimod treatment?

A: Regular monitoring of heart rate, blood pressure, liver function, complete blood count, and ophthalmological evaluations.

Q10: Is there a washout period required when switching from other MS therapies to Fingolimod?

A: Caution is advised when switching from drugs with prolonged immune effects (e.g., natalizumab, mitoxantrone, teriflunomide). Consult appropriate guidelines and resources for specific washout recommendations.