Fingolimod

Fingolimod (fingolimod hydrochloride) is used to treat highly active relapsing-remitting multiple sclerosis. The immunosuppressant acts as a sphingosine-1-phosphate receptor modulator and suppresses inflammatory processes in the CNS that would further destroy the myelin sheaths.

Fingolimod is a sphingosine-1-phosphate receptor modulator that is metabolized by sphingosine kinase to its active metabolite fingolimod phosphate. Fingolimod phosphate binds to sphingosine-1-phosphate (S1P) receptor 1 on lymphocytes even at low nanomolar concentrations, crosses the blood-brain barrier, and binds to S1P receptor 1 on neurons in the CNS. By binding, the drug blocks lymphocyte migration from lymph nodes, reducing infiltration of pathogenic lymphocytes, including pro-inflammatory Th17 cells, into the CNS.

Fingolimod and fingolimod phosphate are protein-bound to a very large extent (> 99%). Fingolimod is absorbed to ≥ 85%. Absolute oral bioavailability is 93%. Food intake did not alter the Cmax or exposure (AUC) of fingolimod. The drug accumulates in erythrocytes at a rate of 86%. Fingolimod is transformed in humans by reversible, stereoselective phosphorylation to the pharmacologically active (S)-enantiomer fingolimod phosphate. Fingolimod clearance from blood is 6.3 ± 2.3 l/h, and the average apparent terminal half-life is 6 to 9 days. After oral administration, approximately 81% of the administered dose is slowly renally eliminated as inactive metabolites.

Treatment of highly active relapsing-remitting multiple sclerosis in patients 10 years of age and older.

Women should not become pregnant during treatment and the use of an active contraceptive method is recommended. If pregnancy occurs during therapy with fingolimod, discontinuation of fingolimod is recommended.

In addition, the receptor modulated by fingolimod (sphingosine-1-phosphate receptor) is known to be involved in vascular formation during embryogenesis.

Fingolimod passes into breast milk in animals. Due to the potential risk of serious side effects in infants from fingolimod, women on treatment should not breastfeed.

The recommended dosage of fingolimod is 0.5 mg once daily. In children aged 10 years and older with a body weight ≤ 40 kg, a once-daily dose of 0.25 mg fingolimod is recommended.

Very frequently (≥ 1/10), the following side effects occur during treatment with fingolimod:

• Influenza
• Sinusitis
• Cough
• Diarrhea
• Back pain
• Elevated liver enzymes (elevated ALT, gamma-glutamyltransferase, aspartate transaminase).

Bradyarrhythmia: Upon initiation of therapy with fingolimod, there may be a transient decrease in heart rate and also a delay in atrioventricular conduction (including transient complete AV block that resolves spontaneously).

Liver function: Increases in liver enzymes, particularly alanine aminotransaminase (ALT) but also gamma-glutamyltransferase (GGT) and aspartate transaminase (AST), have been reported with the use of fingolimod.

Macular Edema: Particularly during the first 3 to 4 months of treatment, macular edema with or without visual symptoms may occur in 0.5 percent of patients treated with 0.5 mg fingolimod.

Infections: Fingolimod dose-dependently reduces peripheral lymphocyte counts to 20-30 percent of baseline by reversible retention (sequestration) of lymphocytes in lymphoid tissue. The following should therefore be noted:Cases of cryptococcal meningitis (a fungal infection), some fatal, have been reported in the postmarketing period after approximately 2 - 3 years of treatment, although a precise association with treatment duration is not known.

Post-marketing progressive multifocal leukoencephalopathy (PML) has been reported with fingolimod therapy

A negative anti-JCV antibody test does not exclude the possibility of subsequent JCV infection

MRI scan should be available for reference prior to initiation of fingolimod treatment (usually within 3 months prior to initiation of treatment)

Human papillomavirus (HPV) infections, including papilloma, dysplasia, warts, and HPV- or HHV-related cancers, have been reported with postmarketing fingolimod treatment

Washout of fingolimod may take up to two months after cessation of therapy and consequently monitoring for infection should continue over this time period

Posterior reversible encephalopathy syndrome

Rare cases of posterior reversible encephalopathy syndrome (PRES) at a dose of 0.5 mg have been reported in clinical trials and post-marketing. PRES is characterized by sudden onset of severe headache, nausea, vomiting, altered mental status, visual disturbances, and seizures.

Cutaneous Neoplasms

Basal cell carcinoma (BCC) and other cutaneous neoplasms have been reported with fingolimod therapy, including malignant melanoma, squamous cell carcinoma, Kaposi's sarcoma, and Merkel cell carcinoma. Monitoring of skin lesions must therefore be ensured and medical evaluation of the skin is recommended at the start of treatment and every 6 to 12 months thereafter.

Antineoplastic, immunomodulatory, or immunosuppressive therapy concomitant use should not occur due to risk of additive effects on the immune system. Caution should also be exercised when patients are switched from long-acting agents that affect the immune system, such as natalizumab, teriflunomide, or mitoxantrone

Vaccinations During and up to two months after treatment with fingolimod, the effectiveness of vaccinations may be impaired. Attenuated live vaccines should not be given because of the risk of infection.

An additional reduction in heart rate is possible with bradycardia-inducing agents (e.g., atenolol and diltiazem). Treatment with fingolimod should not be initiated in patients being treated with beta-blockers or other agents that may reduce heart rate, such as Class Ia and III antiarrhythmic agents, calcium channel blockers (such as verapamil or diltiazem), ivabradine, digoxin, cholinesterase inhibitors, or pilocarpine.

Ketoconazole 1.7-fold increase in exposure (AUC) of fingolimod and fingolimod phosphate due to inhibition of CYP4F2.

CYP3A4 inhibitors Special caution should be exercised with agents that may inhibit CYP3A4 (protease inhibitors, azole antifungals, some macrolides such as clarithromycin or telithromycin).

CYP3A4 inducers(e.g., carbamazepine, rifampicin, phenobarbital, phenytoin, efavirenz, and true St. John's wort) reduction in AUC. Because of the potential impairment of efficacy, their concomitant use should be undertaken with caution. However, concomitant administration of true St. John's wort is not recommended.

The following contraindications exist for the use of fingolimod:

• Immunodeficiency syndrome
• Patients at increased risk for opportunistic infections, including immunocompromised patients (including those currently receiving immunosuppressive therapy or immunocompromised by prior therapy).
• Severe active infections, active chronic infections (hepatitis, tuberculosis)
• Active malignant diseases
• Patients with 3rd degree Mobitz type II or 3rd degree AV block, or sick sinus syndrome if not wearing a pacemaker
• Patients with an existing QTc interval ≥ 500 ms.
• Hypersensitivity to the active substance.

The trade name of Fingolimod is Gilenya.

The drug is a synthetic replica of the natural active ingredient myriocin, which can be obtained from the fungus Isaria sinclairi.

A current (i.e. not older than 6 months) complete blood count (CBC) should be available before starting therapy.

CBC examinations should be performed periodically during treatment, at month 3 and at least annually thereafter, and at signs of infection.

If the total lymphocyte count is confirmed to be < 0.2 × 109/l, treatment should be paused until improvement.

Prior to initiation of therapy, patients must be screened for immunity to varicella (chickenpox).

The effect of fingolimod on the immune system may increase the risk of infections, including opportunistic infections Patients should be instructed to report symptoms of infection to their physician immediately during treatment and for up to 2 months after discontinuation of fingolimod If a patient develops a serious infection, discontinuation should be considered.