Fingolimod (Gilenya) is a sphingosine-1-phosphate receptor modulator, that acts as an immunomodulator by sequestering lymphocytes in the lymph nodes. It is used in the treatment of patients with multiple sclerosis.

Fingolimod (Gilenya) Uses:

• Multiple sclerosis:

  • Uses for the treatment of relapsing forms of multiple sclerosis (MS) in patients of 10 years or more than 10 years to reduce the frequency of clinical exacerbations and to delay the accumulation of physical disability.

Fingolimod (Gilenya) Dose in Adults

Fingolimod (Gilenya) Dose in the treatment of Multiple sclerosis:

• Oral: 0.5 mg once a day;
• Doses exceeding 0.5 mg per day are associated with increased adverse events and no additional benefit.

Note: Administer the first dose and doses following therapy interruption (>14 days) in a setting in which resources to appropriately manage symptomatic bradycardia are available.

Fingolimod (Gilenya) Dose in Childrens

Fingolimod (Gilenya) Dose in the treatment of Multiple sclerosis:

Note:

• Doses exceeding 0.5 mg per day are associated with increased adverse events and no additional benefit.
• The first dose and doses following therapy interruption (see Monitoring Parameters), as well as dose increases, should be administered in a setting in which resources to appropriately manage symptomatic bradycardia are available.

• Children ≥10 years and Adolescents:

  • ≤40 kg: Oral: 0.25 mg once a day.
  • >40 kg: Oral: 0.5 mg once a day.

Fingolimod (Gilenya) Pregnancy Category: C

• Animal reproduction studies have shown that adverse events can be observed.
• Fingolimod elimination takes about 2 months. To avoid possible fetal harm, pregnant women with childbearing potential need to use effective contraception for at least 2 months.
• Continuous data collection is underway to monitor the effects of fingolimod on infants and pregnant women. 
• Pregnant women can be enrolled by their health care providers, or they may enroll themselves in the Gilenya Pregnancy Register (1-877-598-7232 or https://www.gilenyapregnancyregistry.com).

Use of Fingolimod while breastfeeding

• It is unknown if breast milk contains fingolimod.
• The manufacturer suggests that the mother decide whether to stop breastfeeding or discontinue using the drug.
• This is in consideration of the possibility of serious adverse reactions in breastfeeding infants.

Fingolimod (Gilenya) Dose in Kidney Disease:

• The manufacturer's labeling does not provide any dosage adjustments.
• Use caution if you have severe renal impairment (exposure is greater).
• A small pharmacokinetic analysis in patients with stable severe impairment (CrCl below 30 mL/minute), but not on dialysis, suggests that dose adjustments may not be required if increases in exposure to fingolimod or the active metabolite (fingolimod P) are clinically insignificant.

Fingolimod (Gilenya) Dose in Liver disease:

• Mild to moderate impairment (Child-Pugh classes A and B):

  • No dosage adjustment required.

• Severe impairment (Child-Pugh class C):

  • Manufacturer's labeling doesn't provide any adjustments  labeling;
  • Exposure is doubled in severe hepatic impairment;
  • Use with caution and closely monitor.

Common Side Effects of Fingolimod (Gilenya):

• Central Nervous System:

  • Headache

• Endocrine & Metabolic:

  • Increased Gamma-Glutamyl Transfer

• Gastrointestinal:

  • Diarrhea
  • Nausea
  • Abdominal Pain

• Hepatic:

  • Increased Serum Alanine Aminotransferase
  • Increased Serum Aspartate Transaminase

• Infection:

  • Influenza

• Neuromuscular & Skeletal:

  • Back Pain

• Respiratory:

  • Cough
  • Sinusitis

Less Common Side Effects Of Fingolimod (Gilenya):

• Cardiovascular:

  • Hypertension
  • Second Degree Atrioventricular Block
  • Bradycardia
  • First Degree Atrioventricular Block

• Central Nervous System:

  • Migraine
  • Seizure

• Dermatologic:

  • Alopecia
  • Actinic Keratosis
  • Pityriasis Versicolor

• Endocrine & Metabolic:

  • Increased Serum Triglycerides

• Hematologic & Oncologic:

  • Cutaneous Papilloma
  • Leukopenia
  • Basal Cell Carcinoma
  • Lymphocytopenia

• Infection:

  • Herpes Virus Infection
  • Herpes Zoster Infection

• Neuromuscular & Skeletal:

  • Limb Pain
  • Asthenia

• Ophthalmic:

  • Blurred Vision

• Respiratory:

  • Bronchitis
  • Decreased Lung Function
  • Dyspnea
  • Reduced Forced Expiratory Volume

Contraindications to Fingolimod (Gilenya):

• Hypersensitivity to fingolimod (including urticaria and rash), or any component of its formulation.
• Myocardial Infarction
• Angina unstable
• Stroke or transient ischemic attack
• Hospitalization for decompensated heart disease or New York Heart Association (NYHA), class III/IV heart failure within the last 6 months.
• Mobitz Type II second or third-degree atrioventricular block (AV) or sick sinus syndrome (except if the patient has a working pacemaker).
• QTc baseline interval 500 msec long or longer than 500 msec
• Concurrent use of a class III or Ia antiarrhythmic.

Canadian labeling: Additional contraindications not in US labeling

• Patients who are at higher risk of opportunistic infection, such as those who have been treated (eg antineoplastic or immunosuppressive therapies, bone marrow transplantation, total lymphoid radiation or bone marrow irradiation) or suffer from a disease (eg immunodeficiency disorder).
• Severe active infections, including active chronic bacterial or fungal infections (eg, hepatitis and tuberculosis).
• Known active malignancy (except basal cell carcinoma);
• Severe hepatic impairment (Child Puugh class C).

Warnings and precautions

• Block of the Atrioventricular (AV),

  • In the first six hours after the initial dose, third-degree AV blocks and AV blocks with junctional escape were present.
  • Transient asystole or unexplained deaths have also been reported within the first 24 hour. Syncope has also been observed.
  • This may cause transient and asymptomatic AV Conduction Delays.
  • These usually resolve within 24 hours. Recurrences can be observed after discontinuation or subsequent reinitiation.

• Bacterial infections

  • Assess and treat any signs and symptoms of infection promptly.
  • It has been associated with severe opportunistic bacteria infections (eg, Atypical Mycobacteria).

• Bradycardia

  • Initiation should be done in a setting that has the resources and personnel to manage symptomatic bradycardia.
  • The heart rate can drop as quickly as one hour after the first dose. Recovery (but not to baseline) takes place between 8 and 10 hours.
  • The second dose of the drug causes a decrease in heart rate within 24 hours. This may be more noticeable than the 6-hour decrease.
  • A majority of patients are not symptomatic. However, symptoms such as hypotension, dizziness and fatigue, chest pain, palpitations, nausea, and/or dizziness may occur.
  • Symptoms usually resolve in 24 hours.
  • The second dose may cause a decrease in heart rate, but it will be less than the first.
  • After 1 month of continuous therapy, the heart rate usually returns to baseline.

• Cryptococcal infections

  • There have been cases of cryptococcal meningitis, disseminated Cryptococcal infections (including deaths) reported.
  • Although most cryptococcal infections occur after two years of treatment, they can also occur sooner (although the relationship between risk and treatment duration is not known).
  • Cryptococcal infection symptoms should be treated immediately by a doctor.

• Hepatic effects

  • Elevated liver enzymes can occur. Most elevations occur within 6 to 9 month.
  • With re-challenge, liver transaminase elevations could recur.
  • Reports of liver injury due to cholestatic and/or hepatocellular hepatitis have been made
  • Before starting therapy, obtain baseline liver enzymes (bilirubin) from all patients (within 6 month); monitor liver enzymes for patients with symptoms of hepatic impairment (eg, nausea and vomiting, abdominal pains, fatigue, jaundice or dark urine).
  • If you are positive that your liver has been damaged, discontinue treatment. Transaminases can return to normal in as little as 2 months.

• Herpes infection

  • There have been fatalities from severe, life-threatening herpes infections (e.g., disseminated prima herpes virus and herpes simplexencephalitis).
  • If you experience an MS-relapse or multiorgan dysfunction, disseminated herpes infection may be the cause.
  • Kaposi Sarcoma, which is often associated with the human herpesvirus-8, has been reported in cases. If suspected, prompt diagnosis and management are necessary.

• Hypersensitivity reaction

  • Reports of hypersensitivity reactions including urticaria and rash upon treatment initiation have been made.

• Hypertension

  • An increase in blood pressure can occur within a month of the initiation or termination of therapy. Monitor blood pressure during treatment.

• Lymphopenia

  • It is possible to experience a dose-dependent drop in lymphocyte count
  • You should monitor your lymphocyte count for at least two months after you stop therapy to avoid delayed recovery.
  • Patients with a lower baseline lymphocyte count or a BMI below 18.5 kg/m2, and females who have previously been exposed to natalizumab, may be at higher risk.
  • Patients who experience lymphopenia after receiving fingolimod may benefit from an alternate schedule. This could include every other day or 5 days out 7 days.
  • Patients with serious infections may be asked to interrupt treatment with fingolimod
  • Before starting therapy, obtain a CBC including lymphocyte count. Then, every 3 months or as indicated by the doctor.
  • Patients with chronic or acute infections should not be given fingolimod.

• Macular edema

  • Macular edema can occur in the first six months of treatment.
  • Patients who have blurred vision or reduced visual acuity are able present.
  • Patients may experience improvements or resolution of symptoms after discontinuing treatment. However, some patients have experienced a residual decrease in visual acuity.
  • Patients with diabetes mellitus and uveitis have a higher risk.
  • Ophthalmologic exams, including the macula and fundus, should be done prior to treatment, 3 to 4 month after treatment begins, and whenever visual disturbances are reported.
  • Patients with diabetes and a history of uveitis should be examined more often.

• Malignancy

  • Patients should avoid direct sunlight and ultraviolet radiation by wearing sunscreen with a high protection factor and protective clothing.
  • There have been cases of lymphoma, including mycosis fungoides and non-Hodgkin skin cancers.
  • Basal cell carcinoma risk and melanoma are increased by fingolimod usage. Monitor for suspicious skin lesions regularly (especially for patients at high risk for skin cancer) to ensure that you have a prompt evaluation

• Neurotoxicity:

  • The posterior irreversible encephalopathy (PRES) was observed
  • Monitor for symptoms of PRES, such as sudden onset of severe headaches, visual disturbances, seizure; these symptoms can be reversed but could lead to an ischemic stroke, cerebral hemorhage, or both.
  • Delaying treatment and diagnosis can lead to permanent neurological sequelae.
  • Treatment may be stopped if PRES is suspected.

• Progressive multifocal Leukoencephalopathy

  • Multiple cases of progressive multifocal leukoencephalopathy (PML), which were caused by the John Cunningham virus (JC), have been reported.
  • Patients who had been treated with fingolimod for at most 2 years were the majority of PML patients. The relationship between treatment duration and risk is not known.
  • Perform a diagnostic evaluation immediately after you notice any symptoms that suggest PML. Symptoms can progress over several days or weeks and include progressive weakness or clumsiness on one side or both, vision disturbances, mental status changes, and vision problems.
  • Without specific symptoms or signs, cases of PML were diagnosed based upon MRI findings and detection of JC virus DNA within the CSF.
  • Except for prior immunosuppressant usage (eg natalizumab), no risk factors have been identified for PML with Fingolimod.
  • Patients who are not immunocompromised or have never had any previous exposure to immunosuppressant medications have reported cases.
  • It may be helpful to monitor brain MRI for any signs that might be consistent with PML. This will allow for early diagnosis.

• Respiratory effects

  • Reduced forced expiratory volume (FEV) and diffusion lung capacity (DLCO), are both dose-dependent and can occur within 30 days.
  • Therapy should include a spirometric assessment of the respiratory function and evaluation for DLCO if clinically indicated.
  • With drug discontinuation, FEV may be reversed.
  • Multiple sclerosis (MS), patients with impaired respiratory function, have not been evaluated.

• Extension of QT

  • Could cause prolongation of QT;
  • Patients with prolonged QT intervals at baseline (adult males and children: more than 450 msec, adult females: more than 470msec, pediatric females : more than 460msec) or within the first 6 hours after treatment initiation or those at increased risk (eg hypomagnesemia or hypokalemia), will require continuous overnight electrocardiogram monitoring in a medical facility.

• Varicella-zoster infections

  • Fingolimod has been linked to serious, potentially fatal disseminated varicella infection.
  • Varicella virus vaccination is recommended before starting treatment. Patients without a history of chickenpox from a healthcare professional, or without having completed a varicella vaccine course, should be vaccinated. Patients who have not had their varicella vaccine are advised to delay fingolimod treatment until after the varicella-zoster vaccine.

• Cardiovascular:

  • An ECG is required for all patients, due to the possibility of bradycardia or AV conduction delays.
  • Concomitant treatment with drugs that slow the heart rate or AV conduction is required for patients receiving beta-blockers, calcium channel blockers to lower heart rate, digoxin or with other cardiac risk factors such as AV block, sick syndrome, prolonged QT interval, myocardial disease [MI], history of myocardial injury [MI], symptomatic bradycardia, cardiac arrest, cardiac failure, severe sleep apnea [untreated]). Patients who are monitored at record

• Hepatic impairment

  • Patients with liver disease should be cautious. They may be at greater risk for liver enzymes.
  • Take care when treating patients with severe hepatic impairment.

Fingolimod: Drug Interaction

Note: Drug Interaction Categories:

• Risk Factor C: Monitor When Using Combination
• Risk Factor D: Consider Treatment Modification
• Risk Factor X: Avoid Concomitant Use

Monitoring parameters:

• CBC includes lymphocyte counts (baseline, then every three months thereafter, and as clinically required).

Monitoring of the liver:

• Before therapy initiation, baseline bilirubin levels and transaminase levels should be obtained in all patients. Monitor transaminases for patients with hepatic dysfunction symptoms.
  • ECG (baseline; Repeat after initial dose observation period);
  • The heart rate, blood pressure and signs and symptoms associated with bradycardia are measured hourly for six hours after the first dose. Continued observation is necessary if the 6-hour postdose heart beat is below 45 bpm for adults, 55 bpm for patients aged 12 and older, and 60 bpm or more in patients 10 and 11 years. 6-hour postdose heart rates is the lowest measurement postbaseline or if a new-onset second-degree AV block is detected on repeat ECG).
  • If bradycardia symptoms persist, continuous ECG monitoring is required.
  • Patients with prolonged QTc intervals at baseline or 6-hours after a dose are monitored overnight by continuous ECG monitoring in a hospital.
  • QT prolongation may also be a risk due to hypokalemia, hypomagnesemia and congenital long QT syndrome. Concurrent therapy with QT-prolonging drugs with a known danger of torsades, de pointes or other preexisting conditions can also pose a risk.
• For the initial monitoring procedure (ECG, heart beat, blood pressure) to be successful, it must be repeated.
  • A treatment interruption lasting more than one day within the first two weeks of treatment initiation is considered as interruption.OR
  • A treatment interruption lasting more than one week in the weeks 3-4 after treatment initiation is unacceptable.OR
  • After 1 month of treatment initiation, treatment interruptions of more than two weeks are possible
• Ophthalmologic examination at baseline and three to four months after treatment began (continued periodic examinations for the length of therapy for patients with diabetes, uveitis history, or visual problems); If clinically indicated, Respiratory function (DLCO and FEV-1) VZV antibodies (prior starting treatment; for patients without a documented history of chickenpox, or with no medical care professional-confirmed history).
• Signs and symptoms of infection, including progressive multifocal encephalopathy and/or posterior irreversible encephalopathy syndrome (during treatment or at least 2 months following discontinuation), Be on the lookout for skin conditions that could be suspicious After discontinuation of therapy, severe increase in disability.

How to administer Fingolimod (Gilenya)?

Oral: Administer with or without food.

Mechanism of action of Fingolimod (Gilenya):

• Fingolimod-phosphate is an active metabolite from fingolimod. It binds to the sphingosine 1-phosphate receptors 1, 3, 4 and 5.
• Fingolimodphosphate inhibits lymphocytes' ability from lymph nodes to emerge; this reduces central inflammation.

Protein binding:

• >99.7% (fingolimod and fingolimod-phosphate)

Metabolism:

• Hepatic via CYP4F2 to fingolimod-phosphate (active) and other metabolites (inactive); CYP2D6, 2E1, 3A4, and 4F12 also contribute to metabolism

Bioavailability:

• 93%

Half-life elimination:

• 6 to 9 days; prolonged by approximately 50% in patients with moderate or severe hepatic impairment.

Time to peak,

• plasma: 12 to 16 hours

Excretion:

• Urine (~81% as inactive metabolites);
• feces (fingolimod and fingolimod phosphate: <2.5% of dose)

International Brand Names of Fingolimod:

• Gilenya
• Imusera
• Gilenya
• Fingolim
• Finolim

Fingolimod Brand Names in Pakistan:

There is no brand available in Pakistan.