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:

  • Reduces the frequency of clinical exacerbations and delays the development of physical disability in individuals with relapsing forms of multiple sclerosis (MS) who have been diagnosed for 10 years or more.

Fingolimod (Gilenya) Dose in Adults

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

• Oral: 0.5 mg once a day;
• Doses above 0.5 mg daily are linked to an increase in side effects and no added benefit.

Note: Give the first dose and all doses that follow a break in therapy (more than 14 days) in a location with the tools necessary to address symptomatic bradycardia.

Fingolimod (Gilenya) Dose in Children

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

Note:

• Doses above 0.5 mg daily are linked to an increase in side effects and no added benefit.
• The first dose, doses given after a break in therapy (see Monitoring Parameters), as well as dose increments, should be given in an environment with the tools necessary to effectively manage symptomatic bradycardia.

• 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.
• Elimination of fingolimod takes roughly two months. Women who are pregnant and have the ability to have children must utilise reliable contraception for at least two months to prevent potential harm to the foetus.
• Continuous data collection is underway to monitor the effects of fingolimod on infants and pregnant women. 
• The Gilenya Pregnancy Register can be joined by pregnant women themselves or by their medical professionals (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.
• If you have significant renal impairment, proceed with caution (exposure is greater).
• As long as changes in exposure to fingolimod or its active metabolite (fingolimod P) are clinically modest, dosage adjustments may not be necessary in patients with stable severe impairment (CrCl below 30 mL/minute) who are not on dialysis.

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
• Myocardial Infarction
• Angina unstable
• Stroke or transient ischemic attack
• Hospitalisation within the last six months for decompensated heart disease or New York Heart Association (NYHA), class III/IV heart failure
• Atrioventricular block (AV) in the second or third degree or sick sinus syndrome, according to Mobitz Type II (except if the patient has a working pacemaker).
• QTc baseline interval of 500 msec or more in length
• usage of a class III or Ia antiarrhythmic drug concurrently.

Canadian labeling: Additional contraindications not in US labeling

• Patients who have undergone treatment (such as immunosuppressive or anti-cancer medicines, bone marrow transplantation, total lymphoid radiation, or bone marrow irradiation) or who are ill are more likely to get an opportunistic infection (eg immunodeficiency disorder).
• severe current infections, such as ongoing fungal or bacterial infections (eg, hepatitis and tuberculosis).
• aggressive cancer already known (apart from basal cell carcinoma);
• severe liver disease

Warnings and precautions

• Block of the Atrioventricular (AV),

  • Third-degree AV blocks and AV blocks with junctional escape were evident six hours after the initial dose.
  • Within the first 24 hours, there have also been reports of transient asystole or inexplicable fatalities. Additionally, syncope has been noted.
  • Asymptomatic and temporary AV conduction delays may result from this.
  • These normally disappear after a day. After discontinuance or a subsequent reinitiation, recurrences can be seen.

• Bacterial infections

  • Identify any infection-related symptoms and treat them right away.
  • It has a history of causing serious opportunistic bacterial infections (eg, Atypical Mycobacteria).

• Bradycardia

  • Initiation should be done in a setting that has the resources and personnel to manage symptomatic bradycardia.
  • As soon as an hour after the initial dose, the heart rate can begin to decline. Between eight and ten hours pass before recovery (but not to baseline) occurs.
  • 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 heart rate may slow after the second dose, but it won't be as much as after the first.
  • The heart rate often returns to normal after one month of ongoing therapy.

• Cryptococcal infections

  • Meningitis caused by cryptococcal bacteria as well as widely spread illnesses (including fatalities) have been documented.
  • Although they can happen sooner, most cryptococcal infections happen after two years of treatment (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

  • Herpes infections that are severe and life-threatening have caused fatalities (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

  • Upon starting treatment, reports of hypersensitivity reactions, including urticaria and rash, have been made.

• Hypertension

  • Within a month of starting or finishing treatment, blood pressure can rise. During treatment, keep an eye on your blood pressure.

• 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.
  • An alternative schedule may be helpful for those who develop lymphopenia after receiving fingolimod. This can be every other day or five days out of seven.
  • 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

  • During the first six months of treatment, macular edoema can develop

  • Patients with limited vision or hazy vision are welcome to attend.

  • Patients may experience improvements or resolution of symptoms after discontinuing treatment. However, some patients have experienced a residual decrease in visual acuity.
  • Patients who have both uveitis and diabetes mellitus are at greater risk.
  • Prior to treatment, three to four months after treatment starts, and if visual abnormalities are observed, ophthalmologic exams should be performed. These exams should include the macula and fundus.
  • Patients with diabetes and a history of uveitis should be examined more often.

• Malignancy

  • By using sunscreen with a high protection factor and wearing protective gear, patients can stay out of the sun's direct rays and UV radiation.
  • There have been cases of lymphoma, including mycosis fungoides and non-Hodgkin skin cancers.
  • Use of fingolimod raises the risk of melanoma and basal cell carcinoma. To guarantee that you receive a fast evaluation, regularly check for suspicious skin lesions (particularly in individuals who are at high risk for skin cancer).

• Neurotoxicity:

  • The posterior irreversible encephalopathy (PRES) was observed
  • Keep an eye out for PRES symptoms such rapid development of severe headaches, blurred vision, and seizures; while these symptoms can be treated, they can also result in an ischemic stroke, cerebral haemorrhage, or both.
  • Delaying treatment and diagnosis can lead to permanent neurological sequelae.
  • If PRES is suspected, treatment might be halted.

• Progressive multifocal Leukoencephalopathy

  • There have been numerous reports of John Cunningham virus (JC)-related progressive multifocal leukoencephalopathy (PML).
  • The majority of PML patients had been using fingolimod for little more than two years. It is unknown whether treatment length and risk are related.
  • When you observe any symptoms that could indicate PML, get a diagnostic assessment done right away. Progressive weakness or clumsiness on one side or both, vision disturbances, changes in mental state, and vision issues are among the symptoms that might develop over a period of days or weeks.
  • Cases of PML were identified without particular symptoms or signs based on the results of an MRI and the discovery of JC virus DNA in the CSF.
  • Aside from prior use of immunosuppressants (such as natalizumab), no risk factors for PML have been found.
  • Patients who are not immunocompromised or have never had any previous exposure to immunosuppressant medications have reported cases.
  • Monitoring brain imaging for any PML-related symptoms could be useful. This will make an early diagnosis possible.

• Respiratory effects

  • Reduced forced expiratory volume (FEV) and diffusion lung capacity (DLCO) can both happen within 30 days and are both dose-dependent.
  • A spirometric evaluation of respiratory function and an assessment for DLCO, if clinically warranted, should be part of the treatment plan.
  • With drug discontinuation, FEV may be reversed.

• Extension of QT

  • Could cause prolongation of QT;
  • Patients with multiple sclerosis (MS) who have respiratory impairment have not been assessed.

• 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:

  • All patients must have an ECG since bradycardia or AV conduction delays could occur.
  • For patients taking beta-blockers, calcium channel blockers to lower heart rate, digoxin, or with other cardiac risk factors like AV block, sick syndrome, prolonged QT interval, myocardial disease [MI], history of myocardial injury [MI], symptomatic bradycardia, cardiac arrest, cardiac failure, or severe sleep apnea [untreated], concurrent treatment with drugs that slow the heart rate or AV conduction is necessary. Patients who receive routine monitoring

• 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 counts of lymphocytes (baseline, then every three months thereafter, and as clinically required).

Monitoring of the liver:

• All patients should have baseline transaminase and bilirubin levels before starting medication. For patients exhibiting symptoms of hepatic impairment, monitor transaminases..
  • It is necessary to monitor the ECG continuously if bradycardia symptoms continue.
  • Patients in a hospital are monitored overnight by continuous ECG monitoring if they had prolonged QTc intervals at baseline or six hours after receiving a dosage.
  • In addition, hypokalemia, hypomagnesemia, and congenital long QT syndrome may all increase the likelihood of QT prolongation.
  • Additionally risky is concurrent therapy with QT-prolonging medications known to increase the risk of torsades, de pointes, or other preexisting disorders.
• 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 evaluation at the start of treatment and three to four months later (continuous periodic evaluations for the duration of therapy for individuals with diabetes, a history of uveitis, or visual issues); Respiratory function (DLCO and FEV-1) VZV antibodies (before to starting treatment; for patients without a history of chickenpox that has been recorded or who have no medical professional-confirmed
• Infection-related symptoms, such as posterior irreversible encephalopathy syndrome and/or progressive multifocal encephalopathy (during treatment or at least 2 months following discontinuation), Keep an eye out for any suspicious-looking skin disorders. substantial rise in impairment once therapy is stopped.

How to administer Fingolimod (Gilenya)?

Oral: Administer with or without food.

Mechanism of action of Fingolimod (Gilenya):

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

Protein binding:

• >99.7% (fingolimod and fingolimod-phosphate)

Metabolism:

• Fingolimod-phosphate (active) and other metabolites (inactive) are produced in the liver by CYP4F2; additional metabolic enzymes include CYP2D6, 2E1, 3A4, and 4F12.

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.