Fingolimod

Registered South African indications:

• Relapsing multiple sclerosis
  - As a disease modifying therapy to reduce the frequency of relapses and to delay the progression of disability

Fingolimod should be used only by neurologists experienced in the treatment of multiple sclerosis. Fingolimod induces a reduction in heart rate upon treatment initiation, which can lead to bradydysrhythmia. The effect is usually maximal on Day 1, within the first 6 hours, and heart rate usually normalises by 1 month. However, these events may occur at any time. Hourly monitoring for at least 6 hours (ECG, heart rate, and blood pressure) on Day 1 is mandatory for all patients to determine individual response to treatment initiation. Patients who experience these events or have risk factors should have extended monitoring (at least overnight). If patients develop signs or symptoms related to heart rate reduction, monitoring should be extended until the event resolves.

 

Contraindications

South African manufacturer recommendations

• Hypersensitivity to the active ingredient or any of its excipients
• Pregnancy
• Women of childbearing age not using effective contraception
• Breastfeeding
• Immunodeficiency syndrome
• Severe active infections, active chronic infections (hepatitis, tuberculosis)
• Active malignancies
• Those who have had myocardial infarction, unstable angina pectoris, stroke/ transient ischemic attack, decompensated heart failure (requiring inpatient treatment), or New York Heart Association class III/IV heart failure in the last 6 months
• Patients with second-degree Mobitz type II atrioventricular (AV) block or third-degree AV block, or sick-sinus syndrome, if they do not have a pacemaker
• Baseline QTc interval ≥500 msec
• Severe cardiac dysrhythmias requiring anti-dysrhythmic treatment with class Ia or class III anti-dysrhythmic agents
• Coadministration with anti-dysrhythmic medicines; class Ia (e.g.quinidine, procainamide), class III (e.g. amiodarone, sotalol)

International manufacturer recommendations

• Hypersensitivity to the active ingredient or any of its excipients
• Pregnancy
• Women of childbearing potential not using effective contraception
• Severe hepatic impairment
  - Severe pre-existing hepatic injury
• Immunodeficiency syndrome
• Patients with increased risk for opportunistic infections, including immunocompromised patients (including those currently receiving immunosuppressive therapies or those immunocompromised by prior therapies)
• Severe active infections, active chronic infections (hepatitis, tuberculosis)
• Active malignancies
• Those who have had myocardial infarction, unstable angina pectoris, stroke/ transient ischemic attack, decompensated heart failure (requiring inpatient treatment), or New York Heart Association class III/IV heart failure in the last 6 months
• Patients with second-degree Mobitz type II atrioventricular (AV) block or third-degree AV block, or sick-sinus syndrome, if they do not wear a pacemaker
• Baseline QTc interval ≥500msec
• Severe cardiac arrhythmias requiring anti-arrhythmic treatment with class Ia or class III anti-arrhythmic agents

Cautions

South African manufacturer recommendations

• <2 months after stopping treatment in women of childbearing potential
• Severe hepatic impairment
• Elderly
• History of hepatic disease
• Active viral hepatitis
• Diabetes mellitus
• Severe active infection
• Severe respiratory disease
• Pulmonary fibrosis
• Chronic obstructive pulmonary disease (COPD)
• Unconfirmed immunity to varicella (chickenpox)
• Unvaccinated against human papillomavirus (HPV)
• Vaccination within 2 months of stopping treatment
• History of uveitis
• Sino-atrial heart block
• History of symptomatic bradycardia, recurrent syncope or cardiac arrest
• Significant QT prolongation (QTc>470msec [adult female], QTc>460msec [paediatric female] or >450msec [adult and paediatric male])
• Risk factors for QT prolongation
  - Hypokalaemia
  - Congenital long QT syndrome
• Uncontrolled hypertension
• Severe untreated sleep apnoea
• Withdrawal of therapy
• Risk factors for skin cancer
• Sunlight exposure without protection
• Concomitant phototherapy with UV-B-radiation or PUVA-photochemotherapy
• Prior treatment with immunosuppressive or immune-modulating therapies
• Switching from other immunosuppressants
  - Previous therapy with natalizumab
  - Previous therapy with teriflunomide
  - Previous therapy with alemtuzumab
  - Previous therapy with dimethyl fumarate
• Coadministration with corticosteroids (prolonged treatment)
• Coadministration with potent CYP450 inducers
• Mannitol intolerance (certain formulations)
• May impair ability to drive and operate machinery

International manufacturer recommendations

• <2 months after stopping treatment in women of childbearing potential 
• Breastfeeding
• Mild to moderate hepatic impairment
  - History of significant hepatic disease
• Elderly
• Children between 10-12 years old, <40kg or at Tanner stage <2
• Vaccination within 2 months of stopping treatment
• Risk factors for skin cancer
• Sino-atrial heart block
• History of symptomatic bradycardia, recurrent syncope or cardiac arrest
• Significant QT prolongation (QTc>470msec [adult female], QTc >460msec [paediatric female] or >450msec [adult and paediatric male])
• Uncontrolled hypertension
• Diabetes mellitus
• Severe respiratory disease
• Pulmonary fibrosis
• Chronic obstructive pulmonary disease (COPD)
• History of uveitis
• Active viral hepatitis
• Severe active infection
• Severe sleep apnoea
• Hypokalaemia
• Congenital QT prolongation
• Unconfirmed immunity to varicella (chickenpox)
• Unvaccinated against human papillomavirus (HPV)
• Sunlight exposure without protection
• Concomitant phototherapy with UV-B-radiation or PUVA-photochemotherapy
• Withdrawal of therapy
• Prior treatment with immunosuppressive or immunomodulatory therapies
• Switching from other immunosuppressants
  - Previous therapy with natalizumab
  - Previous therapy with teriflunomide
  - Previous therapy with alemtuzumab
  - Previous therapy with dimethyl fumarate
• Coadministration with corticosteroids (prolonged treatment)
• Coadministration with potent CYP450 inducers
• May impair ability to drive and operate machinery

Forms avail. in SA and covered in this monograph: cap

Dosages below include:

• South African manufacturer recommendations
• International manufacturer recommendations

South African manufacturer recommendations

Relapsing multiple sclerosis
- As a disease modifying therapy to reduce the frequency of relapses and to delay the progression of disability

• Oral (cap): 0.5mg, dly

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See additional prescribing points for treatment initiation guidelines

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Fingolimod can be taken with or without food. Do not exceed the recommended dosage

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If a dose is missed, treatment should be continued with the next dose as planned

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International manufacturer recommendations

Treatment should be initiated and supervised by a physician experienced in multiple sclerosis

Highly active relapsing remitting multiple sclerosis
- Highly active disease despite a full and adequate course of treatment with at least one disease modifying therapy
- Rapidly evolving severe relapsing remitting multiple sclerosis defined by 2 or more disabling relapses in one year, and with 1 or more gadolinium enhancing lesions on brain MRI or a significant increase in T2 lesion load as compared to a previous recent MRI

• Oral (cap): 0.5mg, dly

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See additional prescribing points for treatment interruption recommendations

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Fingolimod can be taken with or without food. The capsules should always be swallowed intact, without opening them

Paed. dosages below include:

• South African manufacturer recommendations
• International manufacturer recommendations

South African manufacturer recommendations

• Not established for use in children below 18 years

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Fingolimod in not indicated for use in paediatric patients

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International manufacturer recommendations

Treatment should be initiated and supervised by a physician experienced in multiple sclerosis

Highly active relapsing remitting multiple sclerosis
- Highly active disease despite a full and adequate course of treatment with at least one disease modifying therapy
- Rapidly evolving severe relapsing remitting multiple sclerosis defined by 2 or more disabling relapses in one year, and with 1 or more gadolinium enhancing lesions on brain MRI or a significant increase in T2 lesion load as compared to a previous recent MRI

Younger than 10 years

• Not established for use

10 years and older

• Oral (cap): ≤40kg: 0.25mg, dly
• Oral (cap): >40kg: 0.5mg, dly

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Paediatric patients who start on 0.25mg capsules and subsequently reach a stable body weight above 40kg should be switched to 0.5mg capsules

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When switching from a 0.25mg to a 0.5mg daily dose, it is recommended to repeat the same first dose monitoring as for treatment initiation

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See additional prescribing points for treatment interruption recommendations

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Fingolimod can be taken with or without food. The capsules should always be swallowed intact, without opening them 

Pregnancy

South African manufacturer recommendations

• Contraindicated
• Fingolimod should not be used in pregnancy as safety has not been established. Fingolimod was teratogenic in rats 
• Animal studies have shown reproductive toxicity including foetal loss and organ defects, notably persistent truncus arteriosus and ventricular septal defect. Furthermore, the receptor affected by fingolimod (sphingosine 1-phosphate receptor) is known to be involved in vascular formation during embryogenesis
• Fingolimod is contraindicated in women of childbearing potential not using effective contraception. Therefore, before initiation of treatment in women of childbearing potential, a negative pregnancy result must be available and counselling should be regarding the serious risk to the foetus
• Women of childbearing potential must use effective contraception during treatment and for 2 months after discontinuation of since fingolimod takes approximately 2 months to eliminate from the body after treatment discontinuation

International manufacturer recommendations

• Contraindicated
• Based on human experience, post-marketing data suggest that use of fingolimod is associated with a 2-fold increased risk of major congenital malformations when administered during pregnancy compared with the rate observed in the general population
• The following major malformations were most frequently reported: Congenital heart disease such as atrial and ventricular septal defects, tetralogy of Fallot, renal abnormalities and musculoskeletal abnormalities
• There are no data on the effects of fingolimod on labour and delivery. Animal studies have shown reproductive toxicity including foetal loss and organ defects, notably persistent truncus arteriosus and ventricular septal defect. Furthermore, the receptor affected by fingolimod (sphingosine 1-phosphate receptor) is known to be involved in vascular formation during embryogenesis
• Consequently, fingolimod is contraindicated during pregnancy. Fingolimod should be stopped 2 months before planning a pregnancy. If a woman becomes pregnant during treatment, fingolimod must be discontinued 
• Medical advice should be given regarding the risk of harmful effects to the foetus associated with treatment and ultrasonography examinations should be performed
• Fingolimod is contraindicated in women of childbearing potential not using effective contraception. Therefore, before initiation of treatment in women of childbearing potential, a negative pregnancy test result must be available and counselling should be provided regarding the serious risk to the foetus. Women of childbearing potential must use effective contraception during treatment and for 2 months after discontinuation of fingolimod, since it takes approximately 2 months to eliminate from the body after treatment discontinuation
• When stopping fingolimod therapy for planning a pregnancy the possible return of disease activity should be considered

Breastfeeding

South African manufacturer recommendations

• Contraindicated
• Fingolimod should not be used in breastfeeding women as safety has not been established
• Fingolimod is excreted in the milk of treated animals during lactation

International manufacturer recommendations

• Caution; not recommended
• Fingolimod is excreted in the milk of treated animals during lactation
• Due to the potential for serious adverse reactions in breastfeeding infants, women receiving fingolimod should not breastfeed

Fertility

South African manufacturer recommendations

• Fingolimod is present in seminal ejaculate. Safety regarding an increased risk of male mediated foetal toxicity has not been demonstrated

International manufacturer recommendations

• Data from preclinical studies do not suggest that fingolimod would be associated with an increased risk of reduced fertility

Renal Impairment

South African manufacturer recommendations

• No dose adjustment recommended

International manufacturer recommendations

• No dose adjustment recommended
  Fingolimod was not studied in patients with renal impairment in the multiple sclerosis pivotal studies. Based on clinical pharmacology studies, no dose adjustments are needed in patients with mild to severe renal impairment

Hepatic Impairment

South African manufacturer recommendations

• Mild to moderate: No dose adjustment recommended
• Severe: Caution; no dose adjustment recommended

International manufacturer recommendations

• Mild to moderate: Caution; no dose adjustment recommended
• Severe: Contraindicated
  Fingolimod must not be used in patients with severe hepatic impairment. Although no dose adjustments are needed in patients with mild or moderate hepatic impairment, caution should be exercised when initiating treatment in these patients

Elderly

• Caution; no dose adjustment recommended

Porphyria Information

• Probably not porphyrinogenic (PNP)

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Depression
• Depressed mood
• Headache
• Dizziness
• Migraine
• Seizures
  - Status epilepticus
• Ischaemic stroke (at high doses)
• Haemorrhagic stroke (at high doses)
• Neurological atypical disorders (at high doses)
  - Acute disseminated encephalomyelitis (ADEM)-like events (at high doses)
• Asthenia
• Posterior reversible encephalopathy syndrome (PRES)
• Progressive multifocal leukoencephalopathy (PML)
• Severe exacerbation of disease after fingolimod discontinuation
• Anxiety (paediatrics)

Cardiovascular Disorders

• Bradycardia
  - Hypotension
  - Dizziness
  - Fatigue
  - Palpitations
• Atrioventricular block
• T-wave inversion
• Hypertension
• Peripheral arterial occlusive disease

Respiratory Disorders

• Cough
• Dyspnoea
• Influenza
• Bronchitis
• Sinusitis
• Pneumonia

Gastrointestinal Disorders

• Diarrhoea
• Nausea

Hepatobiliary Disorders

• Acute hepatic failure
• Increased hepatic enzyme
  - Increased alanine transaminase
  - Increased gamma glutamyltransferase
  - Increased aspartate transaminase
• Mild isolated bilirubin (paediatrics)

Endocrine and Metabolic Disorders

• Decreased weight
• Increased blood triglycerides

Musculoskeletal Disorders

• Back pain
• Arthralgia
• Myalgia

Skin and Subcutaneous Tissue Disorders

• Eczema
• Alopecia
• Pruritis
• Tinea versicolor

Immune, Blood and Lymphatic System Disorders

• Decreased neutrophil count
• Herpes viral infections
  - Herpes simplex virus (HSV)
  - Varicella zoster virus (VZV)
• John Cunningham virus (JCV) infections
• Fungal infections
• Cryptococcal infections
  - Cryptococcal meningitis
• Bacterial infections
  - Atypical mycobacterium
• Human papillomavirus (HPV) infections
  - Papilloma
  - Dysplasia
  - Warts
  - HPV-related cancer
• Basal cell carcinoma
• Malignant melanoma
• Lymphoma
  - Epstein-Barr virus (EBV) positive B-cell lymphoma
  - Non-Hodgkin's lymphoma (B-cell and T-cell)
  - Cutaneous T-cell lymphoma (mycosis fungoides)
• Haemophagocytic syndrome (HPS)
• Squamous cell carcinoma
• Kaposi's sarcoma
• Merkel cell carcinoma
• Lymphopenia
• Leucopenia
• Thrombocytopenia
• Autoimmune haemolytic anaemia
• Peripheral oedema
• Hypersensitivity reactions
  - Rash
  - Urticaria
  - Angioedema

Sensory Disorders

• Blurred vision
• Macular oedema

• Class Ia and III antiarrhythmics
• Quinidine
• Procainamide
• Amiodarone
• Sotalol
• Antineoplastic agents
• Immunomodulatory agents
• Immunosuppressive agents
• Natalizumab
• Teriflunomide
• Mitoxantrone
• Live attenuated vaccines
• Bradycardia inducing agents (See additional prescribing points)
• Atenolol
• Diltiazem
• Beta-blockers
• Calcium channel blockers
• Verapamil
• Ivabradine
• Digoxin
• Cholinesterase inhibitors
• Pilocarpine
• CYP4F2 inhibitors (See additional prescribing points)
• Ketoconazole
• CYP3A4 inhibitors
• Protease inhibitors
• Azole antifungals
• Macrolides
• Clarithromycin
• Telithromycin
• Carbamazepine
• Strong CYP3A4 inducers
• Rifampicin
• Phenytoin
• Phenobarbital
• Efavirenz

Other interactions

• St John's wort

• Electrocardiogram (ECG)
  - QTc interval (if prolonged at baseline or 6 hours post dose)
• Heart rate
• Blood pressure
• Hepatic function
  - Bilirubin
  - Transaminase levels
• Full blood count
  - Lymphocyte counts (baseline, 3 monthly and at least two months after stopping therapy)
• Ophthalmologic exam of the fundus, including macula
• Skin examination

Specific cases may require

• Pregnancy status (prior to use) 
• Latent infection screening
  - Hepatitis
  - Tuberculosis
• Varicella-zoster virus (VZV) antibodies screening
• Magnetic resonance imaging (MRI)
• Respiratory function
  - FEV1
  - Diffusion lung capacity for carbon monoxide (DLCO)

Additional observations

• Signs and symptoms of
  - Bradycardia
  - Infection
  - Progressive multifocal leukoencephalopathy (PML)
  - Posterior reversible encephalopathy syndrome
• Additional risks for QT prolongation
  - Hypokalemia
  - Hypomagnesemia
  - Congenital long QT syndrome
• Suspicious skin lesions
• Severe increase in disability after discontinuation

Treatment initiation guidelines

South African manufacturer recommendations

• Initiation of treatment results in a transient decrease in heart rate and may also be associated with atrioventricular conduction delays, including the occurrence of isolated reports of transient, spontaneously resolving complete AV block
• After the first dose, the decline in heart rate starts within one hour, and is maximal within 6 hours. This post-dose effect persists over the following days, although usually to a milder extent, and usually abates over the next weeks. With continued administration, the average heart rate returns towards baseline within one month. However individual patients may not return to baseline heart rate by the end of the first month. Conduction abnormalities were typically transient and asymptomatic. They usually did not require treatment and resolved within the first 24 hours on treatment. If necessary, the decrease in heart rate induced by fingolimod can be reversed by parenteral doses of atropine or isoprenaline
• All patients should have an ECG and blood pressure measurement performed prior to and 6 hours after the first dose
• All patients should be monitored for a period of 6 hours for signs and symptoms of bradycardia with hourly heart rate and blood pressure measurement. Continuous (real time) ECG monitoring during this 6 hour period is recommended
• Should a patient require pharmacological intervention during the first-dose monitoring, overnight monitoring in a medical facility should be instituted and the first-dose monitoring should be repeated after the second dose of fingolimod 

International manufacturer recommendations

• Dizziness or drowsiness may occasionally occur when initiating treatment. On initiation of treatment, it is recommended that patients be observed for a period of 6 hours
• Paediatric patients who start on 0.25mg capsules and subsequently reach a stable body weight above 40kg should be switched to 0.5mg capsules
• The same precautions as for the first dose are recommended when patients are switched from the 0.25mg to the 0.5mg daily dose
• When switching from a 0.25mg to a 0.5mg daily dose, it is recommended to repeat the same first dose monitoring as for treatment initiation

Bradycardia inducing agents

• Experience with fingolimod is limited in patients receiving concurrent therapy with beta-blockers, heart-rate-lowering calcium channel blockers (such as verapamil or diltiazem), or other substances which may decrease heart rate (e.g. ivabradine, digoxin, anticholinesteratic agents or pilocarpine)
• Since the initiation of fingolimod treatment is also associated with slowing of the heart rate, concomitant use of these substances during treatment initiation may be associated with severe bradycardia and heart block. Because of the potential additive effect on heart rate, treatment with fingolimod should not be initiated in patients who are concurrently treated with these substances
• In such patients, treatment with fingolimod should be considered only if the anticipated benefits outweigh the potential risks. If treatment is considered, advice from a cardiologist should be sought regarding the switch to non heart-rate lowering medicinal products prior to initiation of treatment. If the heart-rate-lowering treatment cannot be stopped, cardiologist's advice should be sought to determine appropriate first dose monitoring, at least overnight extended monitoring is recommended

CYP4F2 inhibitors

• The main enzyme involved in the metabolism of fingolimod is partially identified and may be either CYP4F2 or CYP3A4
  - Co-administration of fingolimod with ketoconazole resulted in a 1.7-fold increase in fingolimod and fingolimod phosphate exposure (AUC) by inhibition of CYP4F2

Treatment interruption recommendations

• The same first dose monitoring as for treatment initiation is recommended when treatment is interrupted for:
  - 1 day or more during the first 2 weeks of treatment
  - More than 7 days during weeks 3 and 4 of treatment
  - More than 2 weeks after one month of treatment
• If the treatment interruption is of shorter duration than the above, the treatment should be continued with the next dose as planned

Fingolimod is a sphingosine-1-phosphate (S1P) receptor modulator. Fingolimod is metabolised by sphingosine kinase to the active metabolite fingolimod phosphate. Fingolimod phosphate binds at low nanomolar concentrations to S1P receptor 1 located on lymphocytes, and readily crosses the blood-brain barrier to bind to S1P receptor 1 located on neural cells in the central nervous system (CNS). By acting as a functional antagonist of S1P receptors on lymphocytes, fingolimod phosphate blocks the capacity of lymphocytes to egress from lymph nodes, causing a redistribution, rather than depletion, of lymphocytes. Animal studies have shown that this redistribution reduces the infiltration of pathogenic lymphocytes, including pro-inflammatory Th17 cells, into the CNS, where they would be involved in nerve inflammation and nervous tissue damage. Animal studies and in vitro experiments indicate that fingolimod may also act via interaction with S1P receptors on neural cells.

Capsule 0.5mg

• Myelenea (Forrester Pharma)
• Tuvigin 0.5mg (Novartis South Africa) originator