Modlifin 0.5 Mg Capsules

MODLIFIN is indicated as a disease modifying therapy for the treatment of patients with relapsing multiple sclerosis to reduce the frequency of relapses and to delay the progression of disability.

Posology
Do not exceed the recommended dosage. The recommended dose of MODLIFIN is one 0,5 mg capsule taken orally once daily, which can be taken with or without food. If a dose is missed treatment should be continued with the next dose as planned. On initiation of MODLIFIN treatment, after the first dose, all patients should be observed, with hourly pulse and blood pressure measurement, for a period of at least 6 hours for signs and symptoms of bradycardia. All patients should have an electrocardiogram performed prior to dosing and at the end of 6-hour monitoring period (see section 4.4, bradydysrhythmia subsection). For recommendations related to switching patients from other disease modifying therapies to MODLIFIN, see section 4.4: Prior treatment with immunosuppressive or immune-modulating therapies.
Special populations
Renal impairment
No MODLIFIN dose adjustments are needed in patients with renal impairment (see section 5.2).
Hepatic impairment
No MODLIFIN dose adjustments are needed in patients with mild or moderate hepatic impairment. MODLIFIN should be used with caution in patients with severe hepatic impairment (Child-Pugh class C) (see section 5.2).
Elderly
MODLIFIN should be used with caution in patients aged 65 years and over (see section 5.2).
Diabetic patients
MODLIFIN should be used with caution in patients with diabetes mellitus due to a potential increased risk of macular oedema (see section 4.4).
Paediatric population
MODLIFIN is not indicated for use in paediatric patients (see section 5.2).
Method of administration
For oral use.

• Hypersensitivity to the active substance, fingolimod, or to any of the excipients listed in section 6.1.
• Pregnancy and lactation.
• Concomitant administration with anti-dysrhythmic medicines; Class 1a (e.g., quinidine, procainamide), Class III (e.g., amiodarone, sotalol) (see section 4.4).
• Patients who in the last 6 months 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.
• Patients with severe cardiac dysrhythmias requiring anti-dysrhythmic treatment with Class Ia or Class III anti-dysrhythmic medicines (see section 4.4).
• 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 (see section 4.4).
• Patients with a baseline QTc interval u2265 500 msec (see section 4.4).
• Women of childbearing potential not using effective contraception.

Infections
Fingolimod, as in MODLIFIN, causes a dose dependent reduction of peripheral lymphocyte count to 20 to 30 % of baseline values. This is due to the reversible sequestration of lymphocytes in lymphoid tissues (see section 5). The immune system effects (see section 5) of MODLIFIN may increase the risk of infections including opportunistic infections (see section 4.8). Before initiating treatment with MODLIFIN, a recent complete blood count (CBC) (i.e. within 6 months or after discontinuation of prior therapy) should be available. Initiation of treatment with MODLIFIN should be delayed in patients with severe active infection until resolution. Effective diagnostic and therapeutic strategies should be employed in patients with symptoms of infection while on therapy. Because the elimination of MODLIFIN after discontinuation may take up to two months, vigilance for infection should be continued throughout this period (see below subsection: Stopping MODLIFIN therapy).
Progressive multifocal leukoencephalopathy (PML)
Cases of progressive multifocal leukoencephalopathy (PML) have been reported in the post-marketing setting (see section 4.8). PML is an opportunistic infection caused by JC virus, which may be fatal or result in severe disability. Cases of PML have occurred after approximately 2-3 years of treatment, although an exact relationship with the duration of treatment is unknown. The incidence rate for PML appears to be higher for patients in Japan; the reasons are currently unknown. Additional PML cases have occurred in patients who had been treated previously with natalizumab, which has a known association with PML. Medical practitioners should be vigilant for clinical symptoms or MRI findings that may be suggestive of PML. If PML is suspected, MODLIFIN treatment should be suspended until PML has been excluded. MRI findings suggestive of PML may be apparent before clinical signs or symptoms. Cases of PML, diagnosed based on MRI findings and the detection of JVC DNA in the cerebrospinal fluid in the absence of clinical signs or symptoms specific to PML, have been reported in patients treated with MS medications associated with PML, including MODLIFIN.
Cryptococcal meningitis
Cases of cryptococcal meningitis have been reported in the post-marketing setting after approximately 2-3 years of treatment, although an exact relationship with the duration of treatment is unknown (see section 4.8). Cryptococcal meningitis may be fatal. For this reason patients with symptoms and signs consistent with cryptococcal meningitis should undergo prompt diagnostic evaluation. If cryptococcal meningitis is diagnosed, appropriate treatment should be initiated and MODLIFIN should be discontinued until the patient has fully recovered.
Anti-neoplastic, immune-modulating or immunosuppressive therapies (including corticosteroids) should be co-administered with caution due to the risk of additive immunosuppressive effects (see section 4.5). Specific decisions as to the dosage and duration of treatment with corticosteroids should be based on clinical judgment. Co-administration of a short course of corticosteroids (up to 5 days as per study protocols) did not increase the overall rate of infection in patients treated with fingolimod in the Phase III clinical trials, compared to placebo. Based on these data, short courses of corticosteroids (up to 5 days) can be used in combination with MODLIFIN (see sections 4.5 and 4.8).
Patients receiving MODLIFIN should be instructed to report symptoms of infections to their medical practitioner. Suspension of dosing with MODLIFIN should be considered if a patient develops a serious infection and consideration of benefit-risk should be undertaken prior to re-initiation of therapy. Patients need to be assessed for their immunity to varicella (chickenpox) prior to MODLIFIN treatment. It is recommended that patients without a health care professional confirmed history of chickenpox or documentation of a full course of vaccination with varicella vaccine undergo antibody testing to varicella zoster virus (VZV) before initiating MODLIFIN therapy. A full course of vaccination for antibody-negative patients with varicella vaccine is recommended prior to commencing treatment with MODLIFIN (see section 4.8). Initiation of treatment with MODLIFIN should be postponed for 1 month to allow full effect of vaccination to occur.
Human papilloma virus infection
Human papilloma virus (HPV) infection, including papilloma, dysplasia, warts and HPV-related cancer, has been reported under treatment with fingolimod in the post-marketing setting. Due to the immunosuppressive properties of fingolimod, vaccination against HPV should be considered prior to treatment initiation with fingolimod taking into account vaccination recommendations. Cancer screening, including Pap test, is recommended as per standard of care.
Vaccination
Vaccination may be less effective during and for up to two months after stopping treatment with MODLIFIN (see below subsection: Stopping MODLIFIN therapy). The use of live attenuated vaccines should be avoided (see section 4.5).
Macular oedema
Macular oedema (see section 4.8) with or without visual symptoms has been reported in 0,5 % of patients treated with fingolimod 0,5 mg, as in MODLIFIN, occurring predominantly in the first 3 to 4 months of therapy. An ophthalmic evaluation is therefore recommended at 3 to 4 months after treatment initiation. If patients report visual disturbances at any time while on MODLIFIN therapy, evaluation of the fundus, including the macula, should be carried out. Patients with history of uveitis and patients with diabetes mellitus are at increased risk of macular oedema (see section 4.8). Fingolimod has not been studied in multiple sclerosis patients with concomitant diabetes mellitus. It is recommended that multiple sclerosis patients with diabetes mellitus or a history of uveitis undergo an ophthalmic evaluation prior to initiating MODLIFIN therapy and have follow-up evaluations while receiving MODLIFIN therapy. Continuation of fingolimod in patients with macular oedema has not been evaluated. A decision on whether or not MODLIFIN therapy should be discontinued needs to take into account the potential benefits and risks for the individual patient.
Bradydysrhythmia
Initiation of MODLIFIN treatment results in a decrease in heart rate. After the first dose, the heart rate decrease starts within an hour and the Day 1 decline is usually maximal within 6 hours and usually normalises by one month (see sections 4.3 and 4.4). With continued dosing, heart rate usually returns to baseline within one month of chronic treatment (see Heart rate and rhythm subsection in section 5). In patients receiving fingolimod 0,5 mg this decrease in heart rate, as measured by pulse, averages approximately 8 beats per minute (bpm). Heart rates below 40 bpm have been observed (see section 4.8). Patients who experienced bradycardia were generally asymptomatic but some patients experienced mild to moderate symptoms, including hypotension, dizziness, fatigue and/or palpitations, which usually resolved within the first 24 hours of treatment. Initiation of fingolimod treatment is associated with atrioventricular conduction delays, usually first-degree atrioventricular blocks (prolonged PR interval on electrocardiogram). Second-degree atrioventricular blocks, usually Mobitz type I (Wenckebach) have been observed in less than 0,2 % of patients receiving fingolimod 0,5 mg. The conduction abnormalities typically were transient, asymptomatic, usually did not require treatment and usually resolved within the first 24-hours on treatment (see section 4.8). Cases of transient, complete AV block have been reported during post-marketing use of fingolimod (see section 4.8). Therefore on initiation of MODLIFIN treatment, it is recommended that all patients be observed, with hourly pulse and blood pressure measurement, for a period of 6 hours for signs and symptoms of bradycardia. All patients should have an electrocardiogram performed prior to dosing and at the end of the 6-hour monitoring period. Should post-dose bradydysrhythmia-related symptoms occur, appropriate management should be initiated as necessary and the patient should be observed until the symptoms have resolved. Should a patient require pharmacological intervention during the first dose observation period, overnight monitoring in a medical facility should be instituted and the first dose monitoring strategy should be repeated after the second dose of MODLIFIN. Additional observation until the finding has resolved is also required: u2022 if the heart rate at 6 hours post-dose is 470 msec [adult females], QTc >460 msec [paediatric females] or >450 msec [adult and paediatric males]) (see section section 4.3). MODLIFIN is best avoided in patients with relevant risk factors for QT prolongation, for example, hypokalemia, hypomagnesemia or congenital QT prolongation. Since significant bradycardia may be poorly tolerated in patients with a history of cardiac arrest, uncontrolled hypertension, history of recurrent syncope, or severe untreated sleep apnoea, MODLIFIN should not be used in these patients. If treatment is considered in patients for whom MODLIFIN is not contraindicated, advice from a cardiologist should be sought prior to initiation of treatment in order to determine the most appropriate monitoring strategy, which should last overnight. Fingolimod has not been studied in patients with dysrhythmias requiring treatment with Class Ia (e.g. quinidine, procainamide) or Class III anti-dysrhythmic medicines (e.g., amiodarone, sotalol). Class Ia and Class III anti-dysrhythmic medicines have been associated with cases of Torsades de Pointes in patients with bradycardia. Since initiation of MODLIFIN treatment results in decreased heart rate, MODLIFIN should not be co-administered with these medicines. 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 that may decrease heart rate (e.g. ivabradine or digoxin). Since the initiation of fingolimod treatment is also associated with slowing of the heart rate, concomitant use of these substances during MODLIFIN initiation may be associated with severe bradycardia and heart block. Because of the potential additive effect on heart rate, treatment with MODLIFIN should not be used in patients who are concurrently treated with these substances. If MODLIFIN therapy is discontinued for more than 2 weeks after the first month of treatment the effects on heart rate and atrioventricular conduction may recur on reintroduction of MODLIFIN treatment and the same precautions as for the first dose should apply. Within the first two weeks of treatment, first dose procedures are recommended after an interruption of one day or more. During weeks 3 and 4 of treatment first dose procedures are recommended after treatment interruption of more than seven days.
Liver function
Increased hepatic enzymes, mostly alanine aminotransaminase (ALT) elevation, have been reported in multiple sclerosis patients treated with fingolimod. In clinical trials, a 3-fold or greater elevation in ALT occurred in 8,0 % of patients treated with fingolimod 0,5 mg and the medicine was discontinued if the elevation exceeded a 5-fold increase. Recurrence of ALT elevations occurred upon re-challenge in some patients, supporting a relationship to the medicine. Recent (i.e. within last 6 months) transaminase and bilirubin levels should be available before initiation of treatment with MODLIFIN. Patients who develop symptoms suggestive of hepatic dysfunction, such as unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine during treatment, should have liver enzymes checked and MODLIFIN should be discontinued if significant liver injury is confirmed (see section 4.8). Although it is not known whether patients with preexisting liver disease are at increased risk to develop elevated liver function test (LFT) values when taking MODLIFIN, caution should be exercised when using MODLIFIN in patients with a history of liver disease.
Posterior reversible encephalopathy syndrome
Cases of posterior reversible encephalopathy syndrome (PRES) have been reported at 0,5 mg dose in clinical trials and in the post-marketing setting (see section 4.8). Symptoms reported included sudden onset of severe headache, nausea, vomiting, altered mental status, visual disturbances and seizure. Symptoms of PRES are usually reversible but may evolve into ischaemic stroke or cerebral haemorrhage. Delay in diagnosis and treatment may lead to permanent neurological sequelae. If PRES is suspected, MODLIFIN should be discontinued.
Prior treatment with immunosuppressive or immune-modulating therapies
When switching from other disease modifying therapies, the half-life and mode of action of the other therapy must be considered in order to avoid an additive immune effect whilst at the same time minimising risk of disease reactivation. Before initiating treatment with MODLIFIN, a recent complete blood cell count (i.e. after discontinuation of prior therapy) should be available to ensure any immune effects of such therapies (e.g. cytopenia) have resolved. Beta interferon, glatiramer acetate or dimethyl fumarate MODLIFIN can generally be started immediately after discontinuation of beta interferon, glatiramer acetate or dimethyl fumarate. Natalizumab or teriflunomide Due to the long half-life of natalizumab or teriflunomide, caution regarding potential additive immune effects is required when switching patients from these therapies to MODLIFIN. A careful case-by-case assessment regarding the timing of the initiation of Modifin treatment is recommended. Elimination of natalizumab usually takes up to 2-3 months following discontinuation. Teriflunomide is also eliminated slowly from the plasma. Without an accelerated elimination procedure, clearance of teriflunomide from plasma can take several months to up to 2-years. An accelerated elimination procedure is described in the teriflunomide product information. Accelerated elimination procedure: Cholestyramine and activated charcoal The elimination of teriflunomide from the circulation can be accelerated by administration of cholestyramine or activated charcoal, presumably by interrupting the reabsorption processes at the intestinal level. Teriflunomide concentrations measured during an 11-day procedure to accelerate teriflunomide elimination with either 8 g cholestyramine three times a day, 4 g cholestyramine three times a day or 50 g activated charcoal twice a day following cessation of teriflunomide treatment have shown that these regimens were effective in accelerating teriflunomide elimination, leading to more than 98 % decrease in teriflunomide plasma concentrations, with cholestyramine being faster than charcoal.
Respiratory effects
Minor dose-dependent reductions in values for forced expiratory volume (FEV1) and diffusion capacity for carbon monoxide (DLCO) were observed with fingolimod treatment starting at month 1 and remaining stable thereafter. MODLIFIN should be used with caution in patients with severe respiratory disease, pulmonary fibrosis and chronic obstructive pulmonary disease (see section 4.8).
Return of disease activity (rebound) after MODLIFIN discontinuation
Cases of severe exacerbation of disease have been reported after stopping fingolimod in the post-marketing setting. This was generally observed within 12 weeks after stopping fingolimod, but was also reported up to and beyond 24 weeks after fingolimod discontinuation. Therefore, caution is indicated when stopping fingolimod therapy. If discontinuation of fingolimod is deemed necessary, patients should be monitored for relevant signs and symptoms and appropriate treatment should be initiated as required.
Cutaneous Malignancies
Basal cell carcinoma (BCC) and other cutaneous neoplasms including malignant melanoma, squamous cell carcinoma, Kaposiu2019s sarcoma and Merkel cell carcinoma, have been reported in patients receiving fingolimod (see section 4.8). Periodic skin examination is recommended for all patients, particularly those with risk factors for skin cancer. Since there is, a potential risk of malignant skin growths, patients treated with fingolimod should be cautioned against exposure to sunlight without protection.
Lymphomas
There have been cases of lymphoma in clinical studies and the post-marketing setting. The cases reported were heterogeneous in nature, mainly Non-Hodgkinu2019s Lymphoma, including B-cell and T-cell lymphomas. Cases of cutaneous T-cell lymphoma (mycosis fungoides) have been observed (see section 4.8).
Tumefactive lesions
Rare cases of tumefactive lesions associated with MS relapse were reported in the post-marketing setting. In case of severe relapses, MRI should be performed to exclude tumefactive lesions. Discontinuation of treatment should be considered by the medical practitioner on a case-by-case basis taking into account individual benefits and risks.
Stopping therapy
If a decision is made to stop treatment with MODLIFIN, the medical practitioner needs to be aware that fingolimod remains in the blood and has pharmacodynamic effects, such as decreased lymphocyte counts, for up to two months following the last dose. Lymphocyte counts typically return to normal range within 1-2 months of stopping therapy (see section 5). Starting other therapies during this interval will result in a concomitant exposure to fingolimod. Use of immunosuppressants soon after the discontinuation of MODLIFIN may lead to an additive effect on the immune system and therefore caution should be applied.

Pharmacodynamic interactions
Anti-neoplastic, immunomodulatory or immunosuppressive therapies
Other anti-neoplastic, immunosuppressive or immune modulating therapies should be co-administered with caution due to the risk of additive immune system effects. Specific decisions as to the dosage and duration of concomitant treatment with corticosteroids should be based on clinical judgment (see sections 4.4 and 4.8). Caution should also be applied when switching patients from other long-acting therapies with immune effects such as natalizumab, teriflunomide or mitoxantrone (see section 4.4).
Bradycardia-inducing medicines
When MODLIFIN is used with beta blockers, there is an additional 15 % reduction in heart rate upon MODLIFIN initiation, an effect not seen with calcium channel blockers. Treatment with MODLIFIN should not be initiated in patients receiving beta blockers, heart rate lowering calcium channel blockers (such as verapamil or diltiazem), or other substances which may decrease heart rate (e.g. ivabradine or digoxin) because of the potential additive effects on heart rate. If treatment with MODLIFIN is considered, advice from a cardiologist should be sought regarding the switch to non heart-rate lowering medicines or appropriate monitoring for treatment initiation, which should last overnight (see section 4.4).
Vaccination
During and for at least two months after treatment with MODLIFIN vaccination may be less effective. The use of live attenuated vaccines may carry the risk of infection and should therefore be avoided (see sections 4.4 and 4.8).

MODLIFIN should not be used in pregnancy and lactation (see section 4.3). Safety in pregnancy and lactation has not been established. Fingolimod is teratogenic in animals.
Women of childbearing potential
Due to risk to the foetus, fingolimod is contraindicated during pregnancy and in women of childbearing potential not using effective contraception. Before initiation of treatment, women of childbearing potential must be informed of this risk to the foetus, must have a negative pregnancy test and must use effective contraception during treatment and for 2 months after treatment discontinuation.
Pregnancy
Based on human experience, post-marketing data suggest that the use of fingolimod is associated with a 2-fold increased risk of major congenital malformation when administered during pregnancy compared with the general population. The following major malformations were most frequently reported:
u2022 Congenital heart disease such as atrial and ventricular septal defects, tetralogy of Fallot
u2022 Renal abnormalities
u2022 Musculoskeletal abnormalities
If MODLIFIN is discontinued because of pregnancy or planned pregnancy, the possible return of disease activity should be considered (see section 4.4 - Return of disease activity (rebound) after MODLIFIN discontinuation and stopping therapy).
Breastfeeding
MODLIFIN is contraindicated in breastfeeding (see section 4.3). Fingolimod is excreted in the milk of treated animals during lactation. Due to the potential for serious adverse reactions to fingolimod in nursing infants, women receiving MODLIFIN should not breastfeed.

The clinical status of the patient and adverse event profile of MODLIFIN should be borne in mind when considering the patients ability to perform tasks that require judgement, motor and cognitive skills. Driving may be impaired by such adverse events.

Summary of the safety profile
The most frequent adverse reactions were headache, increased hepatic enzyme, diarrhoea, cough, influenza, sinusitis and back pain.
Tabulated list of adverse reactions
SYSTEM ORGAN CLASS FREQUENCY ADVERSE REACTION
Infections and infestations Frequent Influenza, sinusitis, herpes viral infections, bronchitis, tinea versicolor
Less frequent Pneumonia
Frequency unknown Progressive multifocal leukoencephalopathy (PML)* Cryptococcal infections*
Frequent Basal cell carcinoma Neoplasms, benign, malignant and unspecified (including cysts and polyps)
Less frequent Malignant melanoma, lymphoma**, squamous cell carcinoma, Kaposiu2019s sarcoma**
Frequency unknown Merkel cell carcinoma**
Blood and lymphatic system disorders Frequent Lymphopenia, leucopenia
Less frequent Thrombocytopenia
Frequency unknown Autoimmune haemolytic anaemia** Peripheral oedema**
Immune system disorders Frequency unknown Hypersensitivity reactions, including rash, urticaria and angioedema upon treatment initiation**
Psychiatric disorders Frequent Depression
Less frequent Depressed mood
Nervous system disorders Frequent Headache, dizziness, migraine
Less frequent Seizure, Posterior reversible encephalopathy syndrome (PRES)
Frequency unknown Severe exacerbation of disease after fingolimod discontinuation**
Eye disorders Frequent Vision blurred
Less frequent Macular oedema
Cardiac disorders Frequent Bradycardia, atrioventricular block
Less frequent T-wave inversion**
Vascular disorders Frequent Hypertension
Respiratory, thoracic and mediastinal disorders Frequent Cough, dyspnoea
Gastrointestinal disorders Frequent Diarrhoea
Less frequent Nausea**
Hepato-biliary disorders Frequency unknown Acute hepatic failure**
Skin and subcutaneous tissue disorders Frequent Eczema, alopecia, pruritus
Musculoskeletal, connective tissue and bone disorders Frequent Back pain, myalgia, arthralgia
General disorders and administration site conditions Frequent Asthenia
Investigations Frequent Hepatic enzyme increased (increased alanine transaminase, gamma glutamyl transferase, aspartate transaminase) Weight decreased** Blood triglycerides increased
Less frequent Neutrophil count decreased
*PML and cryptococcal infections have been reported post-marketing. **Adverse reactions from spontaneous reports and literature.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare professionals are asked to report any suspected adverse reactions to SAHPRA via the u201c6.04 Adverse Drug Reactions Reporting Formu201d, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8

At 40 mg (i.e., 80-fold above the recommended dose) administered to healthy volunteers, mild chest tightness or discomfort which was clinically consistent with bronchoconstriction has been reported. MODLIFIN can induce bradycardia. The decline in heart rate usually starts within one hour of the first dose, and is maximal within 6 hours. There have been reports of slow atrioventricular conduction with isolated reports of transient, spontaneously resolving complete AV block (see section 4.4 and 4.8). If the overdose constitutes first exposure to MODLIFIN it is important to observe for signs and symptoms of bradycardia, which could include overnight monitoring. Regular measurements of pulse rate and blood pressure are required and electrocardiograms should be performed (see sections 4.2 and 4.4). Neither dialysis nor plasma exchange would result in meaningful removal of MODLIFIN from the body.