NAME OF THE MEDICINE

The active ingredient of GILENYA is fingolimod. Chemical name: 2-amino-2-(2-(4-octylphenyl)ethyl]propan-1,3-diol hydrochloride Chemical structure:

OH OH

H2N

. HCl

Molecular formula: C19H33NO2 * HCl CAS number: 162359-56-0 Molecular weight: 343.93

DESCRIPTION

Fingolimod hydrochloride is a white to almost white crystalline powder which is freely soluble in water. Fingolimod is a base with pKa of 7.82. Therefore, it has high solubility at low pH and very low solubility at high pH (e.g. < 0.01 mg/mL at pH 6.8). Relevant distribution coefficients are 22.3 in n-Octanol/water and 1290 in n-Octanol/hydrochloric acid 0.1N. Each GILENYA capsule contains 0.56 mg fingolimod hydrochloride (equivalent to 0.5 mg fingolimod), mannitol, magnesium stearate, titanium dioxide and gelatin.

PHARMACOLOGY

Mechanism of Action

Fingolimod is a sphingosine 1-phosphate receptor modulator. Fingolimod is metabolized by sphingosine kinase to the active metabolite fingolimod-phosphate. Fingolimod-phosphate, binds at low nanomolar concentrations to sphingosine 1-phosphate (S1P) receptors 1, 3, and 4 located on lymphocytes, and readily crosses the blood brain barrier to bind to S1P receptors 1, 3, and 5 located on neural cells in the central nervous system. 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. This redistribution reduces the infiltration of pathogenic lymphocyte cells into the central nervous system where they would be involved in nerve inflammation and nervous tissue damage. Animal studies and in vitro experiments indicate that fingolimod may also exert beneficial effects in multiple sclerosis via interaction with S1P receptors on neural cells.

Pharmacodynamics:

Immune system:

Effects on immune cell numbers in the blood:

Within 4-6 hours after the first dose of fingolimod 0.5 mg, the lymphocyte count decreases to approximately 75% of baseline. With continued daily dosing, the lymphocyte count continues to decrease over a two week period, reaching a nadir count of approximately 500 cells/mL or approximately 30% of baseline. Eighteen percent of patients reached a nadir of < 200 cells/mL on at least one occasion. Low lymphocyte counts are maintained with chronic daily dosing. The majority of T and B lymphocytes regularly traffic through lymphoid organs and these are the cells mainly affected by fingolimod. Approximately 15-20% of T lymphocytes have an effector memory phenotype, cells that are important for peripheral immune surveillance. Since this lymphocyte subset typically does not traffic to lymphoid organs it is not affected by fingolimod. Peripheral lymphocyte count increases are evident within days of stopping fingolimod treatment and typically normal counts are reached within one to two months. Chronic fingolimod dosing leads to a mild decrease in the neutrophil count to approximately 80% of baseline. Monocytes are unaffected by fingolimod.

Heart rate and rhythm:

Fingolimod causes a transient reduction in heart rate and atrio-ventricular conduction at treatment initiation (see PRECAUTIONS; Bradyarrhythmia and ADVERSE EFFECTS). The maximal decline of heart rate is seen in the first 4-5 hours post dose, with 70% of the negative chronotropic effect achieved on the first day. Heart rate progressively returns to baseline values within one month of chronic treatment. Pooled analysis of studies with holter monitoring showed that fingolimod increased the rate of new onset first degree A-V heart block (PR > 200 ms) by 12% on Day 1 and that the incidence had reduced to < 1% after 1 week of treatment. Doses <= 1.25 mg were associated with a 7% incidence of heart block cf.3% in subjects given placebo. These blocks were usually asymptomatic and did not require treatment. Autonomic responses of the heart, including diurnal variation of heart rate and response to exercise are not affected by fingolimod treatment. With initiation of fingolimod treatment there is an increase in atrial premature contractions, but there is no increased rate of atrial fibrillation/flutter or ventricular arrhythmias or ectopy. Fingolimod treatment is not associated with a decrease in cardiac output. The decrease in heart rate induced by fingolimod can be reversed by atropine, isoprenaline or salmeterol.

Potential to prolong the QT interval:

In a thorough QT interval study of doses of 1.25 or 2.5 mg fingolimod at steady-state, when a negative chronotropic effect of fingolimod was still present, fingolimod treatment resulted in a prolongation of QTcI, with the upper bound of the 90% CI <=13.0 ms. There is no dose or exposure - response relationship of fingolimod and QTcI prolongation. There is no consistent signal of increased incidence of QTcI outliers, either absolute or change from baseline, associated with fingolimod treatment. In the multiple sclerosis studies, there was no clinically relevant prolongation of QT interval.

Pulmonary function:

Persistent pulmonary inflammation and collagenisation with scarring and pulmonary remodelling were observed in association with fingolimod treatment in chronic animal studies (all tested species; mice, rats, dogs and monkeys). Focal pulmonary metaplastic ossification was evident in mice and rats treated for 2 years, but not 6 months, at a dose of 0.25 mg/kg/day and 0.5 mg/kg/day, respectively. Exposure (AUC) at the no effect level was below the clinical exposure in mice and 3 times the clinical exposure in rats. As these pulmonary changes occurred in multiple species, at low relative exposure and were incompletely reversible, adequate pulmonary monitoring should be considered with long-term treatment. Fingolimod treatment with single or multiple doses of 0.5 and 1.25 mg for two weeks is not associated with a detectable increase in airway resistance as measured by forced expiratory volume in 1 second (FEV1) and forced expiratory flow during expiration of 25 to 75% of the forced vital capacity (FEF25-75). However, single fingolimod doses >=5 mg (10-fold the recommended dose) are associated with a dose-dependent increase in airway resistance. Fingolimod treatment with multiple doses of 0.5, 1.25, or 5 mg is not associated with impaired oxygenation or oxygen desaturation with exercise or an increase in airway responsiveness to methacholine. Subjects on fingolimod treatment have a normal bronchodilator response to inhaled b-agonists.

Pharmacokinetics Absorption:

Fingolimod absorption is slow (tmax of 12-16 hours) and extensive (85%, based on the amount of radioactivity excreted in urine and the amount of metabolites in faeces extrapolated to infinity). The apparent absolute oral bioavailability is high (93%). Food intake does not alter Cmax or exposure (AUC) of fingolimod or fingolimod-phosphate. Therefore GILENYA may be taken without regard to meals (see DOSAGE AND ADMINISTRATION). Steady-state blood concentrations are reached within 1 to 2 months following once-daily administration and steady-state levels are approximately 10-fold greater than with the initial dose.

Distribution:

Fingolimod highly distributes in red blood cells, with the fraction in blood cells of 86%. Fingolimod-phosphate has a smaller uptake in blood cells of <17%. Fingolimod and fingolimod-phosphate are highly protein bound (>99.7%). Fingolimod and fingolimod- phosphate protein binding is not altered by renal or hepatic impairment. Fingolimod is extensively distributed to body tissues with a volume of distribution of about 1200260 L.

Metabolism:

The biotransformation of fingolimod in humans occurs by three main pathways; by reversible stereoselective phosphorylation to the pharmacologically active (S)-enantiomer of fingolimod- phosphate, by oxidative biotransformation mainly via the cytochrome P450 4F2 isoenzyme and subsequent fatty acid-like degradation to inactive metabolites, and by formation of pharmacologically inactive non-polar ceramide analogs of fingolimod. Following single oral administration of [14C] fingolimod, the major fingolimod-related components in blood, as judged from their contribution to the AUC up to 816 hours post dose of total radiolabeled components, are fingolimod itself (23.3%), fingolimod-phosphate (10.3%), and inactive metabolites (M3 carboxylic acid metabolite (8.3%), M29 ceramide metabolite (8.9%) and M30 ceramide metabolite (7.3%)).

Elimination:

Fingolimod blood clearance is 6.32.3 L/h, and the average apparent terminal half-life (t1/2) is 6-9 days. Blood levels of fingolimod-phosphate decline in parallel with fingolimod in the terminal phase yielding similar half-lives for both. After an oral administration, about 81% of the dose is slowly excreted in the urine as inactive metabolites. Fingolimod and fingolimod-phosphate are not excreted intact in urine but are the major components in the faeces with amounts representing less than 2.5% of the dose each. After 34 days, the recovery of the administered dose is 89%.

Linearity:

Fingolimod and fingolimod-phosphate concentrations increase in an apparent dose proportional manner after multiple once daily doses of fingolimod 0.5 mg or 1.25 mg.

Pharmacokinetics in Special Patient Groups Pharmacokinetics in children:

Safety and efficacy of GILENYA in paediatric patients below the age of 18 have not been studied. GILENYA is not indicated for use in paediatric patients.

Pharmacokinetics in the elderly:

The mechanism for elimination and results from population pharmacokinetics suggest that dose adjustment would not be necessary in elderly patients. However, clinical experience in patients aged above 65 years is limited.

Pharmacokinetics in patients with impaired renal or hepatic function:

Severe renal impairment increases fingolimod Cmax and AUC by 32% and 43%, respectively, and fingolimod-phosphate Cmax and AUC by 25% and 14%, respectively. The apparent elimination half-life is unchanged for both analytes. In severe renal impairment Cmax and AUC for M3, an inactive metabolite, were increased by 805% and 1356% respectively. No GILENYA dose adjustments are needed in patients with renal impairment. The pharmacokinetics of single-dose fingolimod (1 or 5 mg), when assessed in subjects with mild, moderate and severe hepatic impairments, showed no change on fingolimod Cmax, but an increase in AUC by 12%, 44% and 103%, respectively. The apparent elimination half-life is unchanged in mild hepatic impairment but is prolonged by 49-50% in moderate and severe hepatic impairment. Fingolimod-phosphate was measured in severe hepatic impairment only, and Cmax, and AUC were decreased by 22% and 29%, respectively. Although hepatic impairment elicited changes in the disposition of fingolimod and fingolimod-phosphate, the magnitude of these changes suggests that the fingolimod dose does not need to be adjusted in mild or moderate hepatic impaired patients. Fingolimod should be used with caution in patients with severe hepatic impairment (Child-Pugh class C).

Ethnicity:

The effects of ethnic origin on fingolimod and fingolimod phosphate pharmacokinetics are not of clinical relevance.

Gender:

Gender has no influence on fingolimod and fingolimod-phosphate pharmacokinetics.

CLINICAL TRIALS

The efficacy of GILENYA has been demonstrated in two studies which evaluated once daily doses of GILENYA 0.5 mg and 1.25 mg in patients with relapsing remitting multiple sclerosis. Both studies included patients who had experienced at least 2 clinical relapses during the 2 years prior to randomization or at least 1 clinical relapse during the 1 year prior to randomization, and had an Expanded Disability Status Scale (EDSS) between 0 to 5.5. Patients with the following conditions were excluded from these studies: other chronic disease of the immune system; known immune deficiency syndrome; history of malignancy other than cutaneous BCC or SCC of the skin; active systemic bacterial, viral or fungal infections; AIDS; HBsAg positive or hepatitis C antibody positive; serious psychiatric condition. Study D2301 (FREEDOMS) was a 2-year randomized, double-blind, placebo-controlled Phase III study in patients with relapsing-remitting multiple sclerosis who had not received any interferon-beta or glatiramer acetate for at least the previous 3 months and had not received any natalizumab for at least the previous 6 months. Neurological evaluations were performed at Screening, every 3 months and at time of suspected relapse. MRI evaluations were performed at Screening, month 6, month 12 and month 24. The primary endpoint was the annualized relapse rate. Median age was 37 years, median disease duration was 6.7 years and median EDSS score at baseline was 2.0. Patients were randomized to receive GILENYA 0.5 mg (n=425) or GILENYA 1.25 mg (n=429), or placebo (n=418) for up to 24 months. Median time on study drug was 717 days on 0.5 mg, 715 days on 1.25 mg and 718.5 days on placebo. The annualised relapse rate was significantly lower in patients treated with GILENYA than in patients who received placebo. The key secondary endpoint was the time to 3-month confirmed disability progression as measured by at least a 1-point increase from baseline in EDSS (0.5 point increase for patients with baseline EDSS of 5.5) sustained for 3 months. Time to onset of 3-month confirmed disability progression was significantly delayed with GILENYA treatment compared to placebo. There were no significant differences between the 0.5 mg and the 1.25 mg doses on either endpoint. The results for this study are shown in Table 1 and Figure 1.

Table 1 Clinical and MRI results of Study D2301

All analyses of clinical endpoints were intent-to treat. MRI analyses used evaluable dataset.

* Indicates statistical significance vs. placebo at two-sided 0.05 level.

Determination of p-values: aggregate ARR by negative binomial regression adjusting for treatment, pooled country, number of relapses in previous 2 years and baseline EDSS; percent of patients maintaining relapse-free logistic regression adjusted for treatment, country, number of relapse in previous 2 years, and baseline EDSS; time to 3-month/6- month confirmed disability progression by Cox's proportional hazards model adjusted for treatment, pooled country, baseline EDSS, and age; new/newly enlarging T2 lesions by negative binomial regression adjusted for treatment and pooled country; Gd-enhancing lesions by rank ANCOVA adjusted for treatment, pooled country, and baseline number of Gd-enhancing lesions; and % change in lesion and brain volume by rank ANCOVA adjusted for treatment, pooled country, and corresponding baseline value.

Figure 1 Kaplan-Meier plot for time to first confirmed relapse up to Month 24- Study D2301 (ITT population)

Study D2302 (TRANSFORMS) was a 1-year randomized, double-blind, double-dummy, active (interferon beta-1a 30 micrograms, intramuscular, once weekly)-controlled Phase III study in patients with RRMS who had not received any natalizumab in the previous 6 months. Prior therapy with interferon-beta or glatiramer acetate up to the time of randomization was permitted. Neurological evaluations were performed at Screening, every 3 months and at the time of suspected relapses. MRI evaluations were performed at Screening and at month 12. The primary endpoint was the annualized relapse rate. Median age was 36 years, median disease duration was 5.9 years and median EDSS score at baseline was 2.0. Patients were randomized to receive GILENYA 0.5 mg (n=431) or 1.25 mg (n=426) or interferon beta-1a 30 micrograms via the intramuscular route once weekly (n=435) for up to 12 months. Median time on study drug was 365 days on 0.5 mg, 354 days on 1.25 mg and 361 days on interferon beta-1a IM. The annualised relapse rate was significantly lower in patients treated with GILENYA than in patients who received interferon beta-1a IM. There was no significant difference between the GILENYA 0.5 mg and the 1.25 mg doses. The key secondary endpoints were number of new or newly enlarging T2 lesions and time to onset of 3-month confirmed disability progression as measured by at least a 1-point increase from baseline in EDSS (0.5 point increase for those with baseline EDSS of 5.5) sustained for 3 months. The number of new or newly enlarging T2 lesions was significantly lower in patients treated with GILENYA than in patients who received interferon beta-1a IM. There was no significant difference in the time to 3-month confirmed disability progression between GILENYA and interferon beta-1a-treated patients at 1 year. There were no significant differences between the 0.5 mg and the 1.25 mg doses on either endpoint. The results for this study are shown in Table 2 and Figure 2.

Table 2 Clinical and MRI results of Study D2302

All analyses of clinical endpoints were intent-to treat. MRI analyses used evaluable dataset.

* Indicates statistical significance vs. Interferon beta-1a at two-sided 0.05 level.

Determination of p-values: aggregate ARR by negative binomial regression adjusting for treatment, country, number of relapses in previous 2 years and baseline EDSS; percent of patients maintaining relapse-free logistic regression adjusted for treatment, country, number of relapse in previous 2 years, and baseline EDSS; risk of disability progression by Cox's proportional hazards model adjusted for treatment, country, baseline EDSS, and age; new/newly enlarging T2 lesions by negative binomial regression adjusted for treatment, country, number of relapses in previous 2 years and baseline EDSS; Gd-enhancing lesions by rank ANCOVA adjusted for treatment, country, and baseline number of Gd- enhancing lesions; and % change in brain volume by Wilcoxon rank sum test.

Figure 2 Kaplan-Meier plot for time to first confirmed relapse up to Month 12 - Study D2302 (ITT population)

Pooled results of studies D2301 and D2302 showed a consistent reduction of annualized relapse rate compared to comparator in subgroups defined by gender, age, prior multiple sclerosis therapy, disease activity or disability levels at baseline.

CONTRAINDICATIONS

Patients who in the last 6 months experienced myocardial infarction, unstable angina, stroke, TIA, decompensated heart failure requiring hospitalization or Class III/IV heart failure. History or presence of Mobitz Type II second-degree or third-degree atrioventricular (AV) block or sick sinus syndrome, unless patient has a functioning pacemaker. Baseline QTc interval >=500 ms. Concomitant treatment with Class Ia or Class III anti-arrhythmic drugs during Gilenya initiation. Refer to PRECAUTIONS for further information. Further, GILENYA should not be administered to patients with known hypersensitivity to fingolimod or any of the excipients.

PRECAUTIONS

Infections

GILENYA causes a dose-dependent reduction in peripheral lymphocyte count to 20 - 30% of baseline values because of reversible sequestration of lymphocytes in lymphoid tissues (see PHARMACOLOGY). GILENYA may therefore increase the risk of infections, some serious in nature. A recent complete blood count should be available before initiating treatment with GILENYA. Because the elimination of fingolimod after discontinuation can take up to two months, continue monitoring for infections throughout this period. Instruct patients receiving GILENYA to report symptoms of infections to a physician. Patients with active acute or chronic infections should not start treatment until the infection(s) is resolved. In MS controlled studies, the overall rate of infections (72%) and serious infections (2%) with GILENYA 0.5 mg was similar to placebo. However, bronchitis and, to a lesser extent, pneumonia were more common in GILENYA-treated patients.

Vaccination

Vaccination may be less effective during and for up to two months after treatment with GILENYA (see PRECAUTIONS, Stopping therapy). The use of live attenuated vaccines should be avoided. As could be considered for any immune modulating drug, before initiating GILENYA therapy, patients without a history of chickenpox or without vaccination against varicella zoster virus (VZV) should be tested for antibodies to VZV. VZV vaccination of antibody negative patients should be considered prior to commencing treatment with GILENYA, following which initiation of treatment with GILENYA should be postponed for 1 month to allow full effect of vaccination to occur.

Macular Oedema

Macular oedema can occur with or without visual symptoms. An ophthalmologic evaluation should be performed before starting GILENYA and at 3-4 months after treatment initiation. Monitor visual acuity at baseline and during routine evaluations of patients. Patients with diabetes mellitus or a history of uveitis are at increased risk and should have regular ophthalmologic evaluations. If patients report visual disturbances at any time while on GILENYA therapy, evaluation of the fundus, including the macula, should be carried out. Continuation of GILENYA in patients with macular oedema has not been evaluated. A decision on whether or not GILENYA therapy should be discontinued needs to take into account the potential benefits and risks for the individual patient.

Bradyarrhythmia

Initiation of GILENYA treatment results in a decrease in heart rate. Initiation of GILENYA treatment has been associated with atrio-ventricular conduction delays, usually as first-degree atrio-ventricular blocks (prolonged PR interval on electrocardiogram). Second-degree atrio-ventricular blocks, usually Mobitz type I (Wenckebach) have been observed in less than 0.5% of patients receiving GILENYA 0.5 mg in clinical trials. The conduction abnormalities typically were transient, asymptomatic, usually did not require treatment and resolved within the first 24-hours on treatment. Isolated cases of transient, spontaneously resolving complete AV block have been reported during post-marketing use of Gilenya (see ADVERSE EFFECTS).

First dose monitoring

Therefore on initiation of Gilenya 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 bradyarrhythmia- 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 pharmacologic intervention during the first dose observation, overnight monitoring in a medical facility should be instituted and the first dose monitoring strategy should be repeated after the second dose of Gilenya. Additional observation until the finding has resolved is also required:

• if the heart rate at 6 hours post-dose is <45 bpm or is the lowest value post-dose (suggesting that the maximum pharmacodynamic effect on the heart is not yet manifest)

• or if the ECG at 6 hours after the first dose shows new onset second degree or higher AV block.

If the ECG at 6 hours shows a QTc interval >470 msec (females) or >450 msec (males) the patient should be monitored overnight in a medical facility. Since initiation of Gilenya treatment results in decreased heart rate and therefore a prolongation of the QT interval, Gilenya must not be used in patients with a baseline QTc interval >=500 msec (see CONTRAINDICATIONS) and should be used with caution in patients with significant QT prolongation (QTc >470 msec (females) or >450 msec (males)). Gilenya is best avoided in patients with relevant risk factors for QT prolongation, (for example, hypokalaemia, hypomagnesemia or congenital QT prolongation) or on concurrent therapy with QT prolonging drugs with a known risk of torsades de pointes (e.g., citalopram, chlorpromazine, haloperidol, methadone, erythromycin). If treatment is considered, advice from a cardiologist should be sought prior to initiation of treatment in order to determine the most appropriate monitoring, which should last overnight. Due to the risk of serious rhythm disturbances, Gilenya is contraindicated in patients with second degree Mobitz type II or higher AV block, or sick-sinus syndrome unless the patient has a functioning pacemaker (see CONTRAINDICATIONS) and should not be used in patients with sino-atrial heart block. Since significant bradycardia may be poorly tolerated in patients with known ischemic heart disease, history of myocardial infarction, congestive heart failure, history of cardiac arrest, cerebrovascular disease, uncontrolled hypertension or severe untreated sleep apnoea period, Gilenya should not be used in these patients. If treatment is considered, advice from a cardiologist should be sought prior to initiation of treatment in order to determine the most appropriate monitoring, which should last overnight. Use of Gilenya in patients with a history of recurrent syncope or symptomatic bradycardia should be based on overall benefit-risk assessment. If treatment is considered, advice from a cardiologist should be sought prior to initiation of treatment in order to determine to most appropriate monitoring which should last overnight. GILENYA has not been studied in patients with arrhythmias requiring treatment with Class Ia (e.g. quinidine, procainamide) or Class III anti-arrhythmic drugs (e.g., amiodarone, sotalol). Class Ia and Class III anti-arrhythmic drugs have been associated with cases of Torsades de Pointes in patients with bradycardia. Since initiation of GILENYA treatment results in decreased heart rate, GILENYA must not be used concomitantly with these drugs during GILENYA initiation (see CONTRAINDICATIONS). Experience with Gilenya is limited in patients receiving concurrent therapy with beta blockers, heart rate lowering calcium channel blockers (such as verapamil, diltiazem or ivabradine), or other substances which may decrease heart rate (e.g. digoxin). Since the initiation of Gilenya treatment is also associated with slowing of the heart rate (see ADVERSE EFFECTS, Bradyarrhythmia), concomitant use of these substances during Gilenya initiation may be associated with severe bradycardia and heart block. Because of the potential additive effect on heart rate, treatment with Gilenya should generally not be initiated in patients who are concurrently treated with these substances. If treatment with Gilenya is considered, advice from a cardiologist should be sought regarding the switch to non heart-rate lowering drugs or appropriate monitoring for treatment initiation (should last overnight). If GILENYA therapy is discontinued for more than 2 weeks after the first month of treatment the effects on heart rate and atrio-ventricular conduction may recur on reintroduction of GILENYA treatment and the same precautions as for initial dosing should apply. Within the first 2 weeks of treatment, first dose procedures are recommended after interruption of one day or more, during week 3 and 4 of treatment first dose procedures are recommended after treatment interruption of more than 7 days.

Liver Function

During clinical trials, 3-fold or greater elevation in liver transaminases occurred in 8.5% of patients treated with GILENYA 0.5 mg and drug was discontinued if the elevation exceeded 5-fold increase. Recurrence of liver transaminase elevations occurred upon re-challenge in some patients, supporting a relationship to the drug. Patients who develop symptoms suggestive of hepatic dysfunction, such as unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine, should have liver enzymes checked and GILENYA should be discontinued if significant liver injury is confirmed (see ADVERSE EFFECTS, Liver Transaminase). Although there are no data to establish that patients with preexisting liver disease are at increased risk to develop elevated liver function tests (LFTs) when taking GILENYA, caution in the use of GILENYA should be exercised in patients with a history of significant liver disease.

Prior Treatment with Immunosuppressants

When switching patients from beta interferon or glatiramer acetate to Gilenya, a washout is not necessary, assuming any immune effects (i.e. cytopenia) of such therapies have resolved. Due to the long half-life of natalizumab, concomitant exposure, and thus concomitant immune effects, could occur if Gilenya is started within the first 2 to 3 months following discontinuation of natalizumab. Therefore careful case-by-case assessment regarding the timing of the initiation of Gilenya treatment is recommended when switching patients from natalizumab to Gilenya. When switching from other immunosuppressive medications, the duration and mode of action of such substances must be considered when initiating Gilenya to avoid additive immune suppressive effects.

Stopping Therapy

If a decision is made to stop treatment with GILENYA, the physician 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 PHARMACOLOGY). Starting other therapies during this interval will result in a concomitant exposure to fingolimod. Use of immunosuppressants soon after the discontinuation of GILENYA may lead to an additive effect on the immune system and therefore caution should be applied.

Effects on Fertility

There are no human data on the effects of fingolimod on male or female fertility. Fingolimod had no effect on fertility in rats up to 10 mg/kg/day (estimated systemic exposure more than 100 times the anticipated clinical exposure) in a study in which both male and female animals were treated and mated. There was no apparent effect on sperm counts. Data from animals does not suggest that fingolimod would be associated with an increased risk of reduced fertility.

Use in Pregnancy (Category D)

Fingolimod and/or its metabolites crossed the placental barrier in pregnant rats and rabbits. When administered during organogenesis, fingolimod was teratogenic in the rat at oral doses of 0.1 mg/kg/day or higher (similar to the clinical dose on a body surface area basis). The most common malformations were persistent truncus arteriosus and ventricular septal defect. At a lower dose (0.03 mg/kg/day), an increased incidence of left umbilical artery was the only finding. A pharmacological mechanism may be responsible as the sphingosine 1-phosphate receptor is involved in vascular formation during embryogenesis. Rabbits showed an increase in skeletal variations at exposures similar to clinical exposure. An increase in post-implantation loss and/or abortion was observed in rat (0.5 mg/kg/day or higher) and rabbit (5 mg/kg/day or higher) studies. Reduced perinatal survival was seen in offspring from rats treated orally from early gestation to weaning with 0.05 mg/kg/day or higher (similar to the clinical dose on a body surface area basis); a no effect dose was not established. Before initiation of GILENYA treatment, women of childbearing potential should be counselled on the potential for serious risk to the foetus and the need for effective contraception during treatment with GILENYA and for at least 2 months following discontinuation of therapy, as it will take approximately 2 months to eliminate the compound from the body upon stopping treatment.

Lactation

Fingolimod and/or its metabolites was excreted in the milk of treated rats during lactation. There were no effects on body weight, development, behaviour, or fertility in rat pups from dams treated with oral fingolimod from early gestation to weaning. Reduced immunocompetence was evident in juvenile rats following oral administration. Because of the potential for serious adverse drug reactions from fingolimod in nursing infants, women receiving GILENYA should not breast feed.

Carcinogenicity

In a 2-year mouse study, an increased incidence of malignant lymphoma was seen at oral doses of 0.25 mg/kg/day and higher, with exposure (plasma AUC) 5-fold the human systemic exposure at a daily dose of 0.5 mg. Exposure at the NOEL was 0.6-fold human exposure. No evidence of carcinogenicity was observed in a 2-year bioassay in rats at oral doses of fingolimod up to 2.5 mg/kg/day, representing a 50-fold margin based on the human systemic exposure (AUC) at the 0.5 mg dose.

Genotoxicity

Fingolimod-induced numerical chromosomal aberrations (polyploidy) in Chinese hamster cells at concentrations more than three orders of magnitude greater than the clinical steady-state plasma levels, but not in human lymphocytes when tested at similar concentrations. Fingolimod was not clastogenic in the in vivo micronucleus tests in mice and rats at exposures at least 500 times that expected clinically.

INTERACTIONS WITH OTHER MEDICINES

Pharmacodynamic Interactions

Anti-neoplastic, immunosuppressive or immune modulating therapies should be co- administered with caution due to the risk of additive immune system effects. Caution should also be applied when switching patients from long-acting therapies with immune effects such as natalizumab or mitoxantrone (see PRECAUTIONS - Prior treatment with immunosuppressants). In multiple sclerosis clinical trials the concomitant treatment of relapses with a short course of corticosteroids was not associated with an increased rate of infection. When fingolimod is used with atenolol, there is an additional 15% reduction of heart rate upon fingolimod initiation, an effect not seen with diltiazem. Treatment with Gilenya should not be initiated in patients receiving beta blockers, heart rate lowering calcium channel blockers (such as verapamil, diltiazem or ivabradine), or other substances which may decrease heart rate (e.g. digoxin) because of the additive effects on heart rate.If treatment with Gilenya is considered, advice from a cardiologist should be sought regarding the switch to non heart-rate lowering medicinal products or appropriate monitoring for treatment initiation (should last overnight) (see PRECAUTIONS). During and for up to two months after treatment with GILENYA vaccination may be less effective. The use of live attenuated vaccines may carry the risk of infection and should therefore be avoided (see ADVERSE EFFECTS).

Pharmacokinetic Interactions

Fingolimod is primarily metabolized via human CYP4F2 with some contribution also observed for CYP2D6 *1, 2E1, 3A4, and 4F12. The potential of co-medications to inhibit the clearance of fingolimod seems low because very few medicinal products (e.g. ketoconazole) are known to inhibit CYP4F2.

Potential of fingolimod and fingolimod-phosphate to inhibit the metabolism of co- medications:

In vitro

inhibition studies in pooled human liver microsomes and specific metabolic probe substrates demonstrated that fingolimod and fingolimod-phosphate have little or no capacity to inhibit the activity of CYP450 enzymes (CYP1A2, CYP2A6, CYP2B6, CYP2C8/9, CYP2C19, CYP2D6, CYP2E1, CYP3A4/5, or CYP4A9/11. Therefore, fingolimod and fingolimod- phosphate are unlikely to reduce the clearance of drugs that are mainly cleared through metabolism by the major cytochrome P450 isoenzymes.

Potential of fingolimod and fingolimod-phosphate to induce its own and/or the metabolism of co-medications:

Fingolimod was examined for its potential to induce human CYP3A4, CYP1A2, CYP4F2, and MDR1 (P-glycoprotein) mRNA and CYP3A, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP4F2 activity in primary human hepatocytes. Fingolimod did not induce mRNA or activity of the different CYP450 enzymes and MDR1 with respect to the vehicle control. Therefore no clinically relevant induction by fingolimod of the tested CYP450 enzymes or MDR1 are expected at therapeutic concentrations.

Transporters

Fingolimod as well as fingolimod-phosphate are not expected to inhibit the uptake of co- medications and/or biologics transported by OATP1B1, OATP1B3 or NTCP. Similarly, they are not expected to inhibit the efflux of co-medications and/or biologics transported by the breast cancer resistant protein (MXR), the bile salt export pump (BSEP), the multidrug resistance-associated protein 2 (MRP2) and MDR1-mediated transport at therapeutic concentrations.

Cyclosporine

The pharmacokinetics of single-dose fingolimod were not altered during co-administration with cyclosporine at steady-state, nor was cyclosporine steady-state pharmacokinetics altered by single-dose, or multi-dose (28 days) fingolimod administration. These data indicate that fingolimod is unlikely to reduce the clearance of drugs mainly cleared by CYP3A4 and show that the potent inhibition of transporters MDR1, MRP2 and OATP-C does not influence fingolimod disposition.

Ketoconazole

The co-administration of oral ketoconazole 200 mg twice daily at steady-state and a single dose of fingolimod 5 mg led to a modest increase in the AUC of fingolimod and fingolimod- phosphate (1.7-fold increase), indicating that potent inhibitors of CYP3A and CYP4F have a weak effect on fingolimod pharmacokinetics. Patients who use GILENYA and systemic ketoconazole concomitantly should be closely monitored, as the risk of adverse reactions is greater.

Isoproterenol, Atropine, Atenolol, and Diltiazem

Single-dose fingolimod and fingolimod-phosphate exposure was not altered by co- administered isoproterenol or atropine. Likewise, the single-dose pharmacokinetics of fingolimod and fingolimod-phosphate and the steady-state pharmacokinetics of both atenolol and diltiazem were unchanged during the co-administration of the latter two drugs with fingolimod.

Population Pharmacokinetics Analysis of Potential Drug-Drug Interactions

A population pharmacokinetics evaluation, performed in multiple sclerosis patients, did not provide evidence for a significant effect of fluoxetine and paroxetine (strong CYP2D6 inhibitors) and carbamazepine (potent enzyme inducer) on fingolimod or fingolimod-phosphate concentrations. In addition, the following, commonly prescribed substances had no clinically relevant effect (<=20%) on fingolimod or fingolimod-phosphate concentrations: baclofen, gabapentin, oxybutynin, amantadine, modafinil, amitriptyline, pregabalin, corticosteriods and oral contraceptives.

Laboratory Tests

Since fingolimod reduces blood lymphocyte counts via re-distribution in secondary lymphoid organs, peripheral blood lymphocyte counts cannot be utilized to evaluate the lymphocyte subset status of a patient treated with GILENYA. Laboratory tests requiring the use of circulating mononuclear cells require larger blood volumes due to reduction in the number of circulating lymphocytes.

DOSAGE AND ADMINISTRATION

The recommended dose of GILENYA 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 GILENYA treatment, after the first dose, 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 (see PRECAUTIONS, Bradyarrhythmia). Patients can switch directly from beta interferon or glatiramer acetate to GILENYA providing there are no signs of relevant treatment-related abnormalities e.g. neutropenia. Caution is advised when switching patients from natalizumab to Gilenya (see PRECAUTIONS -Prior treatment with immunosuppressants).

Children

GILENYA is not indicated for use in paediatric patients (See PHARMACOLOGY).

The Elderly (>= 65 years)

GILENYA should be used with caution in patients aged 65 years and over (see PHARMACOLOGY).

Patients with Renal Impairment

No GILENYA dose adjustments are needed (see PHARMACOLOGY).

Patients with Hepatic Impairment

No GILENYA dose adjustments are needed in patients with mild or moderate hepatic impairment. GILENYA should be used with caution in patients with severe hepatic impairment (Child-Pugh class C) (see PHARMACOLOGY).

Ethnicity

No GILENYA dose adjustments based on ethnic origin are needed (see PHARMACOLOGY).

Gender

No GILENYA dose adjustments are needed based on gender (see PHARMACOLOGY).

Diabetic Patients

GILENYA should be used with caution in patients with diabetes mellitus due to a potential increased risk of macular oedema (see PRECAUTIONS).

OVERDOSAGE

No cases of overdosage have been reported. However, single doses up to 80-fold the recommended dose (0.5mg) were well tolerated in healthy volunteers. At 40 mg, 5 of 6 subjects reported mild chest tightness or discomfort which was clinically consistent with small airway reactivity. Fingolimod can induce bradycardia (see PHARMACOLOGY, Heart rate and rhythm). There have been reports of slow atrioventricular conduction with isolated reports of transient, spontaneously resolving complete AV block (see PRECAUTIONS and ADVERSE EFFECTS). If the overdose constitutes first exposure to Gilenya 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 DOSAGE AND ADMINISTRATION and PRECAUTIONS). Neither dialysis nor plasma exchange would result in meaningful removal of fingolimod from the body. Contact the Poisons Information Centre on 13 11 26 for advice on management of overdosage.

PRESENTATION AND STORAGE CONDITIONS

GILENYA 0.5 mg : white to almost white powder in white opaque body and bright yellow opaque cap gelatin capsules, size 3, radial imprint with black ink "FTY 0.5 mg" on cap and two radial bands imprinted on body with yellow ink. Blister packs of 7, 28 and 84. Not all pack sizes marketed in Australia.

Storage:

Store below 30 degrees Celsius. Protect from moisture.

NAME AND ADDRESS OF THE SPONSOR

Novartis Pharmaceuticals Australia Pty Limited ABN 18 004 244 160 54 Waterloo Road North Ryde NSW 2113

= Registered Trademark

POISON SCHEDULE OF THE MEDICINE

Poison Schedule: S4

DATE OF FIRST INCLUSION IN THE AUSTRALIAN REGISTER OF THERAPEUTIC GOODS (THE ARTG)

19 January 2011

DATE OF MOST RECENT AMENDMENT

11 October 2012