Summary Basis of Decision for Gilenya

 

3.3.1 Pharmacodynamics

The initiation of Gilenya* treatment resulted in dynamic effects which were observed within hours following the first dose. The prinicipal dynamic effects were transient decreased heart rate, transient atrioventricular (AV) conduction blocks and a progressive reduction in lymphocycte count from baseline values (approximately 70%) that remained stable with chronic dosing. At supra-therapeutic doses (≥10-times the proposed dose of 0.5 mg/day), a dose-dependent increase in airway resistance was also observed.

3.3.2 Pharmacokinetics

Absorption

With daily oral administration of Gilenya*, at steady state, the maximum blood concentration (C_max) of fingolimod is reached at 6 hours. Steady state blood concentrations of fingolimod are reached within 1-2 months following once daily dosing and are approximately 10-times greater than the initial dose. Food intake did not alter the maximum plasma concentration (C_max) or exposure area under the curve (AUC) of fingolimod or its active metabolite (fingolimod-phosphate) but, the time to reach maximum plasma drug concentrations (T_max) was increased when Gilenya* was taken with food. Gilenya* can be taken either with or without food. The apparent absolute bioavailability of fingolimod is 93%.

Distribution

Fingolimod and its pharmacologically active metabolite (fingolimod-phosphate) were highly bound to plasma proteins in human plasma. The distribution of fingolimod in human red blood cells was high (86%), while the uptake of the active metabolite was much lower (17%).

Fingolimod was extensively distributed to the body tissues with a volume of distribution of approximately 1,200±260 L.

Metabolism

Biotransformation of fingolimod in humans occurred by three main pathways: by reversible stereoselective phosphorylation to fingolimod-phosphate [only pharmacologically active (S)-enantiomer AML629, inactive (R)-enantiomer AML627 not detected]; by ω-hydroxylation catalyzed predominantly by the CYP4F2 enzyme followed by further oxidations to form inactive metabolites; and by formation of pharmacologically inactive ceramide analogues of fingolimod.

Following single oral administration of radiolabelled fingolimod, the major fingolimod-related components in blood were fingolimod itself (23.3% of total radioactivity AUC), the active metabolite fingolimod-phosphate (10.3%), and the inactive metabolites [M3 carboxylic acid metabolite (8.3%), m²9 ceramide metabolite (8.9%), and M30 ceramide metabolite (7.3%)].

Excretion

Following oral administration, approximately 81% of the dose was slowly excreted in the urine as inactive metabolites. Fingolimod and its active metabolite AML629 were not excreted intact in the urine, but were 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 was 89%. The average apparent terminal half-life of fingolimod and fingolimod-phosphate is 6 to 9 days.

Drug Interactions

The co-administration of anti-neoplastic, immunosuppressive, or immune modulating therapies along with Gilenya* is not recommended due to the risk of additive immune system effects. Caution should be taken when switching patients from long-acting therapies with immune effects such as natalizumab or mitoxantrone. Patients should be reminded of the potential for increased risk of infection due to the risk of additive immune system effects of corticosteroids.

During and for up to 2 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.

Due to the potential for additive effects on the PR interval prolongation and heart rate decrease that occur when Gilenya* treatment is initiated, treatment initiation in patients taking PR interval prolonging and heart rate lowering drugs (e.g. antiarrhythmics, beta blockers, calcium channel blockers) should be done with caution. Because Gilenya* treatment initiation may result in QTc prolongation, use of Gilenya* in patients taking other QTc prolonging drugs should be avoided. If initiation of treatment with Gilenya* in patients taking other QTc prolonging drugs is deemed necessary, it should be done with caution after an assessment by a healthcare professional with expertise in cardiovascular disease.

CYP3A4 was shown to contribute to the in vitro metabolism of fingolimod. Caution should be observed if Gilenya* is to be used with CYP3A inhibitors.

Special Populations

Pregnant Women

Animal studies have shown reproductive toxicity including foetal loss and organ defects indicative of teratogenicity. The use of Gilenya* in women who are or may have become pregnant should only be considered if the potential benefit justifies the potential risk to the foetus.

Women of Childbearing Potential

Before starting Gilenya* treatment, women of childbearing potential should be counselled on the potential for serious risk to the foetus and the need for highly effective contraception during treatment with Gilenya*. Since it will take approximately two months to eliminate fingolimod from the body upon stopping treatment, the potential for risk to the foetus may persist and contraception should be continued during that period.

Hepatic Impairment

Gilenya* is contraindicated in patients with severe hepatic impairment (Child-Pugh Class C). Although no dose adjustments are needed in patients with mild or moderate hepatic impairment, caution should be exercised when initiating treatment in these patients.

Patients with pre-existing liver disease were excluded from MS clinical studies. Therefore, it is not known if the risk of developing elevated liver function tests, more severe liver, or other adverse events during treatment with Gilenya* is similar or increased for these patients compared to patients with normal liver function.

Renal Impairment

Caution is recommended when using Gilenya* in patients with severe renal impairment.

Pediatrics (<18 years of age)

Gilenya* is not indicated for use in pediatric patients.

Geriatrics (>65 years of age)

Clinical studies of Gilenya* did not include sufficient numbers of patients aged 65 years and over to assess efficacy and safety in this age group. Due to the greater frequency of reduced hepatic, renal, immune, pulmonary and cardiovascular function, other concomitant diseases and concomitant drug therapy in geriatric patients, treatment with Gilenya* warrants caution and may necessitate additional or more frequent monitoring than is recommended for younger adults.

3.3.3 Clinical Efficacy

The efficacy of Gilenya* was primarily assessed through two Phase III controlled studies which included a two-year, placebo-controlled study (Study D2301) and a one-year active-control study (Study D2302).

In both studies, patient demographics were representative of adult patients with the relapsing-remitting form of MS, with the majority being females (~70%) and the median age being 36-37 years (range 18-55 years for inclusion). Patients also had to meet several entrance criteria as follows: had a diagnosis of MS as defined by 2005 revised McDonald criteria with a relapsing-remitting course (at least one documented relapse during the previous year, or two documented relapses during the previous two years); had a Kurtzke Expanded Disability Status Scale score of 0 to 5.5; and were neurologically stable with no evidence of relapse or corticosteroid treatment within 30 days before randomization. Baseline disease characteristics of the patient population enrolled indicated that the median disability score was 2.0 and disease duration since diagnosis was less than 5 years for the majority (60%).

Study D2301 was a two-year multicentre, placebo-controlled study comparing the efficacy and safety of two oral doses of Gilenya* (0.5 mg and 1.25 mg) versus a matched placebo in patients with the relapsing-remitting form of MS. A total of 1,272 patients were randomized and treated with either Gilenya* 0.5 mg, Gilenya* 1.25 mg, or a placebo. The primary endpoint compared the annualized relapse rate (ARR) [at years] for each dose of Gilenya* to placebo. Secondary efficacy endpoints evaluated in this study included: the time to three-month confirmed disability progression (key secondary endpoint); the impact on other relapse- and disability progression-related outcomes e.g., time to first relapse; proportion of relapse-free patients; etc. Several magnetic resonance imaging (MRI) measures, such as the number of new or newly enlarged T2 brain lesions, number of active (T1 Gd-enhancing) brain lesions, and change in brain volume were also evaluated as secondary endpoints.

Approximately 80% of patients completed Study D2301. At the study endpoint (2 years) the ARR was significantly lower for both Gilenya* groups compared to the placebo group. Relapse reduction relative to placebo was 60% for the 1.25 mg group and 54% in the 0.5 mg group, with no significant difference between the two Gilenya* doses tested. At two years, the time to three-month confirmed disability progression was significantly delayed with both doses of Gilenya* compared to placebo. In addition, several MRI measurements such as the number (and volume) of new/newly enlarged T2 lesions, the number of T1 Gd-enhancing (active lesions), and change from baseline in brain volume at the two-year mark also showed statistically significant treatment effects for both Gilenya* doses tested compared to placebo. Other aspects of relapse, which were evaluated as secondary endpoints, were consistent with the above noted results.

Study D2302 was a one-year randomized, double-blind active-control study comparing two doses of Gilenya* (0.5 mg and 1.25 mg) to 30 µg interferon-beta-1a (IFN-beta) injected once weekly. Due to the fact that IFN-beta is administered by intramuscular injection, the study utilized a double-dummy design. The same primary efficacy endpoint previously specified in study D2301 was used for this study. Two key secondary endpoints in the D2302 study were: number of new or newly enlarged T2 lesions at Month 12; and the time to three-month confirmed disability progression. Other secondary endpoints were similar to those evaluated in Study D2301.

Approximately 89% of patients completed study D2302. Results showed that the ARR was significantly lower in both Gilenya* groups compared with the IFN-beta group, with a relative reduction in relapse rate of 52% with 0.5 mg Gilenya*. The number of new or newly enlarged T2 lesions (key secondary endpoint) was significantly lower in patients treated with Gilenya* (in both dosing groups) than in the IFN-beta treatment group. Other MRI results (secondary endpoints) showed that the number of active (T1 Gd-enhancing) lesions, the number of patients free of active lesions, and change from baseline in brain volume also showed statistically significant treatment effects with both Gilenya* doses. There was no significant difference in the time to three-month confirmed disability progression (key secondary endpoint) between either Gilenya* group and the IFN-beta group at the one-year mark. This lack of effect on disability progression is considered to be due to the twelve-month duration of the study being insufficient time for enough events to occur to observe an effect on disability progression in relapsing MS patients.

3.3.4 Clinical Safety

The clinical safety of Gilenya* was based in part on the safety results of the two Phase III pivotal clinical studies previously described in section 3.3.3 Clinical Efficacy. Additional safety information was obtained from the Gilenya* non-pivotal and pharmacology studies, the Summary of Safety Reports from MS clinical studies, as well as, the use of Gilenya* in a discontinued renal transplant drug development program. The following documentation was also consulted: transcripts from the United States Food and Drug Administration (FDA) Peripheral and Central Nervous System Advisory Committee Meeting; FDA review reports; approved US and European Union (EU) labelling; and publications identified in literature searches.

In study D2301, adverse events (AEs) reported by at least 2% of the patients in any treatment group that were at least twice as frequent with 0.5 mg Gilenya* compared to placebo included: alanine transaminase (ALT) increased, gamma-glutamyl transferase (GGT) increased; hepatic enzyme increased; bronchitis; leucopenia; lymphopenia; and migraine. Several of these AEs (bronchitis, leukopenia, lymphopenia) can be attributed to the pharmacology of Gilenya* or have been reported previously (hepatic enzyme elevations).

The overall incidence of serious AEs was similar between the treatment groups (10-13% in all treatment groups). Serious AEs reported most frequently with 1.25 mg Gilenya* included: MS relapse; epilepsy; macular oedema; abnormal liver function test; lymphopenia; and depression (all reported in ≤0.7%). Serious AEs which were reported more frequently with Gilenya* 0.5 mg included: bradycardia; urinary tract infection; chest pain; non-cardiac chest pain; basal cell carcinoma; MS relapse; and abnormal liver function test (all reported in ≤0.9%). There were no cases of macular oedema reported in the 0.5 mg Gilenya* treatment group.

All bradycardia AEs that were reported as serious occurred within six hours following the first dose administration. These bradycardia events were described as asymptomatic and not medically severe. However, hospitalization for further observation was mandated when patients did not meet discharge criteria at six hours after the first dose.

There were three deaths reported in study D2301. One death (suicide) occurred in the 1.25 mg Gilenya* group and two deaths (road traffic accident and pulmonary embolism) occurred in the placebo group. The suicide death in the 1.25 mg Gilenya* group was considered unrelated to Gilenya* by the study investigator.

Discontinuations of study drug due to AEs occurred with similar frequency in the 0.5 mg Gilenya* and placebo groups (7.5%-7.7%), but were almost twice as frequent in the 1.25 mg Gilenya* group (14.2%). Collectively, the most frequent AEs leading to discontinuation were abnormalities in liver function tests, which occurred more frequently in both Gilenya* dosing groups than in the placebo group. In the 1.25 mg Gilenya* group, 1.2% of patients discontinued due to macular oedema AEs compared to no patients in the 0.5 mg Gilenya* group or in the placebo group. Increases in ALT greater than five times the upper limit of normal (ULN) and macular oedema were protocol-mandated reasons for discontinuation of the study drug.

Although in Study D2301 macular oedema was only reported with the 1.25 mg dose (7 reports, 1.6%), in Study D2302 macular oedema AEs were confirmed with both doses of Gilenya*, which included four events (1%) with 1.25 mg Gilenya* and two events (0.5%) with 0.5 mg Gilenya*.

In study D2302, the most common AEs, serious AEs, AEs leading to discontinuation, were similar to those reported in study D2301. Serious AEs of concern which occurred in study D2302, but not in study D2301, included two reports of peripheral arterial disease and two fatal herpes infections. Both fatal herpes infections occurred in the 1.25 mg Gilenya* group following approximately eleven months of treatment. One death was due to primary disseminated varicella zoster. This patient had no history of varicella infection, had not been vaccinated against varicella zoster virus (VZV), and a few days prior to the AE onset was treated with high-dose steroid therapy for an MS relapse. The other death was due to herpes simplex encephalitis. This patient presented symptoms that were at first suspected to be caused by an MS relapse and the patient was initially treated with high-dose steroid therapy. Following a delayed diagnosis of viral encephalitis and treatment with acyclovir and therapies for cerebral oedema, the patient died. Each of the fatal herpes infections had the confounding factor of the patient receiving a short course of high-dose steroid therapy, just prior to or just after onset of the AE, which may have contributed to further immunosuppression. However, a possible role for Gilenya* in the occurrence or exacerbation of these AEs cannot be excluded. The VZV vaccine is highly effective for immunizing against VZV infections. The fatal case of varicella zoster led to the prominent warning in the Product Monograph stating that VZV immunization prior to initiating Gilenya* treatment, is an appropriate precaution to be taken in patients who are sero-negative for VZV.

The AEs which have been consistently observed with Gilenya* are primarily attributed to its pharmacology and/or are known to occur with this drug. Key safety issues which were studied by the sponsor in clinical pharmacology safety studies and were further evaluated in the Phase III safety and efficacy clinical studies (D2301 & D2302) included: infections; lymphopenia; cardiovascular effects; vascular effects; respiratory effects; macular oedema; hepatic enzyme elevations and impairment; and malignancies.

Infections

In the safety dataset for all MS controlled clinical studies, there was little difference in the overall frequency of infections reported with Gilenya* compared to control treatments. The types of infections that were reported more frequently with Gilenya* than placebo or IFN-beta were restricted mainly to lower respiratory tract and lung infections, primarily bronchitis and some cases of pneumonia. There were few reports of severe or serious infections. Individual studies showed slightly higher frequencies of herpes virus infection or herpes zoster AEs with Gilenya*, and two fatal primary herpes infections were reported in Study D2302. Although the overall dataset of controlled clinical studies did not show a consistent increased rate of herpes infections with Gilenya*, the two fatal herpes infections in patients treated with the 1.25 mg dose suggest a potential increased risk for serious herpes infections with Gilenya* which cannot be excluded.

The clinical study data suggest that Gilenya* was not associated with an increased rate of most types of infections. However, because one of the two fatal herpes infections that occurred in Study D2302 was due to primary varicella, the VZV vaccine is strongly recommended prior to initiating treatment in patients with no previous VZV infections or vaccination. In addition data from a clinical pharmacology study indicated that antibody-mediated primary immune responses (i.e., to new pathogens) can be reduced during treatment with 0.5 mg and 1.25 mg Gilenya*. This study also showed that during Gilenya* treatment a T-cell-mediated primary immune response could occur, but that a greater proportion of patients treated with Gilenya* compared to placebo lost the ability to respond to a second challenge with the same antigen four weeks following first exposure. This indicates that although antibody-mediated and cell-mediated primary immune responses could occur during Gilenya* treatment, they may be less effective, and this has implications both for responding to infectious agents and for developing immunity to a pathogen when vaccinated. Therefore, physicians and patients should be aware that during treatment and for approximately 2 months after discontinuing treatment, there is a potentially increased risk of developing infections, immunizations with live vaccines is not recommended because there is the risk of developing the infection that the vaccine is supposed to protect from, and non-live vaccines may be less effective. Gilenya* treatment should not be initiated when there is an active severe infection or in patients who are immunocompromised.

Lymphopenia

Gilenya* induced a rapid decline in peripheral blood lymphocyte counts within the first few hours of dose administration, with counts reduced to 50% of the baseline values after 8 hours. With chronic daily dosing lymphocyte counts continued to decrease over the first two weeks and reached a low point (~0.5 x 10⁹/L) that is approximately 30% of baseline values. In the clinical studies, lymphocyte counts below 0.2 x 10⁹/L were considered clinically notable values, for which treatment interruption was to be considered. These values were reached at least once in the two-year study (D2301) by 18% of patients administered 0.5 mg Gilenya* and 4% of patients administered 0.5 mg Gilenya* had lymphocyte counts below 0.2 x 10⁹/L for at least 180 days. A complete blood cell count should be obtained before initiating treatment to ensure a patient is not lymphopenic, and may be checked during an active infection. Recovery of lymphocyte counts to baseline levels typically takes approximately two months following treatment discontinuation, during which time the immune effects may still be present and the patient at an increased risk for infections. During this time, initiating treatment with other immunosuppressive therapies would warrant extreme caution.

Cardiovascular Effects

Gilenya* has effects on cardiac electrophysiology and blood pressure that have implications for cardiovascular safety. The effects on cardiac electrophysiology include: heart rate decreases (bradycardia); prolongation of the PR interval [atrioventricular (AV) block]; and prolongation of the QT interval. These three effects are most prominent during treatment initiation and attenuate with continued dosing.

With the first dose, 0.5 mg Gilenya* caused a decrease in heart rate that was maximal at approximately 4-5 hours post-dose, with an average decrease of 7-13 bpm. With chronic daily dosing, the heart rate returned to baseline gradually over approximately one month. Bradycardia AEs were reported more frequently within the Gilenya* treatment groups than in the controlled treatment groups and almost all of these events in the Gilenya* groups occurred on the first day of treatment. Most bradycardia AEs were asymptomatic and detected because of the protocol-mandated electrocardiograph (ECG) at 6 hours following first-dose administration. Patients who had symptoms reported dizziness, fatigue, palpitations, dyspnea, arrhythmia, and chest pain or chest discomfort.

The initiation of Gilenya* treatment was also associated with PR interval prolongation and AV block. The maximum increase in PR interval in a study of healthy volunteers was shown to be 19 ms with 1.25 mg and 5 mg doses of Gilenya*, and occurred approximately 6-hours post-dose. After seven days of treatment, the prolonging effect on PR interval diminished. In Phase III clinical studies, 1^st degree AV block was detected by the ECG at 6 hours following the first dose in 4.7% of patients administered 0.5 mg Gilenya* compared to 1.5% of patients administered a placebo. Second degree AV block (Mobitz type 1) was detected in 0.2% of patients administered Gilenya* and no patients administered a placebo. These conduction abnormalities were typically asymptomatic and resolved within 24 hours of treatment. Bradycardia and AV block AEs that were reported as serious AEs typically were not serious or severe. Rather, the classification as serious AEs reflected hospitalization for continued observation when discharge criteria were not met with respect to heart rate and other ECG findings at 6 hours after the first dose.

Gilenya* has also been shown to cause QTc prolongation. A thorough QT study, which evaluated doses of 1.25 mg and 2.5 mg (2.5 and 5 times the recommended therapeutic dose) at steady-state showed that Gilenya* was associated with a statistically significant QTc prolongation on Day 7, with a maximum effect of approximately 11 ms at 6 hours post-dosing, for both doses. In the two-year Phase III clinical study (D2301), QTcF intervals (QT interval corrected using Fridericia's formula) were prolonged by 7-8 ms in the 0.5 and 1.25 mg Gilenya* groups compared to 2.5 ms in the placebo group. More patients had QTcF increases of 30-60 ms compared to baseline in the Gilenya* groups (6.6%-7.5%) than in the placebo group (2.4%). The effect of Gilenya* on the QT interval diminished by one month of treatment. In the MS clinical studies, clinically relevant effects on prolongation of the QTc interval have not been observed.

Patients with low resting heart rate (<55 bpm and those with history of syncope, sick sinus syndrome, 2^nd-degree or higher AV block, ischemic heart disease, or congestive heart failure or other significant cardiovascular disease were excluded from the Phase III clinical studies. Before initiating treatment in such patients, advice from a healthcare professional with expertise in cardiovascular disease is recommended. There are limited data from clinical studies with patients taking Gilenya* while being treated with beta-blockers, calcium channel blockers or other heart rate-lowering medications. Therefore, caution should also be exercised when initiating treatment in patients on beta blockers, or other substances which may decrease heart rate because of the potential for additive effects on heart rate. As a precaution it is recommended that an ECG be obtained prior to initiating treatment and that all patients be observed for at least 6 hours in the clinic after receiving the first dose, with periodic assessments of heart rate.

Gilenya* is associated with QTc interval prolongation. Patients with risk factors for QT prolongation were excluded from the Phase III clinical studies and treatment with QT prolonging drugs should be avoided in these patients because the risk of QT prolongation and torsade de pointes is expected to be greater. Since Gilenya* produces a moderate prolongation of the QT interval, it is recommended that if treatment is deemed necessary for patients on QT prolonging drugs, treatment should be initiated in consultation with a healthcare professional with expertise in cardiovascular disease and a follow-up ECG should be considered. Known Class Ia and Class III anti-arrhythmic drugs have been associated with torsade de pointes in patients with bradycardia, Gilenya* should not be co-administered with these drugs.

Vascular Effects

In the two-year Phase III study (D2301), small decreases in mean systolic and diastolic blood pressure (4-5 mm Hg maximal decrease) occurred at 4 hours after the first dose of Gilenya* (0.5 mg and 1.25 mg). With chronic daily dosing, mean systolic and diastolic blood pressure increased approximately 1-2 mm Hg beginning at approximately 2 months and persisted throughout the 24 months of treatment. Hypertension was reported as an AE more frequently with Gilenya* than with placebo (6.1% for 0.5 mg Gilenya* versus 3.8% placebo). This suggests that blood pressure should be monitored regularly during treatment.

Serious vascular AEs, which were reported in MS patients receiving higher doses of Gilenya* (1.25 mg and 5 mg) in clinical studies, included: ischemic and hemorrhagic strokes [number (n) = 3 - while on study drug]; peripheral arterial occlusive disease (n = 2); and posterior reversible encephalopathy syndrome (n = 1).

Respiratory Effects

In studies using doses higher than the recommend dose of 0.5 mg, the initiation of Gilenya* treatment was associated with a small dose-dependent decrease in airway resistance that was detected with pulmonary function tests (PFTs) as a decrease in forced expiratory volume in 1 second (FEV₁), which was maintained with chronic treatment. In the Phase II MS clinical study, respiratory AEs (mainly dyspnea) were more common with the 5 mg dose than with 1.25 mg, or placebo.

With the lower doses of Gilenya* used in the Phase III clinical studies, decreases from baseline in PFTs including FEV₁, and diffusion capacity for carbon monoxide (DLCO) were more frequent with Gilenya* (dose-dependent) compared to control treatments. The effects on FEV₁ changes were reversible after treatment discontinuation. Pulmonary function changes were not always associated with clinical symptoms. Cough and dyspnea were the most frequently reported respiratory AEs in the Gilenya* groups in the Phase III studies, and were reported at slightly higher frequencies with Gilenya* compared to the control treatments. Serious respiratory-related AEs that were not associated with infections, which occurred more frequently with Gilenya* (1.25 mg only) than control treatments were infrequent and included dyspnea, pleurisy, and asthma. A safety pharmacology study was conducted in MS patients with moderate asthma who were treated for 10 days with 0.5 mg, 1.25 mg, 2.5 mg Gilenya* or placebo. Although the 0.5 mg dose was associated with a decrease in FEV₁ and a 2-fold increase in the use of short-acting asthma rescue medication, these effects were not statistically significantly different from those in the placebo group. However, because Gilenya* had not reached steady state concentrations in this study, the results of this study do not exclude the potential for significant effects on pulmonary function in asthmatic patients receiving chronic Gilenya* treatment. Patients with compromised respiratory function (pulmonary fibrosis, active pulmonary disease, abnormal PFTs) were excluded from the MS clinical studies. Therefore, caution is warranted if Gilenya* is used in patients with respiratory diseases and evaluation of lung function is recommended when clinically indicated.

Macular Oedema

Gilenya* causes dose-dependent macular oedema. This was initially observed in the discontinued renal transplantation clinical program, which included patients with diabetes, who are at greater risk of developing macular oedema. Macular oedema was twice as frequent in patients treated with Gilenya* (diabetic and non-diabetic) compared to patients in the control group. The rate of macular oedema AEs was 7 times greater in diabetic patients compared to non-diabetic patients regardless of treatment received (i.e., Gilenya* or mycophenolate mofetil).

Patients with macular oedema and/or diabetes were excluded from the MS clinical studies and these studies used lower doses of Gilenya* than the renal transplant studies. In the Phase III studies patients had a complete ophthalmologic examination that included examination of central foveal thickness at screening and at the study endpoint. There were several regular ophthalmologic examinations in between. The frequency of macular oedema AEs in the MS clinical studies has been low (<2%, 0.4% for the 0.5 mg dose) and is dose-dependent. In most cases, the macular oedema was detected at a scheduled ophthalmologic examination, between 1 and 3 months, after starting Gilenya* treatment and was usually associated with reduced vis

ual acuity. Macular oedema resolved within 1 to 6 months for most patients following protocol-mandated discontinuation of treatment with Gilenya*. Due to the risk of macular oedema, it is recommended that all patients have an ophthalmologic evaluation 3-4 months after treatment initiation and that an evaluation of the macula be performed any time a patient reports vision disturbances. For patients with diabetes (excluded from the clinical studies conducted) or a history of uveitis or macular oedema, ophthalmologic evaluations are recommended prior to initiating treatment and regularly during treatment. Discontinuation of treatment is recommended when macular oedema occurs.

Hepatic Enzyme Elevations and Hepatic Impairment

In the Phase III clinical studies asymptomatic elevations in hepatic enzyme [alanine aminotransferase (ALAT), aspartate transaminiase (AST), and gamma-glutamyl transferase (GGT)] were observed as early as 2 weeks after initiating treatment in both Gilenya* groups, and reached maximum levels at Month 6-9 for ALT, at Month 2 for AST, at Month 9-12 for GGT and remained stable thereafter. In the two-year (D2301) study increases in ALT ≥3 x ULN were seen in 8.5% - 12.5% of patients treated with Gilenya* compared to 1.7% of those that received placebo. Alanine aminotransferase elevations ≥5 x ULN were seen in 1.9% - 3.1% of patients treated with Gilenya* compared to 1.0% of those that received placebo. Findings were similar, but of much lower frequency, for AST. Treatment was discontinued in patients experiencing elevations ≥5 x ULN. Hepatic enzyme elevations were reversible after Gilenya* discontinuation and recurrences of liver enzyme elevations were reported upon re-challenge in some patients. Bilirubin and serum alkaline phosphatase levels remained stable and there were no patients meeting Hy's law criteria for hepatotoxicity. Although hepatic enzyme elevations were asymptomatic in the clinical studies, patients were monitored at 3-month intervals. Hepatic enzymes should be checked prior to initiating treatment with Gilenya*, at 3-month intervals for the first year of treatment and periodically thereafter. Treatment interruption is recommended when there is confirmation of elevations above 5 x ULN and if patients present symptoms.

The pharmacokinetics of a single-dose of fingolimod (1 or 5 mg) was assessed in patients with mild, moderate, and severe hepatic impairment. There was no change in the C_max of fingolimod, but exposure AUC was increased by 12%, 44% and 103% in mild, moderate and severe impairment, respectively. Elimination half-life was prolonged by 49-50% with moderate and severe hepatic impairment. The pharmacokinetics of fingolimod-phosphate (active metabolite) were not evaluated, but based on other pharmacokinetic studies the elimination half-life of the active metabolite is similar to that of fingolimod and is also expected to be prolonged in moderate and severe hepatic impairment. The findings of increased fingolimod exposure and a 4-fold delay in recovery of lymphocyte counts that was observed in severe hepatic impairment compared to normal hepatic function, leads to contraindication in patients with severe hepatic impairment (Child-Pugh class C). Gilenya* should be used with caution in patients with mild and moderate hepatic impairment (Child-Pugh classes A and B) and, close monitoring of these patients is recommended because it is not known if patients with mild or moderate hepatic impairment are at increased risk of developing elevated liver function tests, more severe liver injury or other adverse events during treatment with Gilenya*.

Malignancies

Due to the reduction in circulating lymphocytes produced by Gilenya* and the potential effect on immunosurveillance, the risk of malignancies is a concern. The available data indicate that there have been a couple of cases of lymphoma in MS patients who were treated with higher doses of Gilenya*. An increased incidence of lymphoma was also reported in the two-year mouse carcinogenicity study.

Basal cell carcinoma is the most common skin cancer reported in the general population and the incidence is elevated 10-16 fold in solid organ transplant patients receiving immunosuppressive therapies compared to the non-transplanted population. In the entire MS dataset from completed controlled clinical studies, basal cell carcinoma was reported in 0.8% of patients on 0.5 mg Gilenya* compared to 0.6% of patients on placebo and 0.2% of patients on IFN-beta (approximately half as many patients on placebo and IFN-beta compared to Gilenya*, and duration of exposure to IFN-beta was approximately half that of Gilenya*). Squamous cell carcinoma is also disproportionately increased in solid organ transplant patients receiving immunosuppressive therapies, such that there is a 100-fold greater incidence of squamous cell carcinoma in solid organ transplant patients compared to the non-transplanted population. In the entire MS dataset from completed controlled clinical studies, squamous cell carcinoma has been reported in 1 patient treated with 5 mg fingolimod and 1 patient treated with IFN-beta. Additional cases of squamous cell carcinoma have been reported in an ongoing Phase III MS clinical study, but the treatments received in these cases remain blinded. Because many patients in the Gilenya* Phase III MS clinical studies had their first dermatologic examination after several months of treatment, without having had a dermatologic examination prior to starting treatment, it was not known in many cases whether a skin lesion was present prior to initiating treatment. There are no long term, controlled data from MS patients to characterize the risk of malignancies with Gilenya* at this time.

3.3.5 Additional Issues

The Risk Management Plan (RMP) submitted by the sponsor was found to be deficient regarding the details of the protocols provided for the worldwide post-approval safety study and the worldwide, prospective voluntary, pregnancy registry that will be established. The sponsor has provided revised protocols for each of these studies and responses to address other minor deficiencies identified in the RMP, which will be followed up by the Marketed Pharmaceuticals and Medical Devices Bureau (MPMDB) of the Marketed Health Products Directorate (MHPD). The sponsor's proposed Product Monograph, which is the primary risk mitigation tool, was revised extensively by Health Canada to clearly identify, for prescribers and patients, the nature and seriousness of known risks associated with Gilenya* treatment.