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Keywords:

  • multiple sclerosis;
  • fingolimod;
  • guideline

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Fingolimod
  5. Present position in MS clinic
  6. How to use fingolimod in MS clinic
  7. Adverse events
  8. Conclusion
  9. References
  10. Appendix: Japanese Guidelines for the Use of Fingolimod in MS Patients

Fingolimod functions as a modulator of sphingosine-1-phosphate (S1P) receptors expressed on the surface of T and B lymphocytes, leading to their internalization. Loss of S1P receptors results in sequestration of central memory T cells enriched by Th17 cells in lymph nodes. After successful treatment of an animal model of multiple sclerosis (MS), clinical trials of oral fingolimod in patients with relapsing-remitting MS showed a 60% reduction in the annualized rate of relapse. The United States Food and Drug Administration approved fingolimod as a first-line drug for MS treatment in 2010, and data have been accumulated thereafter. However, MS experts recommend that the drug should remain as a second-line option, because the long-term risks for infection and malignancy have not been fully elucidated. Also, because of different genetic backgrounds, Asian MS patients might require special attention regarding other infectious agents and secondary cancer as compared with those reported in Caucasian patients. Furthermore, some Japanese patients who developed severe symptoms were later shown to be positive for the anti-aquaporin-4 antibody. In addition, reports of some Western MS patients have noted worsening after initiation, as well as discontinuation of fingolimod treatment. Finally, the optic spinal type of MS and neuromyelitis optica spectrum disorders are more prevalent in Asian than Western countries. Thus, establishment of criteria for determining which Asian MS patients would benefit from fingolimod treatment is mandatory.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Fingolimod
  5. Present position in MS clinic
  6. How to use fingolimod in MS clinic
  7. Adverse events
  8. Conclusion
  9. References
  10. Appendix: Japanese Guidelines for the Use of Fingolimod in MS Patients

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) in which autoimmune mechanisms have been implicated. It is important to prevent inflammatory events in the CNS, as they are closely associated with demyelination, as well as axonal damage leading to brain atrophy during a long-term disease course.[1] Interferon beta (IFN-β) was the first disease-modifying drug (DMD) found to reduce clinically apparent disease relapses (by 30%), as well as radiological disease activity more efficaciously as compared with a placebo group. Another DMD that followed IFN-β was glatiramer acetate; however, only some MS patients can achieve disease activity free status with these DMD.[2] Under these circumstances, fingolimod became available on the market after approval from the United States Food and Drug Administration (FDA) in 2010 as the first oral drug for reducing the frequency of clinical exacerbations and delaying the progression of physical disability in patients with relapsing-remitting MS (RRMS).[3]

In the Asia–Pacific region, approval of fingolimod, also known as Imusera and Gilenya, was delayed for 1–2 years, after which approval was obtained in September 2011, and the drug became available 2 months later in Japan. During the next 2 years, more than 2000 patients with MS were reported to have been administered the drug. Therefore, this is considered an appropriate time to overview the Japanese guidelines for MS therapy, especially in reference to usage of fingolimod.[4] In the present review article, the English version of the Japanese guidelines describing use of fingolimod for MS is included as an appendix.

Fingolimod

  1. Top of page
  2. Abstract
  3. Introduction
  4. Fingolimod
  5. Present position in MS clinic
  6. How to use fingolimod in MS clinic
  7. Adverse events
  8. Conclusion
  9. References
  10. Appendix: Japanese Guidelines for the Use of Fingolimod in MS Patients

Fingolimod is a compound isolated from Isaria sinclairii, which functions as a modulator of the sphingosine-1-phosphate (S1P) receptor, leading to internalization of S1P receptors expressed on the surfaces of T and B cells. As both of these lymphocytes usually egress from secondary lymphoid organs to systemic circulation based on the difference in level of S1P, which is low in lymph nodes and relatively high in plasma, the loss of S1P receptors on lymphocytes results in their unresponsiveness to the gradient of S1P, resulting in sequestration in lymph nodes.[3] T cells are more affected than B cells,[5] whereas CD4 cells in blood appear to be much more decreased than CD8 cells.[6]

After successful treatment of an animal model of MS with experimental autoimmune encephalomyelitis (EAE) using fingolimod,[5, 7] clinical trials for patients with RRMS showed a nearly 60% reduction in annualized relapse rate (ARR).[3, 7] In addition, a double-blind parallel group phase II study of this drug using 171 Japanese patients with relapsing MS also showed its significant efficacy in reducing the number of newly developed gadolinium (Gd)-enhanced lesions shown by magnetic resonance imaging (MRI) of the brain during a 6-month period.[8] ARR in patients treated with a 0.5-mg dose of fingolimod was significantly reduced by 49% as compared with the placebo group (0.50 vs 0.99).[8] These findings suggest that oral fingolimod at 0.5 mg provides results in MS patients in Asia comparable with those seen in Western countries.

Fingolimod might also be effective in patients who are poor responders to first-line DMD, as substantial proportions of patients participating in the Trial Assessing Injectable Interferon versus FTY720 Oral in Relapsing-Remitting Multiple Sclerosis (TRANSFORMS) study had previously been treated with IFN-β (approximately 50%) or glatiramer acetate (approximately 15%).[9] However, the major concern with regard to this drug is that many aspects of its pharmacological actions and long-term adverse effects remain unknown.

Present position in MS clinic

  1. Top of page
  2. Abstract
  3. Introduction
  4. Fingolimod
  5. Present position in MS clinic
  6. How to use fingolimod in MS clinic
  7. Adverse events
  8. Conclusion
  9. References
  10. Appendix: Japanese Guidelines for the Use of Fingolimod in MS Patients

Although the FDA approved fingolimod as a 3first-line treatment for RRMS in September 2010, the European Medicines Agency (EMA) approved its use as a second-line drug in March 2011. Meanwhile, MS experts in the USA proposed that the drug should remain as a second-line option because of unforeseen long-term risks for infection and malignancy.[3] Furthermore, the Canadian MS working group also placed this drug as a second-line treatment option.[10] Therefore, the general consensus in Western countries seems to be that fingolimod has the same position as the anti-CD49d monoclonal antibody natalizumab for treatment of RRMS.[3, 10] According to the Japanese guidelines for MS (see Appendix Japanese Guidelines for the Use of Fingolimod in MS Patients for fingolimod), the drug should be used as a second-line option in patients showing only a suboptimal response to IFN-β1a and/or IFN-β1b, or in those with intolerable adverse events associated with those treatments or very high disease activity.[4]

It is difficult to select suboptimal responders for first-line DMD. However, the following criterion for identification of highly active RRMS patients as possible recipients of fingolimod therapy has been proposed by the EMA: At least one relapse in the previous year while on therapy along with ≥9 hyperintensity lesions or ≥1 Gd-enhanced lesions on brain MR images.[11] Non-responders are also defined as those who showed an unchanged or increased relapse rate or ongoing severe relapses, as compared with the previous year, or those experiencing ≥2 disabling relapses during a 1-year follow-up period along with ≥1 Gd-enhanced lesions or a significant increase in T2 lesion load as compared with findings in a recent brain MRI examination.[11] Another criterion for introducing fingolimod therapy is the presence of permanent neurological deficits along with ≥1 relapses or the development of new white matter lesions despite the use of the first-line DMDs in 1 year.[3]

No indications of fingolimod for children with MS have been established.[3] Also, the drug is contraindicated for pregnant women, and this possibility must be checked before initial administration.[4] Female patients should continue contraception use while on this therapy and for at least 2 months after discontinuation of the drug. In addition, patients should avoid breast-feeding while taking this drug.[3, 4]

How to use fingolimod in MS clinic

  1. Top of page
  2. Abstract
  3. Introduction
  4. Fingolimod
  5. Present position in MS clinic
  6. How to use fingolimod in MS clinic
  7. Adverse events
  8. Conclusion
  9. References
  10. Appendix: Japanese Guidelines for the Use of Fingolimod in MS Patients

When a physician considers that a second-line treatment will be necessary for a patient with RRMS, a 0.5-mg dose of fingolimod taken orally once a day is the treatment of choice in Japan, as natalizumab is not yet available at the time of writing (November 2013). Physicians should obtain full informed consent after explaining the risks and benefits of this treatment, and after carrying out laboratory testing (especially total and differential leukocyte counts, and aminotransferase levels) and an electrocardiography (ECG) examination.[3]

According to lessons learned in two large-scale phase III trials, the FTY720 Research Evaluating Effects of Daily Oral Therapy in Multiple Sclerosis (FREEDOMS)[12] and TRANSFORMS[9] studies, as well as a Japanese phase II clinical trial,[8] bradycardia and atrioventricular (AV) block are major adverse events that can occur within 1 h after administration of fingolimod. Heart rate usually reaches its nadir within 6 h, with a mean decrease of 10 b.p.m. This phenomenon is considered to be due to modulation of S1P1 and S1P3 receptor activities on atrial myocytes.[7] Such a decrease in heart rate can last for several days. Therefore, heart rate and blood pressure should be measured every hour for at least 6 h after the initial administration of fingolimod, and then preferably for an additional 18 h. A 12-lead ECG should also be carried out before and at 6 h, and then continuously monitored for 24 h after initial administration. If severe bradycardia is documented during monitoring, additional administration of the drug should be avoided.[3] As sudden death was reported within 24 h of administration, it is recommended to keep patients hospitalized for several days while monitoring their vital signs and ECG. Special attention should also be given to patients with second-degree or higher AV block, sick sinus syndrome, ischemic heart diseases or congestive heart failure, or those with decreased heart rate under treatment with β-blockers, calcium antagonists or digitalis drug, or patients with a history of syncope or those showing hypokalemia, congenital long QT syndrome, or QT prolongation. Furthermore, it must be noted that fingolimod is contraindicated for patients who are taking class Ia (quinidine, procainamide) or class III (amiodarone, sotalol) anti-arrhythmia drugs.[4] Management of acute and early side-effects encountered after introducing fingolimod is summarized in Table 1.

Table 1. Requirements at initiation of fingolimod treatment for inpatients
  1. a

    Medications, diabetes mellitus, uveitis, hepatitis, cardiovascular events, pulmonary disease, pregnancy.

  2. AQP4, Aquaporin-4; ECG, electrocardiography.

Before initial doseHistory takinga
Electrocardiography
Blood pressure and pulse rate (vital signs)
Complete blood cell count
Liver function test
Varicella zoster virus titer
Test for anti-AQP4 antibody
Spirometry when necessary
Ophthalmological assessment
Dermatological assessment
First 6 h after initial doseVital signs (every hour)
ECG at 6 h
6–24 h (preferably more) after initial doseVital signs (at appropriate timing)
ECG (continuous real-time monitoring)

Patients can be discharged if all of the following criteria are met: (i) pulse rate exceeds 80% of baseline (45 b.p.m. or preferably more); (ii) pulse rate exceeds the minimum value observed within 6 h after administration; and (iii) the patient has no bradyarrhythmia-related signs or symptoms including dizziness, fatigue, or palpitations.[4] The patient should then be examined every month in the outpatient clinic with regard to response to treatment and presence of adverse events.[3]

Adverse events

  1. Top of page
  2. Abstract
  3. Introduction
  4. Fingolimod
  5. Present position in MS clinic
  6. How to use fingolimod in MS clinic
  7. Adverse events
  8. Conclusion
  9. References
  10. Appendix: Japanese Guidelines for the Use of Fingolimod in MS Patients

During administration of fingolimod, the following five risks must be cautiously managed: (i) bradyarrhythmia and sudden death after the initial dose; (ii) infections; (iii) macular edema; (iv) abnormal hepatic function; and v) potential harmful effects toward pregnancy. How to cope with (i) and (v) is described in the previous section, whereas management of the remaining three risks and other potential complications are described following. A recommended plan for follow-up examinations in the clinic is summarized in Table 2.

Table 2. Check list during fingolimod therapy for outpatients
Neurological examination (monthly)
Complete blood cell count (15 days, 1, 2, 3 months, then every 3 months)
Liver function test (15 days, 1, 2, 3 months, then every 3 months)
Spirometry if necessary (1 month)
Ophthalmological assessment (1, 3, 6 months, then every 6 months)
Dermatological assessment (annually)

Infection

Because fingolimod causes a decrease in circulating lymphocytes to some extent, infections (bacterial, fungal or viral) might occur during therapy. In a Japanese clinical trial,[8] the incidence of infection was higher with fingolimod (0.5 mg, 49.1%; 1.25 mg, 57.4%) than with a placebo (40.4%). Upper respiratory infections including nasopharyngitis and pharyngitis occurred in the placebo (36.8%), as well as the 0.5-mg fingolimod (45.6%) and 1.25-mg fingolimod (44.4%) groups. In contrast, some patients suffered from bronchitis while on therapy in the fingolimod groups (1.8% and 5.6% with doses of 0.5 and 1.25 mg, respectively), whereas none in the placebo group were noted.[8] According to a dataset obtained in overseas trials involving more than 2000 participants, the frequency of infection was higher in patients when the lymphocyte count decreased to <200/mm3 (61.6%) as compared with in those with a lymphocyte count >200/mm3, though that was equivalent to the rate in the placebo group (58.6%).[4] It is recommended that fingolimod be temporarily discontinued when a patient shows a lymphocyte count <200/mm3 twice in 2 weeks, and they should be followed until the count returns to normal (>600/mm3) for considering resumption of therapy.[3, 4]

Administration of fingolimod has been known to result in entrapment of naïve T cells and central memory T cells (TCM) in lymph nodes because of their expression of CCR7 on the cell surface, whereas effector memory T cells (TEM) that lack CCR7 are not affected.[13] The beneficial effects of fingolimod in preventing MS relapse could be as a result of a decrease in IL-17-producing Th17 cells, which have been found to be enriched in the TCM population,[14] and an increase in CD4+CD25+ regulatory T cells (Treg).[15] In contrast, the long-term consequences of those effects rendered by fingolimod are not fully understood in regard to infectious events and malignancy.[3]

Fingolimod does not suppress the activity of lymphocytes, thus theoretically it also does not affect primary immune responses to pathogens.[7] Nevertheless, fatal infections have been reported with this therapy, including disseminated herpes zoster virus infection, herpes simplex virus encephalitis and progressive multifocal leukoencephalopathy.[3, 4, 7] In addition, one patient died from large B-cell lymphoma associated with Epstein–Barr virus infection.[4] Therefore, fingolimod is contraindicated for patients suffering from serious infection and, when that occurs, the drug must be immediately discontinued and appropriate treatments begun.[4] In this regard, it is recommended that the Varicella zoster antibody titer should be checked before initiating fingolimod therapy, with vaccination considered 1 month before therapy if the result is negative.[3, 4] Furthermore, use of live vaccines must be avoided during fingolimod treatment and until normalization of lymphocyte count is achieved after withdrawal of this therapy.[4] As fingolimod inhibits recruitment of lymphocytes to inflammatory lesions, the drug should be used with caution for patients who are positive for the anti-HIV or anti-HTLV-1 antibody, as well as carriers of the type B or C hepatitis virus.[4]

Macular edema

Macular edema can appear in the early stage (3–4 months) of fingolimod therapy. That frequency was <1% in patients taking a 0.5-mg dose in an overseas trial,[9] with a comparable result reported in Japanese patients. Macular edema is mostly asymptomatic, though some patients have experienced blurred vision or reduced visual acuity.[4] Patients with diabetes mellitus and those with a history of uveitis have increased risk. All patients must be examined by an ophthalmologist, preferably using optical coherence tomography, before beginning and then periodically during fingolimod therapy (after 1, 3 and 6 months of treatment, then every 6 months thereafter).[3, 4] Macular edema will likely be resolved within months after discontinuation of therapy.[3]

Abnormal hepatic function

Aminotransferase, γ-GTP and bilirubin levels might become elevated with administration of fingolimod. In clinical trial results in Japan, the incidence rate of abnormal liver function was 31.1%. Most of those incidents occurred within 3–4 months after initiation of fingolimod therapy, though some occurred even later. Thus, liver function tests should be carried out at baseline and periodically during therapy (after 15 days, 1, 2, 3 and 6 months of treatment, and every 3 months thereafter). Fingolimod should be carefully administered to patients with a current or previous history of hepatic dysfunction, and avoided in those with active viral hepatitis.[4]

Other side-effects and complications

Some patients might experience hypertension during fingolimod therapy.[3] As administration of the drug can cause a mild decrease in lung function during the first month because of the effect on S1P3,[7] spirometry should be carried out before initiating treatment if pulmonary risk factors are present.[3] In overseas trials carried out over a period of 12–24 months, the reported neoplasms were basal-cell carcinoma, melanoma, squamous cell carcinoma and Bowen's disease of the skin, as well as breast cancer, cervical carcinoma, endometrial cancer and prostate cancer.[9, 12] Therefore, annual referrals to a dermatologist before and after initiating fingolimod therapy are recommended.[3]

In addition, case reports of unexpected outcomes and complications seen with fingolimod therapy can provide an opportunity to share important clinical experiences,[16] as this therapy could paradoxically enhance disease activity[17] or cause transformation of the disease, including hemorrhagic encephalitis[18] and tumefactive MS.[19-21] It has been reported that transition of therapy from natalizumab to fingolimod might precipitate MS patients developing highly active disease.[22, 23] Furthermore, cessation of fingolimod treatment can induce a marked increase in Gd-enhancing lesions on MR images.[24, 25] The variety of possible clinical manifestations provide warning of the uncertainty of overall changes in the immune system brought about with fingolimod therapy. Reducing Th17 cells in the blood by its administration might also enhance the activity of Th1 cells, which are a main population related to inflammatory events in some patients.[26] Another possibility is that fingolimod inhibits the function of Treg,[27] which could play a crucial role in suppressing autoimmunity in a subpopulation of patients.

Putting the guidelines into practice in Japan

As there are no established international guidelines for the use of fingolimod in patients with MS,[3] an attempt to publish Japanese guidelines for this purpose is quite challenging. However, the contents of the present article, as well as those of the English translation of the guidelines attached as an appendix, are thought to be reasonable when considering the current status of MS treatment options available in Japan and recent advances in MS research.[1, 2] Nevertheless, MS expert opinions state that patients should discontinue immunosuppressive drugs or treatment with natalizumab at least 3 months (preferably 6 months for those who received long-term treatment with intravenous mitoxantrone or cyclophosphamide) before the initiation of fingolimod therapy, and other treatment options for MS should be postponed until 2 months after withdrawal of fingolimod.[3]

It is also important for physicians to always be alert to the possibility of adverse events and complications characteristic to Japanese and Asian patients with MS, because of the differences in genetic backgrounds and environmental factors. In this regard, special attention should be given to different types of neoplasms and infectious agents as compared with those reported in overseas trials. For example, although there was no patient with skin cancer, one case of malignant lymphoma was reported in the previously mentioned Japanese clinical trial.[4] Furthermore, it is important to note that a substantial proportion of patients with MS show optic spinal types of manifestations,[28] and patients with neuromyelitis optica spectrum disorders are more prevalent in Japan and Asia than in Western countries.[29] One lesson from the clinical trial in Japan is that testing for the anti-aquaporin-4 (AQP4) antibody using a sensitive assay system is mandatory before initiation of fingolimod therapy, as patients who showed marked exacerbation of the disease shortly after beginning this treatment were later found to be positive for this antibody.[4] Therefore, fingolimod should not be given to patients possessing the anti-AQP4 antibody,[4] though its causal relationship to adverse events is not known. It should also be kept in mind that the efficacy and safety of fingolimod have not been established for patients who once showed long spinal cord lesions extending more than three vertebral segments,[4] as such patients were excluded from the Japanese clinical trial.[8]

Conclusion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Fingolimod
  5. Present position in MS clinic
  6. How to use fingolimod in MS clinic
  7. Adverse events
  8. Conclusion
  9. References
  10. Appendix: Japanese Guidelines for the Use of Fingolimod in MS Patients

Although oral fingolimod is a promising therapy for suppressing MS activity, it should remain as a second-line treatment option until more is known about all aspects of its pharmacological effects on the immune system and other organs, including the CNS.[7] In Japan and other Asian countries, patients should be cautiously selected for this therapy by checking for the presence of the anti-AQP4 antibody, as well as present or past history of long spinal cord lesions on MR images.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Fingolimod
  5. Present position in MS clinic
  6. How to use fingolimod in MS clinic
  7. Adverse events
  8. Conclusion
  9. References
  10. Appendix: Japanese Guidelines for the Use of Fingolimod in MS Patients

Appendix: Japanese Guidelines for the Use of Fingolimod in MS Patients

  1. Top of page
  2. Abstract
  3. Introduction
  4. Fingolimod
  5. Present position in MS clinic
  6. How to use fingolimod in MS clinic
  7. Adverse events
  8. Conclusion
  9. References
  10. Appendix: Japanese Guidelines for the Use of Fingolimod in MS Patients

Q1. Is fingolimod effective for secondary prevention?

Recommendations

Fingolimod has shown efficacy in the secondary prevention of relapsing-remitting MS and inhibition of disability progression (grade A: strongly recommended according to strong scientific evidence). The usual dose of fingolimod for adults is 0.5 mg taken orally once daily. It is unnecessary to consider the effect of food on the administration of fingolimod.

Efficacy and safety of fingolimod have not been established in patients with progressive MS, those positive for anti-aquaporin-4 (AQP4) antibody, and those with spinal cord lesions extending three or more vertebral segments.

Background and objectives

Only interferon (IFN)-β has been listed in the National Health Insurance (NHI) price list as a secondary prophylactic for multiple sclerosis (MS) in Japan. However, as it is administered by injection, IFN-β might cause injection-related adverse drug reactions, which could pose difficulties for the introduction and continuation of IFN-β treatment. In addition, IFN-β is ineffective in some patients. Given this background, the demand for oral drugs that are more effective than IFN-β for treatment of MS has been high.

Fingolimod hydrochloride is a chemical derivative of a natural product, myriocin derived from Isaria sinclairii, a species of fungus that attacks insects including cicada larvae. Lymphocytes circulate in the secondary lymphoid tissues (e.g. lymph nodes), lymphatic vessels and blood vessels. In the migration of lymphocytes from the secondary lymphoid tissue, sphingosine-1-phosphate (S1P) receptors play an important role. Concentrations of S1P are lower in the secondary lymphoid tissues than in serum, which creates a concentration gradient between blood and the secondary lymphoid tissues. As S1P concentrations are low in the secondary lymphoid tissues, lymphocytes expressing S1P receptors are released from the secondary lymph nodes into the peripheral blood in the direction of the concentration gradient from low to high concentration. This facilitates S1P binding to S1P receptors, and the effects of this interaction.[30, 31] After rapid phosphorylation in the body, fingolimod acts as a functional antagonist to induce internalization of S1P1 receptors on lymphocytes, and inhibits release of lymphocytes from the lymph nodes, which in turn decreases the peripheral lymphocyte count. Based on this action mechanism, fingolimod is believed to control relapse of MS by inhibiting the movement of self-reactive T cells from the peripheral blood into the central nervous system (CNS).[32]

FTY720 (generic name: fingolimod hydrochloride capsule: Imusera and Gilenya) has been listed on the NHI price list since 26 September 2011 in Japan, and is indicated for the secondary prevention and delay of disability progression in MS.

Comments and evidence

1. Secondary prevention of relapsing-remitting MS by fingolimod: An overseas phase III 2-year placebo-controlled clinical study (FREEDOMS study) was carried out in 1272 relapsing-remitting MS patients who had scores of 0–5.5 on the Expanded Disability Status Scale (EDSS) and had experienced one or more relapses in the previous year, or two or more in the previous 2 years.[33] The study showed that the annual recurrence rate decreased to 0.18 in the fingolimod 0.5 mg group (n = 425) as compared with 0.4 in the placebo group (n = 418; P < 0.001), showing a significant decrease by 54% of the placebo. The rate also decreased significantly in the fingolimod 1.25 mg group to 0.16 (P < 0.001). The no recurrence rates were 46%, 70% and 75% in the placebo, fingolimod 0.5 mg, and fingolimod 1.25 mg groups, respectively, showing significant decreases in recurrence rate in the fingolimod groups. The percentage of patients without progression of disability (3-month disability progression measured by EDSS) was 82% and 83% in the fingolimod 0.5 and 1.25 mg groups, respectively, as compared with 76% in the placebo group, showing that fingolimod significantly inhibited disability progression by 30% as compared with placebo (P = 0.02). The percentage of patients without new or enlarging lesions or gadolinium-enhanced lesions in head MRI was significantly greater in the fingolimod group as compared with the placebo group (P < 0.001). Brain volume decreased by 1.31% from baseline after 2-year administration in the placebo group, whereas the brain volume decreases were merely 0.84% and 0.89% (P < 0.001 vs placebo) in the fingolimod 0.5 and 1.25 mg groups, respectively, showing that fingolimod significantly inhibited decreases in brain volume (evidence level II).[33]

An overseas phase III 1-year clinical study of fingolimod to compare once-weekly intramuscular injection of IFN-β1a (TRANSFORMS study), fingolimod 1.25 mg and fingolimod 0.5 mg for 1 year[9] was carried out in 1292 relapsing-remitting MS patients who had scores of 0–5.5 on the EDSS, and had experienced one or more relapses in the previous year, or two or more in the previous 2 years. The study showed that the annual recurrence rate decreased significantly to 0.16 in the fingolimod 0.5 mg group (n = 429) and to 0.20 in the fingolimod 1.25 mg group (n = 420) as compared with 0.33 in the IFN-β1a group (n = 431; P < 0.001). The numbers of new or newly enlarging T2-enhanced lesions were 1.7 and 1.5 in the fingolimod 0.5 and 1.25 mg groups, respectively, showing significant differences from 2.6 in the IFN-β1a group (P = 0.04). The percentage of patients with no gadolinium-enhanced lesions was 90.1% and 91.2% in the fingolimod 0.5 and 1.25 mg groups, respectively, showing significant increases from 80.8% in the IFN-β1a group (P < 0.01). Changes in disability progression (3-month disability progression measured by EDSS) were +0.01, –0.08 and –0.11 in the IFN-β1a, fingolimod 0.5 and 1.25 mg groups, respectively, showing no significant difference among the groups (evidence level II).[9] However, in the TRANSFORMS study,[9] the percentage of patients with previous IFN-βtreatment was 49.1%, 50.8%, and 47.6% in the fingolimod 1.25 mg, 0.5 mg and IFN-β1a groups, respectively, which shows that approximately 50% of patients had previous treatment with IFN-β. In addition, the mean annual recurrence rate of MS before the start of treatment with fingolimod was as high as 1.5 in all of the three groups, which suggests that non-responders and/or suboptimal responders were enrolled in the TRANSFORMS study. It should be therefore noted that the aforementioned results do not necessarily show superiority of fingolimod to IFN-β1a.

In the aforementioned two phase III studies (FREEDOMS study,[33] TRANSFORMS study,[9]) no significant difference in the therapeutic effect was evident between the fingolimod 0.5 and 1.25 mg groups. However, severe adverse events leading to drug withdrawal occurred in 5.6%. 10.0%, and 3.7% of the fingolimod 0.5 mg, fingolimod 1.25 mg and IFN-β 1a groups, respectively, showing that the incidence was highest in the fingolimod 1.25 mg group. In addition, two patients died as a result of herpes virus infection,[9] and the recommended usual dosage of fingolimod was set at 0.5 mg taken once daily orally for adults.[34]

In Japan, a 6-month placebo-controlled phase II clinical study was carried in 171 Japanese patients with relapsing MS who had scores of 0–6.0 on the EDSS, had experienced one or more relapses in the previous year, or two or more in the previous 2 years, and/or had one or more gadolinium-enhanced T1 lesions (evidence level II).[35] The study showed significant decreases in the annual recurrence rate in the fingolimod 0.5 mg group (n = 57, 0.50, 49% decrease; P < 0.05) and in the fingolimod 1.25 mg group (0.41, 58% decrease; P < 0.05) as compared with the placebo group (n = 57, 0.99). Regarding MRI-based disease activity, the percentage of patients with no gadolinium-enhanced lesions after 3 and 6 months of administration was 70.0% (= 0.04) and 86.0% (P < 0.001) in the fingolimod 0.5 and 1.25 mg groups, respectively, as compared with 40.4% in the placebo group, showing significant increases. At month 6 of administration, the mean numbers of new or enlarging T2 lesions were 1.1 and 0.9 in the fingolimod 0.5 and 1.25 mg groups, respectively, as compared with 6.1 in the placebo group, showing significant decreases in the fingolimod groups (P < 0.001 for the both). These results showed that fingolimod in relation to placebo significantly inhibits disease activity in Japanese patients with relapsing MS, as it did in Western patients (evidence level II).[35]

In addition, in analysis of 143 patients who had completed the aforementioned study and continued treatment with fingolimod for 6 months in a Japanese phase II extension study, the number of T1 lesions, the number of new T2 lesions/newly enlarging T2 lesions and frequency of relapse were all decreased in patients who switched from placebo to fingolimod, and patients who continued treatment with fingolimod for 12 months showed persistent efficacy or further improvement in the aforementioned parameters (evidence level I).[36]

2. The backgrounds of patients with progressive MS, those positive for anti-AQP4 antibody, and those with spinal cord lesions extending three or more vertebral segments for which efficacy and safety of fingolimod have not been established.

Efficacy and safety of fingolimod for treatment of progressive MS has not been established, because most of the clinical trials (evidence level II) in and outside Japan[33, 9, 35] were carried out in patients with relapsing-remitting MS.

In a Japanese phase II clinical trial, four patients positive for anti-AQP4 antibody reported serious adverse events suggestive of a causal relationship with primary diseases, and therefore efficacy and safety of fingolimod have not been established in patients positive for anti-AQP4 antibody (evidence level IV).[36, 37] One resident of an overseas country developed neuromyelitis optica (NMO) spectrum disorder; in this case, large brain lesions appeared after administration of fingolimod, and the patient was later found to be positive for anti-AQP4 antibody (evidence level V).[38] In a Japanese phase II clinical trial, patients with spinal cord lesions extending three or more vertebral segments were excluded, and thus efficacy and safety of fingolimod have not been established in these patients (evidence level IV).[35, 38] Notably, of 68 patients tested for anti-AQP4 antibody, four patients (5.9%) were positive, though patients with long spinal cord lesions were excluded before enrolment in the clinical trial. It has been reported that the conditions of these four patients became aggravated after the start of treatment with the fingolimod.[36] These findings suggest that the anti-AQP4 antibody test should be carried out before administration of fingolimod to exclude positive patients, as well as patients with symptoms suggestive of NMO or NMO spectrum disorder, regardless of the presence or absence of a long spinal cord lesions.[35-37]

Q2. In what cases should fingolimod be used?

Answer

Inasmuch as fingolimod was approved for the indication of relapsing-remitting MS in 2010 in overseas countries, the collection of long-term safety and efficacy data is still ongoing. For potential indications in Japan, fingolimod should be regarded as a second-choice drug for patients with relapsing-remitting MS who are non-responders to IFN-β, who have difficulties in continuation of IFN-β because of adverse drug reactions or other reasons, or whose disease activity is high.

Comments and evidence

Significant reduction of relapse rates were reported in the FREEDOMS study[33] and TRANSFORMS study[9] in foreign patients with relapsing-remitting MS treated with fingolimod. Fingolimod significantly inhibited disability progression in the FREEDOMS study, showing a significant therapeutic effect (evidence level II).[33, 9]

Fingolimod was approved for the indication of treatment of relapsing-remitting MS at 0.5 mg once daily by oral administration in Russia and the USA in September 2010, and in Europe in March 2011. Fingolimod was positioned as a first-choice drug for relapsing-remitting MS by the FDA in the USA,[39] and as a second-choice monotherapy for adult patients with highly active relapsing-remitting MS by the European Medicines Agency (EMA). “Highly active relapsing-remitting MS” in Europe is defined as follows: (i) having one relapse episode per year and nine or more T2 lesions in head MRI or having one or more gadolinium-enhanced T1 lesions despite treatment with IFN-β; (ii) non-responder to IFN-β, that is, having no change in his/her relapse frequency, or increased frequency, or repeatedly having severe relapses; and (iii) having sudden disease progression, two or more relapses per year accompanied by severe disabilities, and one or more gadolinium-enhanced T1 lesions in head MRI, or having remarkably increased number of T2 lesions on the latest head MRI as compared with the previous head MRI.[11] Because fingolimod has various adverse drug reactions, and long-term safety has not been established for the drug, Pelletier et al.[40] (in the USA) proposed the positioning of fingolimod as a second-choice drug for patients with relapsing-remitting MS who have one or more relapses per year despite treatment with IFN-β or glatiramer acetate and/or who have new leukoaraiosis lesions in head MRI.[40]

As fingolimod was approved quite recently in 2010 in overseas countries, collection of long-term safety and efficacy data for the drug is still ongoing. For potential indications in Japan, it is ideal to position fingolimod as a second-choice drug (as it is in Europe) for patients with relapsing-remitting MS who are non-responders to IFN-β, who have difficulties in continuation of IFN-β because of adverse drug reactions of IFN-β and other reasons, or who have highly active MS.

As patients with spinal cord lesions extending three or more vertebral segments were excluded in the Japanese phase II clinical trial[35] and Japanese phase II extension study,[36] efficacy and safety of the drug have not been established for these patients (evidence level IV).[35, 41, 37] Administration of fingolimod should be avoided in patients positive for anti-AQP4 antibody.

Q3. How should fingolimod be used?

Recommendations

Fingolimod is orally administered at 0.5 mg once daily for secondary prevention of multiple sclerosis and inhibition of disability progression.

Decreased heart rate might appear for several days after the start of fingolimod therapy. Heart rate might greatly drop, in particular, in the early stage of administration. It is recommended to initiate fingolimod therapy in a hospital where patients can be closely monitored and appropriate treatments can be provided, in collaboration with cardiovascular specialists if possible (grade C1: recommended despite a lack of scientific evidence).

Background and objectives

No abnormal changes were observed during a 6-h observation period after initial administration in overseas studies. However, cardiac arrest at 21 h after administration[42] in one case, and death (cause unknown) within 24 h after administration in another case were reported.[43] No causal relationship with fingolimod was established in either case. However, because these events appeared within 24 h after administration, the sentence “Strict monitoring should be used after initial administration of fingolimod” was added to the sections on warnings and important basic precautions on 19 March 2012 in accordance with the notification by the Safety Division, PFSB, MHLW.[43-45]

Comments

For cardiovascular adverse events observed in the FREEDOMS study,[33] the incidence rates were 0.7%, 2.1%, and 3.3% in the placebo, fingolimod 0.5 mg and fingolimod 1.25 mg groups, respectively, for bradycardia and 0.7%, 0.5%, and 1.4%, respectively, for first- and second-degree atrioventricular block. For serious cardiovascular adverse events in the TRANSFORMS study,[9] the incidence rates were 0%, 0.5%, and 2.4% in the IFN-β 1a, fingolimod 0.5 mg and fingolimod 1.25 mg groups, respectively, for bradycardia and 0%, 0.4%, and 1.2%, respectively, for first- and second-degree atrioventricular block. In the Japanese phase II clinical trial,[35] the incidence rates were 0%, 5.3%, and 14.8%, in the placebo, fingolimod 0.5 mg and fingolimod 1.25 mg groups, respectively, for bradycardia, and 0%, 1.8%, and 5.6%, respectively, for second-degree atrioventricular block. One patient of the fingolimod 1.25 mg group experienced Wenckebach-type second-degree atrioventricular block and bradycardia; however, because the patient satisfied the criteria for discharge during the 6-h monitoring period on day 2 of administration,[37] the monitoring was discontinued and the patient was discharged while continuing fingolimod therapy.[43]

Vital signs should be monitored for at least 6 h after initial administration of fingolimod, and 12-lead electrocardiography should be carried out before initial administration and at 6 h after initial administration. Heart rate and blood pressure should be measured every hour for at least 6 h after the start of fingolimod therapy. For 24 h after initial administration, electrocardiogram should be continuously monitored in addition to measurement of heart rate and blood pressure. Careful observation should be carried out for the following patients:

  1. Patients with second-degree or higher atrioventricular block, sick sinus syndrome, ischemic heart diseases, or congestive cardiac failure.
  2. Patients with decreased heart rate, under treatment with β-blockers, calcium antagonists or digitalis drug, or patients with history of syncope.
  3. Patients with hypokalemia, congenital long QT syndrome or QT prolongation.

When signs or symptoms of bradyarrhythmia are detected during monitoring, the patient should be kept under observation until these signs or symptoms disappear or become stable.

Bradycardia might last for several days after administration of the drug, and heart rate might greatly decrease in the early stage of administration. It is therefore recommended to initiate fingolimod therapy under supervision and in collaboration with cardiovascular specialists if possible to appropriately provide treatment. As sudden death was reported within 24 h after initial administration of fingolimod, it is recommended to hospitalize patients for at least several days after initial administration to monitor blood pressure, pulse rate, and the presence or absence of arrhythmia.

A decrease in heart rate usually appears within 1 h after initial administration of fingolimod, and reaches a nadir by 6 h (pulse rate decreased by approximately 10 b.p.m.). Patients can be discharged if all of the following criteria are met: (i) pulse rate at discharge exceeds 80% of baseline (45 b.p.m. or more is ideal); (ii) pulse rate at discharge exceeds the minimum value observed by 6 h after administration; and (iii) the patient has no bradyarrhythmia-related signs or symptoms (dizziness, fatigue, palpitations).[43-45, 37]

Fingolimod is contraindicated for patients under treatment with class Ia (quinidine, procainamide) or class III (amiodarone, sotalol) anti-arrhythmia drugs. Concomitant use of these drugs is contraindicated, because it might cause further decrease in heart rate and aggravate arrhythmia.[43-45, 37]

Fingolimod might increase bradycardia in patients with second-degree or higher atrioventricular block, sick sinus syndrome, ischemic heart diseases, congestive cardiac failure and decreased heart rate, and in patients receiving treatment with β-blockers. Caution must be used in providing fingolimod therapy for these patients. Fingolimod should be carefully administered to patients with a history of syncope.

As additional enhancement of the hypotensive effect of fingolimod is likely to occur, the use of digitalis drugs, β-blockers and calcium channel antagonists should not be initiated within 1 week before or after the initial dose of fingolimod.[43-45, 37]

Q4. What adverse drug reactions does fingolimod possibly cause?

Answer

In administration of fingolimod, caution must be used for the following five risks:

  1. Bradyarrhythmia and sudden death after the initial dose
  2. Infections (including vaccination, viral hepatitis carriers and progressive multifocal leukoencephalopathy)
  3. Macular edema
  4. Abnormal hepatic function
  5. Risk in pregnant women and fetuses

For bradyarrhythmia and sudden death after the initial dose, cases of cardiac arrest and death of unknown cause within 24 h after administration have been reported even though no abnormal changes were observed during the 6 h-observation period after the initial dose. For infections, infection-related deaths have been reported in and outside Japan. For risk in pregnant women and fetuses, congenital anomalies have been reported. The physician should carefully administer fingolimod while being mindful of these risks.

Comments: Overview of the warning signs of adverse drug reactions[35, 37, 43, 42, 45] and countermeasures

1. Bradyarrhythmia and sudden death after the initial dose: At the start of fingolimod administration, transient decreases in heart rate and/or delayed atrioventricular conduction might occur. In the Japanese clinical trial,[35] the incidence rates were 0%, 5.3%, and 14.8% in the placebo, fingolimod 0.5 mg and fingolimod 1.25 mg groups, respectively, for bradycardia, and 0%, 1.8%, and 5.6%, respectively, for second-degree atrioventricular block. One patient receiving 1.25 mg of fingolimod developed Wenckebach-type second-degree atrioventricular block and bradycardia; however, the patient satisfied the discharge criteria[37] during the 6-h monitoring period on day 2 of administration. Monitoring was therefore discontinued, and the patient was discharged and continued fingolimod therapy.[43]

In overseas studies, no abnormal changes were observed during the 6-h monitoring period after the initial dose of fingolimod. In these studies, two serious adverse events were reported: (i) cardiac arrest and persistent bradycardia 21 h after initial dose in a 20-year-old male whose heart rate normalized 48 h after the initial dose[42]; and (ii) death within 24 h of the initial dose in a female aged in her 50s.[42, 45] As of 29 February 2012, a total of 11 deaths have been reported among more than 34 000 patients receiving fingolimod worldwide.[46] The 11 fatalities were related to MS complications (n = 3), myocardial infarction (n = 3), drowning (n = 2), sudden death during sleeping (n = 2; including one case of arrhythmia) and hypertension complicated with cardiovascular disease (n = 1). In the last case, no abnormal changes were observed during the 6-h observation period after the initial dose of fingolimod as aforementioned, and sudden death occurred within 24 h of the initial dose. The event occurred in a 59-year-old female who had received treatment with metoprolol and amlodipine for hypertension. As of February 2012, the causes of these deaths were unknown.[43, 42, 45]

Based on these reports of adverse drug reactions, methods for use of fingolimod are described in detail to promote appropriate use. See the details in response to Q3, “How should fingolimod be used?”

2. Infections (including vaccination, viral hepatitis carriers, and progressive multifocal leukoencephalopathy): Because fingolimod can cause a decrease in peripheral blood lymphocyte levels, infections (bacterial, fungal or viral) might occur during fingolimod therapy. In the Japanese clinical trial,[35] the incidence of infection was 73 out of 161 patients (45.3%), and the major infections were nasopharyngitis (28%), pharyngitis (5.0%), cystitis (3.1%), and bronchitis (1.9%). According to the dataset from overseas trials, the frequency of infection was higher in patients with decreased lymphocyte count of <200/mm3 after use of fingolimod than those with lymphocyte count of >200/mm3 (61.6%, which was almost equivalent to that of the placebo group [58.6%]).

In the overseas clinical trial (TRANSFORMS study),[9] disseminated herpes zoster-related (n = 1) and herpes encephalitis-related (n = 1) deaths have been reported in the 1.25 mg group. In the Japanese phase II clinical trial, one patient died as a result of malignant lymphoma and lymphoproliferative diseases probably associated with Epstein–Barr virus infection. Autopsy was carried out, and the diagnosis was diffuse large B-cell lymphoma of the brain, lymphoproliferative disorders of the lungs, kidneys, and thyroid, and cutaneous T-cell lymphoma.[37, 43] A warning was therefore added based on the clinical course in fatal cases (all treated with frequent steroid pulse therapy). That is, if a patient has symptoms suggestive of relapsing MS and is receiving steroid pulse therapy, these symptoms should be carefully examined to determine their causal relationship with infection before initiation of fingolimod therapy. Blood tests should be carried out at baseline and periodically during administration of fingolimod. When serious infections occur, fingolimod therapy should be discontinued and appropriate treatments should be provided.

Fingolimod is contraindicated for patients with serious infections.

As primary infection with Varicella and Herpes zoster during fingolimod therapy might become severe, medical history of Varicella and Herpes zoster, and the presence/absence of vaccination must be confirmed before administration of the drug. Vaccination should be considered, if necessary, and if vaccination is used, fingolimod therapy must be postponed until the vaccination takes effect.

In the clinical pharmacology studies, the primary antibody response to vaccination was inhibited in the fingolimod groups as compared with the placebo group. However, the rates of response (development of antibodies to vaccine antigens) were comparable between the placebo group and fingolimod 0.5 mg group. As inoculation of a new antigen cannot be expected to have a sufficient effect, caution should be used when inoculating inactivated vaccines during fingolimod therapy and for 2 months after withdrawal of fingolimod (precautions for coadministration). Because of the risk of infection, use of live vaccines must be avoided during fingolimod therapy and after withdrawal of fingolimod until normalization of lymphocyte count can be confirmed (contraindications for coadministration). The reason is inoculation of live vaccines under immunosuppression might cause proliferation of vaccine viruses, and lead to manifestations and continuation of pathological conditions.[37, 41]

As fingolimod has almost no effect on effector memory T cells that play an important role in adaptive immunity,[41] the drug is expected to have little effect on existing infections. However, because fingolimod inhibits recruitment of lymphocytes to inflammatory lesions, care should be exercised when administering fingolimod to carriers of anti-HIV antibody, anti-HTLV-1 antibody and type B/C hepatitis.[47]

Onset of progressive multifocal leukoencephalopathy (PML) has been associated with the use of an anti-MS drug, natalizumab, in overseas countries. In general, PML manifests when latent JC viruses are reactivated in immunocompromised patients. Because fingolimod was reported not to affect effector memory T cells that supervise reactivation of latent viruses,[48, 32, 49] PML should not appear in response to administration of fingolimod in theory, and also no cases of PML have been reported in the clinical trials in and outside of Japan or in post-marketing surveillance of fingolimod in overseas countries. According to a recent report, however, lesions suggestive of PML were detected in the head MRI of a foreign patient who received fingolimod for approximately 3 months starting 6 weeks after the discontinuation of 3.5-year treatment with natalizumab. JC virus detection in the patient's spinal fluid led to the diagnosis of PML. The causal relationship between fingolimod and PML and the details are currently being investigated.[50]

3. Macular edema: Macular edema including asymptomatic macular edema might appear, in particular, in the early stage of fingolimod therapy. Macular edema in the overseas clinical trials[9, 33] occurred in two of 854 patients (0.2%) in the 0.5 mg group, and most of the incidents appeared by 3–4 months after initiation of fingolimod therapy. In the Japanese phase II clinical trial,[35] macular edema was reported in one patient of the fingolimod 0.5 mg group (27 months after administration), but was ruled out by a retinal specialist of the Data and Safety Monitoring Board.

Commonly there are no visual symptoms in the early stage of macular edema, and most cases of macular edema after fingolimod therapy were asymptomatic, whereas some had blurred vision or reduced visual acuity in the early stage.

Patients with diabetes mellitus or those with a history of uveitis have increased risk for onset of macular edema, and should undergo ophthalmic examinations at baseline and thereafter periodically during administration (1, 3 and 6 months after the initiation of fingolimod therapy, and thereafter every 6 months).[37, 43, 45, 44]

To reduce the risk of macular edema, there should be collaboration with ophthalmologists as described in the section on warnings.[32] Fingolimod therapy should be used only by physicians with sufficient knowledge of the safety and efficacy of fingolimod and experience of the treatment of MS in medical institutions capable of managing emergent conditions. As serious ophthalmic diseases including macular edema might appear, fingolimod should only be used when fully trained ophthalmologists are available for collaboration. The aforementioned is required for institutions planning to use fingolimod.[37, 43, 45, 44]

4. Abnormal hepatic function[37, 43, 45, 44]: Liver function tests can become elevated (increased ALT, AST, γ-GTP) during administration of fingolimod. In the clinical trial in Japan, the incidence rate of abnormal liver function was 31.1% (50/161 patients). Most of the incidents occurred within 3–4 months after initiation of fingolimod therapy, but some occurred even later. Liver function tests should be carried out at baseline and periodically during the administration of fingolimod (15 days, 1, 2, 3 and 6 months after the initiation dose, and thereafter every 3 months). The abnormal liver function tests were defined as ALT of >90 U/L, AST of >82 U/L, γ-GTP of >130 U/L and total bilirubin of > 2.0 mg/dL. Liver function tests should be carried out in patients with onset of clinical symptoms suggestive of hepatic dysfunction. If any abnormal change is detected, discontinue fingolimod therapy and provide appropriate treatments. Fingolimod should be carefully administered to patients with a current or previous history of hepatic dysfunction.[37, 43, 45, 44]

Fingolimod and reactivation of viral hepatitis

Because fingolimod has little effect on effector memory T cells that play an important role in adaptive immunity,[41] the drug is considered to have less of an effect on existing infections. In previous clinical trials, patients with viral hepatitis were excluded. Therefore, there is no clinical experience of fingolimod treatment in these patients, and accordingly no fulminant reactivated viral hepatitis infection has been reported. However, abnormal, hepatic function has been reported as an adverse drug reaction of fingolimod, and therefore it is expected that fingolimod will be carefully administered to patients with a current or previous history of liver disorders. Fingolimod should be avoided in patients with active viral hepatitis, and carefully used in those with a history of viral hepatitis.

5. Risk in pregnant women and fetuses (reproductive toxicity)

It is known that the S1P1 receptor (with which fingolimod interacts) is involved in angiogenesis during embryogenesis.[51] In animal studies of fingolimod, increased incidences of embryo/fetal deaths (rats, rabbits), visceral anomalies (persistent truncus arteriosus, ventricular septal defect in rats), skeletal anomaly (in rabbits) and other developmental toxicities were reported.[37, 43]

In the clinical trials of fingolimod in MS patients in and outside Japan carried out by February 2011, 19 of 50 pregnant women delivered offspring during administration of fingolimod. Of the 19 offspring, 17 were normal, one had congenital tibial curvature, and one had acrania (lack of a cranial bone) and died 2 days after the birth. Of the remaining 31 fetuses, six were spontaneously aborted, 14 were artificially aborted (1 with Fallot's tetralogy and congenital heart disease) and 11 were prenatal.[43] In the Japanese clinical trial, four cases of pregnancy were reported (placebo group, 1; fingolimod 1.25 mg group, 3). Of the four pregnant patients, three underwent induced abortion, and pregnancy is ongoing in the remaining one.[41] Three cases of malformation have been reported by now, including congenital tibial curvature (n = 1), acrania (n = 1) and Fallot's tetralogy (n = 1), and thus safety of fingolimod in pregnant women has not been established. Fingolimod therapy is therefore contraindicated for pregnant women or women who could possibly be pregnant. Physicians must explain the potential fetal risks to women of childbearing potential, confirm absence of pregnancy at baseline, and instruct them to use effective contraceptive methods during and for 2 months after withdrawal of fingolimod therapy. Contraception is required for 2 months after the final dose, because fingolimod has a long elimination half-life (6–9 days), and it might take 2 months at the longest to eliminate fingolimod from the bloodstream after withdrawal; hence, potential risks to fetuses might still exist during the period.[37, 43]

Because animal studies (rats) have shown that fingolimod is excreted in breast milk, nursing mothers should avoid breast feeding during treatment.[37, 43]

6. Other precautions during administration

6.1 Risks of malignant tumor.[37, 43, 41]

Safety data from overseas clinical trials showed that the fingolimod and placebo groups had the same estimated incidence rates of malignant tumors of the skin (and other malignant tumors); thus, fingolimod is not correlated with incidence rates of malignant tumors. However, a death related to malignant lymphoma and lymphoproliferative diseases probably caused by Epstein–Barr virus infection has been reported in Japan (n = 1). The patient participated in the Japanese phase II extension study (received fingolimod 0.5 mg in the extension study after the 6-month placebo-controlled study), and discontinued fingolimod because of recurrence of MS after 261 days of administration. At 6 months after the discontinuation, findings suggestive of malignant tumor or atypical malignant lymphoma were detected, and the patient died approximately 1 year after the discontinuation. The autopsy showed a diagnosis of diffuse large B-cell lymphoma, lymphoproliferative disorders of the lungs, kidneys, and thyroid, and cutaneous T-cell lymphoma. In this case, the lymphoproliferative disorder was serious (fatal) and judged to be related to the investigational drug. In the Japanese phase II clinical trial (0.5 mg group), another case of malignant tumor (n = 1) was reported, and left breast cancer was detected 2 years and 4 months after administration of fingolimod. Because the follow-up periods were not long enough to detect the reported adverse events, risks of malignant tumor by long-term administration of fingolimod cannot be completely ruled out.[41]

6.2. Serious adverse events in patients positive for anti-aquaporin 4 (AQP4) antibody

In the Japanese phase II clinical trial[35] and Japanese phase 2 extension study,[36] patients with spinal cord lesions extending three or more vertebral segments were excluded, and thus efficacy and safety of fingolimod have not been established in these patients.[35, 36] Use of fingolimod should be avoided in patients positive for anti-AQP4 antibody.

It has been reported that four patients positive for anti-AQP4 antibody in the Japanese phase II clinical trial had serious adverse events (chest discomfort, recurrence of primary disease, leukoencephalopathy, neuromyelitis optica [NMO]). A relationship of serious adverse events with NMO was suspected.[37, 41, 36] Narratives for these patients are provided below.

  • Case 1 (fingolimod 0.5 mg group): The patient developed bradycardia and chest discomfort 4 days after the administration of fingolimod, and administration of the drug was discontinued. The patient was then found to be positive for anti-AQP4 antibody.
  • Case 2 (fingolimod 1.25 mg group): The patient developed decreased heart rate after the initial dose of fingolimod, and also developed recurrent MS and decreased heart rate 5 days after the administration of fingolimod. The patient discontinued the drug because of liver disorder (78 days after the initial dose), and then experienced recurrence of MS (83 days after the initial dose). The patient was later found to be positive for anti-AQP4 antibody.
  • Case 3 (switched from placebo to fingolimod 0.5 mg): The patient developed NMO 29 days after the administration of fingolimod, and was later found to be positive for anti-AQP4 antibody.
  • Case 4 (switched from placebo to fingolimod 1.25 mg): The patient developed headache and leukoencephalopathy 10 days after the administration of fingolimod. Spinal fluid was negative for JC virus, and thus progressive multifocal leukoencephalopathy was ruled out. The patient was later found to be positive for anti-AQP4 antibody.

A case of NMO spectrum disorder has been reported in an overseas country[38]; in this case, large brain lesions appeared after the administration of fingolimod and the patient was later found to be positive for anti-AQP4 antibody. Including the four patients positive for anti-AQP4 antibody in the Japanese clinical trial, there were a few cases of serious adverse events for which a relationship with NMO was suspected. Carry out the anti-AQP4 antibody test before starting fingolimod therapy, and avoid the use of fingolimod in patients positive for anti-AQP4 antibody and those with suspected NMO or NMO spectrum disorder.[35, 37, 38]