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, 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 during the 6-h monitoring period on day 2 of administration. Monitoring was therefore discontinued, and the patient was discharged and continued fingolimod therapy.
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; 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. 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, 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), 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, 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.
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.
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, 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. 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, 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. 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. 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. 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
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.
6.2. Serious adverse events in patients positive for anti-aquaporin 4 (AQP4) antibody
In the Japanese phase II clinical trial and Japanese phase 2 extension study, 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; 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]