Summary Of Exposure |
A) USES: Fingolimod is used for the treatment of patients with relapsing forms of multiple sclerosis to reduce the frequency of clinical exacerbations and delay the progression of physical disability.
B) PHARMACOLOGY: Fingolimod, a sphingosine-1-phosphate receptor modulator, blocks the capacity of lymphocytes to egress from lymph nodes, reducing the number of lymphocytes in peripheral blood. The exact mechanism is unknown, but it may reduce lymphocyte migration into the central nervous system.
C) EPIDEMIOLOGY: Limited overdose data. OVERDOSE: Based on premarketing experience, single doses up to 80-fold the recommended dose (0.5 mg) resulted in no significant clinical events. Events are anticipated to be an extension of therapeutic adverse effects A 4-year-old child ingested a single 0.5-mg tablet and subsequently developed AV block I and II, as well as hypotension and mild bradycardia. He recovered with supportive care.
D) WITH THERAPEUTIC USE
1) ADVERSE EFFECTS: Events appear to be dose-dependent. COMMON: The most common adverse events, occurring in more than 10% of patients, include headache, influenza, cough, diarrhea, back pain, and asymptomatic liver transaminase elevations. A decrease in lymphocyte count has been observed shortly after the start of therapy; lymphocyte counts reach a mean of 500 to 600 mm(3) within hours and then stabilize. Leukopenia and neutropenia may also be observed. Other events have included bradycardia, hypertension, dyspnea, herpes infections, depression, dry mouth, blurred vision, and dizziness.
E) WITH POISONING/EXPOSURE
1) MILD TO MODERATE TOXICITY: Transient mild bradycardia and atrioventricular (AV) conduction disturbances may develop. Fingolimod may increase the risk of infection and macular edema. Mild elevations in transaminase concentrations may occur.
2) SEVERE TOXICITY: Symptomatic bradydysrhythmias and AV blocks, dyspnea, severe infections, and hepatic injury.
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Heent |
3.4.3) EYES
A) WITH THERAPEUTIC USE 1) EYE CHANGES a) Eye pain and blurred vision have been reported with therapeutic use (Prod Info GILENYA(R) oral capsules, 2010).
2) MACULAR EDEMA a) Macular edema with or without visual symptoms may develop in patients receiving fingolimod (Prod Info GILENYA(R) oral capsules, 2010; Cohen et al, 2010). The exact cause remains unknown (Horga et al, 2010).
b) In phase III trials, macular edema was confirmed in 13 patients receiving fingolimod. Most cases were observed after 3 to 4 months of therapy, and symptoms resolved with the discontinuation of therapy (Horga et al, 2010).
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Cardiovascular |
3.5.2) CLINICAL EFFECTS
A) BRADYCARDIA 1) WITH THERAPEUTIC USE a) Bradycardia has developed after the first dose of fingolimod. Onset is usually within 1 hour with a nadir mean heart rate at 4 hours. Maximal decline is usually reached at 6 hours. The mean decrease in heart rate has been relatively minor (range: 8 to 16.6 beats/min). The effect resolves over time with continued treatment. A patient's heart rate usually returns to baseline within 1 month of initiating therapy (Prod Info GILENYA(R) oral capsules, 2010; Cohen et al, 2010; Horga et al, 2010; Kovarik et al, 2008a).
b) MECHANISM: Fingolimod can produce a negative chronotropic effect on the heart by activating the cardiac G protein-gated potassium channel, resulting in a lower heart rate (Kovarik et al, 2008). In a proof-of-concept study in patients with multiple sclerosis, nadir mean heart rate occurred 4 hours after the initial dose. A mean decrease in heart rate of 13. 8 beats/min was observed in patients receiving 1.25 mg fingolimod. Patients receiving 5 mg fingolimod had a mean decrease in heart rate of 16.6 beats/min. With ongoing once-daily therapy, heart rate returned to baseline (Kovarik et al, 2008a). The effects appear transient due to subsequent sphingosine-1-phosphate receptor desensitization (Kovarik et al, 2008).
c) In a 2-year, placebo-controlled clinical trial in adult patients with relapsing-remitting multiple sclerosis, bradycardia was reported in 4% of patients who received fingolimod 0.5 mg once daily (n=425) compared with 1% of patients who received placebo (n=418) (Prod Info GILENYA(R) oral capsules, 2010).
d) MONITORING: In a placebo-controlled study in healthy individuals, oral doses of fingolimod (1.25 mg or 5 mg) produced an increase in PR interval on day 1 of therapy, while no increases in the QRS or QT interval were observed. By day 7, the increase in PR interval had ceased (Schmouder et al, 2006).
2) WITH POISONING/EXPOSURE a) CASE REPORT (CHILD): Age-related transient bradycardia (58 to 78 bpm) was reported in a 4-year-old child 2 to 10 hours following ingestion of a single 0.5-mg fingolimod tablet (Hojer & Olsson, 2014).
b) CASE REPORT (ADULT): A 33-year-old woman, with a history of multiple sclerosis and depression, developed bradycardia (48 beats/min) and hypotension (87/57 mmHg) approximately 21 hours after ingesting 28 0.5-mg fingolimod tablets, as well as 4 500-mg phenoxymethylpenicillin tablets. Following a 300 mcg IV bolus of atropine, the patient's heart rate and blood pressure increased to 67 beats/min and 110/72 mmHg, respectively. Approximately 25 hours post-ingestion, bradycardia and hypotension recurred, but resolved following administration of another dose of atropine. Approximately 7 hours later, a third episode of hypotension and bradycardia occurred, but resolved spontaneously without therapeutic intervention (Stephenson et al, 2014).
B) LOW BLOOD PRESSURE 1) WITH THERAPEUTIC USE a) In clinical trials, fingolimod was found to produce mild transient decreases in blood pressure (a mean reduction of 5 to 6 mmHg below baseline) several hours after drug administration in up to 15% of patients (Horga et al, 2010).
2) WITH POISONING/EXPOSURE a) CASE REPORT (CHILD): Hypotension (77/34/ mmHg) was reported in a 4-year-old child 2 to 10 hours following ingestion of a single 0.5-mg fingolimod tablet. The patient recovered with supportive care (Hojer & Olsson, 2014).
b) CASE REPORT (ADULT): A 33-year-old woman, with a history of multiple sclerosis and depression, developed bradycardia (48 beats/min) and hypotension (87/57 mmHg) approximately 21 hours after ingesting 28 0.5-mg fingolimod tablets, as well as 4 500-mg phenoxymethylpenicillin tablets. Following a 300 mcg IV bolus of atropine, the patient's heart rate and blood pressure increased to 67 beats/min and 110/72 mmHg, respectively. Approximately 25 hours post-ingestion, bradycardia and hypotension recurred, but resolved following administration of another dose of atropine. Approximately 7 hours later, a third episode of hypotension and bradycardia occurred, but resolved spontaneously without therapeutic intervention (Stephenson et al, 2014).
C) HYPERTENSIVE EPISODE 1) WITH THERAPEUTIC USE a) During clinical trials, fingolimod 0.5 mg caused an average increase of approximately 2 mmHg in systolic pressure and approximately 1 mmHg in diastolic pressure. Blood pressure elevations were noted approximately 2 months after treatment initiation and persisted throughout therapy (Prod Info GILENYA(R) oral capsules, 2010).
b) INCIDENCE: In a 2-year, placebo-controlled clinical trial in adult patients with relapsing-remitting multiple sclerosis, hypertension was reported in 6% of patients who received fingolimod 0.5 mg once daily (n=425) compared with 4% of patients who received placebo (n=418) (Prod Info GILENYA(R) oral capsules, 2010).
D) ATRIOVENTRICULAR BLOCK 1) WITH THERAPEUTIC USE a) In a placebo-controlled trial, first- and second-degree atrioventricular (AV) block was observed infrequently during fingolimod therapy. Most cases did not result in the discontinuation of therapy (Kappos et al, 2010).
b) Transient AV conduction delays may occur with the first dose of fingolimod. In a clinical trial, patients with relapsing-remitting multiple sclerosis who had 24-hour Holter monitoring, second degree AV block (Mobitz type I [Wenckebach]) was reported in 3.7% of patients after the first dose of fingolimod 0.5 mg once daily (n=351) compared with 2% of patients who received placebo (n=347). Most conduction abnormalities were asymptomatic, and resolution usually occurred within the first 24 hours. However, some patients did require atropine or isoproterenol (Prod Info GILENYA(R) oral capsules, 2010).
c) CASE REPORT: A 24-year-old woman, with no previous history of cardiovascular abnormalities, developed first degree AV block, progressing to second degree AV block with a heart rate of 30 bpm, approximately 4 hours after receiving fingolimod 0.5 mg orally for treatment of relapsing remitting multiple sclerosis. Following continued observation and monitoring, the patient reverted to normal sinus rhythm the following day. Rechallenge with 0.5 mg fingolimod resulted in the development of first degree conduction delay greater than 400 ms 5 hours later, with progression to second degree AV block that persisted for 18 hours. Following discontinuation of the drug, the patient's cardiovascular status gradually improved, with a PR interval of 220 to 310 ms and a heart rate greater than 50 bpm, and she was discharged home. Follow-up, one month later, revealed a heart rate of 77 bpm, sinus dysrhythmia, and a PR interval of 210 ms, with a normal echocardiogram (Voon et al, 2014).
2) WITH POISONING/EXPOSURE a) CASE REPORT (CHILD): A 4-year-old child presented to the emergency department after ingesting a single 0.5-mg fingolimod tablet. Prior to presentation (45 minutes post-ingestion), the patient had received 10 g of activated charcoal. At presentation, 90 minutes post-ingestion, the patient's vital signs were normal; however, an ECG revealed AV-block I with a prolonged PQ interval (196 ms). Approximately 2 to 10 hours post-ingestion, the patient was hypotensive (77/34 mmHg) and bradycardic (58 to 78 bpm). A repeat ECG demonstrated AV block I alternating with AV block II with Wenckebach phenomenon. Following supportive care and 24 hours of observation, the patient recovered and was discharged. An ECG, performed 2 days later, showed normal sinus rhythm with a shortened PQ-time (164 ms) (Hojer & Olsson, 2014).
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Respiratory |
3.6.2) CLINICAL EFFECTS
A) DYSPNEA 1) WITH THERAPEUTIC USE a) In a 2-year, placebo-controlled clinical trial in adult patients with relapsing-remitting multiple sclerosis, dyspnea was reported in 8% of patients who received fingolimod 0.5 mg once daily (n=425) compared with 5% of patients who received placebo (n=418) (Prod Info GILENYA(R) oral capsules, 2010).
b) In clinical trials, minor dose-dependent increases in airway resistance were observed during the initiation of fingolimod therapy. Symptoms did not progress, and no dose adjustment was required (Horga et al, 2010).
B) COUGH 1) WITH THERAPEUTIC USE a) Cough is one of the most common adverse events (occurring in 10% or more of patients) reported with fingolimod therapy (Prod Info GILENYA(R) oral capsules, 2010).
C) BRONCHITIS 1) WITH THERAPEUTIC USE a) In a 2-year, placebo-controlled clinical trial in adult patients with relapsing-remitting multiple sclerosis, bronchitis was reported in 8% of patients who received fingolimod 0.5 mg once daily (n=425) compared with 4% of patients who received placebo (n=418) (Prod Info GILENYA(R) oral capsules, 2010).
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Neurologic |
3.7.2) CLINICAL EFFECTS
A) HEADACHE 1) WITH THERAPEUTIC USE a) Headache was one of the most common adverse events (occurring in 10% or more of patients) reported with fingolimod therapy (Prod Info GILENYA(R) oral capsules, 2010).
b) In a 2-year, placebo-controlled clinical trial in adult patients with relapsing-remitting multiple sclerosis, headache was reported in 25% of patients who received fingolimod 0.5 mg once daily (n=425) compared with 23% of patients who received placebo (n=418) (Prod Info GILENYA(R) oral capsules, 2010)
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Gastrointestinal |
3.8.2) CLINICAL EFFECTS
A) DIARRHEA 1) WITH THERAPEUTIC USE a) Diarrhea is one of the most common adverse events (occurring in 10% or more of patients) reported with fingolimod therapy (Prod Info GILENYA(R) oral capsules, 2010).
b) In a 2-year, placebo-controlled clinical trial in adult patients with relapsing-remitting multiple sclerosis, diarrhea was reported in 12% of patients who received fingolimod 0.5 mg once daily (n=425) compared with 7% of patients who received placebo (n=418) (Prod Info GILENYA(R) oral capsules, 2010).
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Hepatic |
3.9.2) CLINICAL EFFECTS
A) INCREASED LIVER ENZYMES 1) WITH THERAPEUTIC USE a) An increase in liver transaminase may develop with therapy. During clinical trials, the recurrence of elevated liver transaminase concentrations occurred with rechallenge in some patients. Most elevations occurred within 3 to 4 months, and serum transaminase concentrations returned to normal within 2 months of drug cessation (Prod Info GILENYA(R) oral capsules, 2010).
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Hematologic |
3.13.2) CLINICAL EFFECTS
A) LYMPHOCYTE DISORDER 1) WITH THERAPEUTIC USE a) A dose-dependent reduction in peripheral lymphocyte count (20% to 30% reduction from baseline values) has been observed with fingolimod therapy. Fingolimod causes reversible sequestration of lymphocytes in lymphoid tissues by blocking the capacity of lymphocytes to egress from lymph nodes. The low lymphocyte counts are maintained with chronic daily dosing, which may increase the risk of infections (Prod Info GILENYA(R) oral capsules, 2010).
B) LYMPHOCYTOPENIA 1) WITH THERAPEUTIC USE a) In a 2-year, placebo-controlled clinical trial in adult patients with relapsing-remitting multiple sclerosis, 18% of patients who received fingolimod 0.5 mg once daily (n=425) had a lymphocyte count of less than 200 cells/microL on at least 1 occasion compared with none of the patients who received placebo (n=418). The count remains low due to daily dosing; however, the lymphocyte count starts to rise within a few days of discontinuation with normal concentrations within 1 to 2 months (Prod Info GILENYA(R) oral capsules, 2010).
C) LEUKOPENIA 1) WITH THERAPEUTIC USE a) In a 2-year, placebo-controlled clinical trial in adult patients with relapsing-remitting multiple sclerosis, leukopenia was reported in 3% of patients who received fingolimod 0.5 mg once daily (n=425) compared with less than 1% of patients who received placebo (n=418) (Prod Info GILENYA(R) oral capsules, 2010).
D) MALIGNANT LYMPHOMA (CLINICAL) 1) WITH THERAPEUTIC USE a) In premarketing clinical trials, a small number of patients developed lymphomas (ie, cutaneous T-cell lymphoproliferative disorders or diffuse B-cell lymphoma) after receiving fingolimod therapy (0.5 mg doses or above) (Prod Info GILENYA(R) oral capsules, 2010). No association between fingolimod use and the risk of cancer could be established during phase III trials (Horga et al, 2010).
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Dermatologic |
3.14.2) CLINICAL EFFECTS
A) ECZEMA 1) WITH THERAPEUTIC USE a) Eczema and pruritus have been reported infrequently in adult patients with relapsing-remitting multiple sclerosis treated with fingolimod (Prod Info GILENYA(R) oral capsules, 2010).
B) ALOPECIA 1) WITH THERAPEUTIC USE a) Alopecia has been reported infrequently in adult patients with relapsing-remitting multiple sclerosis treated with fingolimod (Prod Info GILENYA(R) oral capsules, 2010).
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Musculoskeletal |
3.15.2) CLINICAL EFFECTS
A) BACKACHE 1) WITH THERAPEUTIC USE a) Back pain was one of the most common adverse events (occurring in 10% or more of patients) reported with fingolimod therapy (Prod Info GILENYA(R) oral capsules, 2010).
b) In a 2-year, placebo-controlled clinical trial in adult patients with relapsing-remitting multiple sclerosis, back pain was reported in 12% of patients who received fingolimod 0.5 mg once daily (n=425) compared with 7% of patients who received placebo (n=418) (Prod Info GILENYA(R) oral capsules, 2010).
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Reproductive |
3.20.1) SUMMARY
A) Fingolimod is classified as FDA pregnancy category C. There are no adequate and well-controlled studies of fingolimod use during pregnancy. It should only be used if the benefit to the mother outweighs the potential risk to the fetus.
3.20.2) TERATOGENICITY
A) ANIMAL STUDIES 1) In animal studies, there was evidence of teratogenicity, including visceral malformation, when rats were exposed to oral fingolimod. There were increased incidences of fetal malformations and embryofetal deaths when pregnant rats were given oral doses of 0.1 and 0.3 mg/kg/day or 1, 3, and 10 mg/kg/day during organogenesis; there was no increase at a dose of 0.03 mg/kg/day which is less than the recommended human dose (RHD) on a mg/m(2) basis. The highest no-effect dose for these effects was less than the RHD of 0.5 mg/day. In another rat study, pup survival was decreased at all doses and there was a neurobehavioral deficit in offspring at the highest dose when rats were given oral doses of 0.05, 0.15, and 0.5 mg/kg/day during pregnancy and lactation. For these effects, the low-effect dose is 0.05 mg/kg/day, which is similar to the RHD. In rabbit studies, there were increased incidences of embryofetal mortality and fetal growth retardation when oral fingolimod doses of 0.5, 1.5, and 5 mg/kg/day were given during organogenesis. The no-effect dose for these effects was approximately 20 times the RHD (Prod Info GILENYA(TM) oral capsules, 2012).
3.20.3) EFFECTS IN PREGNANCY
A) LACK OF INFORMATION 1) Although there are no adequate and well-controlled studies of fingolimod use in pregnant women, the sphingosine 1-phosphate receptor, which is affected by fingolimod, is known to be involved in vascular formation during embryogenesis. In animal studies, there was evidence of embryofetal death and teratogenicity, including visceral malformations. Therefore, fingolimod should be used in pregnant women only if the potential maternal benefit outweighs the potential fetal risks. Women of childbearing potential should use effective contraception to avoid pregnancy during and for 2 months after stopping fingolimod, as fetal risk may continue after fingolimod discontinuation. A pregnancy registry has been established for pregnant patients who receive fingolimod, and patients may be enrolled by calling 1-877-598-7237 or by visiting www.gilenyapregnancyregistry.com (Prod Info GILENYA(TM) oral capsules, 2012).
B) PREGNANCY CATEGORY 1) Fingolimod is classified as FDA pregnancy category C(Prod Info GILENYA(TM) oral capsules, 2012).
C) FINGOLIMOD EXPOSURE DURING PREGNANCY 1) During the fingolimod clinical development program, a total of 89 pregnancies were reported. Of these 89 pregnancies, 11 were from the placebo group, 4 were from the interferon beta-1a group, and 74 were from the fingolimod treatment group. Of the 74 pregnancies in the fingolimod treatment group, only 66 pregnancies had in utero exposure to fingolimod. The total fingolimod exposure for women up to 50 years of age was 7702 patient years and 25% of fingolimod patients received treatment for 3 years or longer. Of the 66 pregnancies with in utero exposure, live births were reported in 42% while spontaneous abortion and elective abortion were reported in 14% and 36%, respectively. At the time of the report, 6% of pregnancies were still ongoing and one patient was lost to follow up. The expected duration of in utero fingolimod exposure in live births, elective abortions, and spontaneous abortions were greater than 8 weeks to less than or equal to 12 weeks, greater than 4 weeks to less than or equal to 8 weeks, and greater than 4 weeks to less than or equal to 12 weeks, respectively. A total of 5 pregnancies were exposed to fingolimod in utero for a duration greater than 12 weeks. Of these 5 pregnancies, 4 resulted in the live birth of healthy infants and one pregnancy was still ongoing. When excluding ongoing pregnancies, elective abortions, and patients lost to follow up, the outcomes of only 37 pregnancies are known. Of these 37 pregnancies, spontaneous abortion occurred in 24%, 70% resulted in healthy infants with no congenital anomalies, and 5% resulted in an infant with a congenital abnormality. These abnormalities were congenital unilateral posteromedial bowing of the tibia and acrania (Karlsson et al, 2014).
D) ANIMAL STUDIES 1) EMBRYONAL DEATH a) RATS: There were increased incidences of fetal malformations and embryofetal deaths when pregnant rats were given oral doses of 0.1 and 0.3 mg/kg/day or 1, 3, and 10 mg/kg/day during organogenesis; there was no increase at a dose of 0.03 mg/kg/day which is less than the recommended human dose (RHD) on a mg/m(2) basis. The highest no-effect dose for these effects was less than the RHD of 0.5 mg/day (Prod Info GILENYA(TM) oral capsules, 2012).
b) RABBITS: In rabbit studies, there were increased incidences of embryofetal mortality and fetal growth retardation when oral fingolimod doses of 0.5, 1.5, and 5 mg/kg/day were given during organogenesis. The no-effect dose for these effects was approximately 20 times the RHD (Prod Info GILENYA(TM) oral capsules, 2012).
3.20.4) EFFECTS DURING BREAST-FEEDING
A) LACK OF INFORMATION 1) BREAST MILK a) It is not known whether fingolimod is excreted in human milk. A decision should be made whether to discontinue the drug or discontinue nursing, taking into account the importance of the drug to the mother (Prod Info GILENYA(TM) oral capsules, 2012).
B) ANIMAL STUDIES 1) Fingolimod is excreted in the milk of rats during lactation (Prod Info GILENYA(TM) oral capsules, 2012).
3.20.5) FERTILITY
A) ANIMAL STUDIES 1) No effect on fertility was observed in male and female rats given up to the highest dose tested (10 mg/kg/day) (approximately 200 times the recommended human dose on a mg/m(2) basis) (Prod Info GILENYA(TM) oral capsules, 2012).
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Carcinogenicity |
3.21.2) SUMMARY/HUMAN
A) Basal cell carcinoma has been reported in patients administered fingolimod 0.5 mg.
3.21.4) ANIMAL STUDIES
A) BASAL CELL CARCINOMA 1) Basal cell carcinoma was reported in 2% of patients administered fingolimod 0.5 mg compared with 1% with placebo (Prod Info GILENYA(R) oral capsules, 2016).
B) MALIGNANT LYMPHOMA 1) MICE: Fingolimod was administered at oral doses of 0, 0.025, 0.25, and 2.5 mg/kg/day for up to 2 years with an increased incidence of malignant lymphomas observed in males and females at the highest dose. Note: The lowest dose (0.025 mg/kg/day) is less than the recommended human doses of 0.5 mg/day on a body surface area (mg/m(2)) (Prod Info GILENYA(R) oral capsules, 2010).
C) LACK OF EFFECT 1) RATS: There was no increase in the incidence of tumors in rats administered fingolimod. The highest dose tested (2.5 mg/kg/day) was approximately 200 times the recommended highest dose on a mg/m(2) basis (Prod Info GILENYA(R) oral capsules, 2010).
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Genotoxicity |
A) Fingolimod was found to be negative in a series of in vitro assays (ie, Ames, mouse lymphoma thymidine kinase, chromosomal aberration in mammalian cells) and in vivo (ie, micronucleus in mouse and rat) studies (Prod Info GILENYA(R) oral capsules, 2010).
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