Forcado
UkraineTable of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT FORZADO (FORZADO)
Composition:
Active substance: fingolimod;
1 hard capsule contains 0.56 mg of fingolimod hydrochloride equivalent to 0.5 mg of fingolimod;
Excipients: beta-cyclodextrin, magnesium stearate, hard gelatin capsule No. 3 (capsule shell composition: gelatin, purified water, yellow iron oxide (E 172), titanium dioxide (E 171), sodium lauryl sulfate).
Pharmaceutical form. Hard capsules.
Main physicochemical properties: hard gelatin capsules of size "3", consisting of an opaque dark yellow cap printed in black ink with "FGM" and an opaque white body printed in black ink with "0.5 mg", filled with powder ranging from white to almost white.
Pharmacotherapeutic group. Selective immunosuppressants.
ATC Code: L04A A27.
Pharmacological Properties
Pharmacodynamics
Mechanism of Action
Fingolimod is a sphingosine-1-phosphate (S1P) receptor modulator. Fingolimod is metabolized by sphingosine kinase to its active metabolite, fingolimod phosphate. At low nanomolar concentrations, fingolimod phosphate binds to sphingosine-1-phosphate type 1 (S1P₁) receptors located on the surface of lymphocytes, readily crosses the blood-brain barrier, and binds to S1P₁ receptors on neurons in the central nervous system (CNS). By acting as a functional antagonist of S1P receptors on lymphocytes, fingolimod phosphate inhibits the ability of lymphocytes to exit lymph nodes, resulting in redistribution of lymphocytes rather than a reduction in total lymphocyte count in the body. Animal studies have shown that this redistribution reduces pathological lymphocyte infiltration, including pro-inflammatory Th17 cells, into the CNS, where they could otherwise damage nerve fibers and neural tissue. Animal studies and in vitro experiments indicate that fingolimod may also act via interaction with S1P receptors on neuronal surfaces.
Pharmacodynamic Effects
Within 4–6 hours after the first dose of 0.5 mg fingolimod, the number of lymphocytes in peripheral blood decreases to approximately 75% of baseline. With continued daily administration, lymphocyte counts continue to decline over 2 weeks, reaching a nadir of about 500 cells/µL or approximately 30% of baseline. In 18% of patients, lymphocyte counts fell below 200 cells/µL at least once. With regular daily dosing, lymphocyte counts remain low. Most T- and B-lymphocytes regularly circulate through lymphoid organs and are primarily affected by fingolimod. Approximately 15–20% of T-lymphocytes are effector memory cells that play a key role in peripheral immune surveillance. Since this lymphocyte subset generally does not recirculate through lymphoid organs, it is not significantly affected by fingolimod. Lymphocyte counts in peripheral blood begin to increase within several days after discontinuation of fingolimod, with normalization occurring within 1–2 months. Continuous fingolimod use leads to a modest reduction in neutrophil counts, to approximately 80% of baseline. Monocytes are not affected by fingolimod.
At the initiation of treatment, fingolimod causes a transient reduction in heart rate and slows atrioventricular conduction. The maximum reduction in heart rate occurs within the first 6 hours after drug administration, with about 70% of the negative chronotropic effect achieved on the first day of treatment. With continued administration, heart rate returns to baseline within 1 month. The heart rate reduction caused by fingolimod can be reversed by administration of atropine or isoprenaline. Inhaled salmeterol has been shown to have a moderate positive chronotropic effect. At the start of fingolimod treatment, an increase in atrial extrasystoles is observed, but this is not associated with increased incidence of atrial fibrillation/flutter, ventricular arrhythmias, or ectopy. Fingolimod treatment does not reduce cardiac output. Autonomic cardiac functions, including circadian heart rate variability and response to exercise, are not affected by fingolimod.
This effect may be partially mediated by the S1P₄ receptor; however, this receptor is not the primary receptor responsible for lymphocyte count reduction. In vitro studies in guinea pigs and isolated rabbit aorta and coronary artery models have investigated the mechanisms causing bradycardia and vasoconstriction. It has been concluded that bradycardia is primarily due to activation of the inward rectifier potassium channel or G-protein-activated inward rectifier K⁺ channel (IKACh/GIRK), while vasoconstriction appears to be mediated via Rho-kinase and calcium-dependent mechanisms.
Single and repeated administration of fingolimod at doses of 0.5 and 1.25 mg over two weeks is not associated with a significant increase in airway resistance, measured by forced expiratory volume in 1 second (FEV₁) and forced expiratory flow (FEF) at 25–75% of forced vital lung capacity. However, dose-dependent increases in airway resistance were observed after single doses of fingolimod ≥ 5 mg (10 times the recommended dose). Repeated administration of fingolimod at doses of 0.5, 1.25, or 5 mg was not associated with impaired oxygenation or oxygen saturation during exercise, nor with increased airway reactivity to methacholine. Patients receiving fingolimod treatment exhibit a normal bronchodilator response to inhaled beta-agonists.
Pharmacokinetics
Pharmacokinetic data were obtained in healthy adult volunteers, adult kidney transplant recipients, and adult patients with multiple sclerosis.
The pharmacologically active metabolite is fingolimod phosphate.
Absorption
Fingolimod is slowly absorbed (Tmax: 12–16 hours) and to a large extent (≥85%). The apparent absolute bioavailability after oral administration is 93% (95% confidence interval: 79–111%). Steady-state plasma concentrations are reached within 1–2 months after once-daily dosing and are approximately 10 times higher than after the first dose.
Food intake does not affect the maximum plasma concentration (Cmax) or exposure (AUC) of fingolimod. Cmax of fingolimod phosphate was slightly reduced (by 34%), while AUC remained unchanged. Therefore, the drug can be administered independently of food intake.
Distribution
Fingolimod is extensively distributed into erythrocytes (fraction of fingolimod in blood cells: 86%). Fingolimod phosphate has limited ability to enter blood cells (<17%). Both fingolimod and fingolimod phosphate are highly bound to plasma proteins (>99%).
Fingolimod is extensively distributed into body tissues (volume of distribution: approximately 1200 ± 260 L). A study involving 4 healthy volunteers who received a single intravenous dose of radiolabeled fingolimod analog demonstrated that fingolimod penetrates into the brain. In a study of 13 male patients with multiple sclerosis receiving 0.5 mg daily orally, the average amount of fingolimod (and fingolimod phosphate) in semen at steady state was approximately 10,000 times lower than the administered dose (0.5 mg).
Biotransformation
In humans, biotransformation of fingolimod occurs via stereoselective reverse phosphorylation to the pharmacologically active (S)-enantiomer of fingolimod phosphate. Fingolimod is eliminated primarily through oxidative biotransformation, mainly by the CYP4F2 isoenzyme and possibly other isoenzymes, followed by degradation similar to fatty acids into inactive metabolites. Formation of pharmacologically inactive, nonpolar ceramide analogs of fingolimod has also been observed. The main enzyme involved in fingolimod metabolism has been partially identified and may be either CYP4F2 or CYP3A4.
After a single oral dose of [14C]fingolimod, the main circulating components related to fingolimod, based on their contribution to the AUC of total radioactivity over 34 days post-dose, were unchanged fingolimod (23%), fingolimod phosphate (10%), and inactive metabolites [carboxylic acid metabolite M3 (8%), ceramide metabolite M29 (9%), and ceramide metabolite M30 (7%)].
Elimination
The plasma clearance of fingolimod is 6.3 ± 2.3 L/h, and the mean apparent terminal half-life (T½) is 6–9 days. The decline in plasma concentrations of fingolimod and fingolimod phosphate during the terminal phase occurs in parallel, resulting in similar half-lives for both compounds.
After oral administration, approximately 81% of the dose is slowly excreted in urine as inactive metabolites. Fingolimod and fingolimod phosphate are not excreted unchanged in urine but are the main compounds found in feces, with each accounting for less than 2.5% of the administered dose. By day 34, 89% of the administered dose has been eliminated.
Linearity
After repeated administration of 0.5 mg and 1.25 mg once daily, concentrations of fingolimod and fingolimod phosphate increase almost dose-proportionally.
Pharmacokinetic Characteristics in Specific Patient Populations
The pharmacokinetics of fingolimod and fingolimod phosphate do not differ between men and women, among patients of different ethnic backgrounds, or in patients with mild to severe renal impairment.
In patients with mild, moderate, or severe hepatic impairment (Child-Pugh classes A, B, and C), no changes in Cmax of fingolimod were observed, but AUC increased by 12%, 44%, and 103%, respectively. In patients with severe hepatic impairment (Child-Pugh class C), Cmax of fingolimod phosphate was reduced by 22%, but AUC was not significantly altered. The pharmacokinetics of fingolimod phosphate were not evaluated in patients with mild or moderate hepatic impairment. In patients with mild hepatic impairment, the apparent half-life was unchanged, while in those with moderate or severe hepatic impairment, it was prolonged by approximately 50%.
Fingolimod should not be used in patients with severe hepatic impairment (Child-Pugh class C). Fingolimod should be used with caution in patients with mild or moderate hepatic impairment.
Clinical experience and pharmacokinetic data in patients aged 65 years and older are limited. Fingolimod should be used with caution in patients aged 65 years and older.
Pediatric Population
In pediatric patients (10 years of age and older), concentrations of fingolimod phosphate increase almost dose-proportionally within the dose range of 0.25 mg to 0.5 mg.
Steady-state concentrations of fingolimod phosphate in pediatric patients (10 years and older) are approximately 25% lower with daily doses of 0.25 mg or 0.5 mg compared to adult patients receiving 0.5 mg once daily.
No data are available for children under 10 years of age.
Clinical characteristics.
Indications.
Forsado is indicated as a disease-modifying monotherapy for highly active relapsing-remitting multiple sclerosis in the following groups of adult patients and children aged 10 years and older:
- Patients with highly active disease.
This group includes patients in whom a full and adequate (at least one year) course of treatment with at least one disease-modifying agent (exceptions and washout period information are provided in the sections “Special precautions” and “Pharmacological properties”) has failed to demonstrate a therapeutic effect.
- Patients with rapidly evolving severe relapsing-remitting multiple sclerosis.
Presence of two or more disabling relapses within one year or detection on brain MRI of one or more gadolinium-enhancing lesions, or an increase in the number of T2-hyperintense lesions compared to the previous MRI.
Contraindications.
Immunodeficiency syndrome.
Increased risk of opportunistic infections, including in patients with compromised immunity (including patients receiving immunosuppressive therapy or patients with immunity compromised due to prior treatment).
Severe acute infections, active chronic infections (hepatitis, tuberculosis).
Malignant neoplasms in active phase.
Severe hepatic impairment (Child-Pugh class C).
Myocardial infarction occurred within the last 6 months, unstable angina, stroke, transient ischemic attack (TIA), decompensated heart failure (requiring hospitalization), NYHA class III/IV heart failure.
Severe cardiac arrhythmias requiring concomitant use of class Ia or class III antiarrhythmic agents.
Second-degree Mobitz type II atrioventricular block, third-degree atrioventricular block, sick sinus syndrome (in patients without a cardiac pacemaker).
QTc interval ≥ 500 ms.
Pregnancy. Contraindicated in women of childbearing potential who are not using effective contraceptive methods.
Hypersensitivity to the active substance or to any of the excipients.
Interaction with other medicinal products and other forms of interactions.
Antineoplastic agents, immunosuppressants or immunomodulators
Due to the potential additive effect on the immune system, fingolimod should not be used concomitantly with antineoplastic agents, immunosuppressants, or immunomodulators.
Caution should also be exercised when switching to fingolimod in patients previously treated with long-acting immunomodulatory drugs such as natalizumab, teriflunomide, or mitoxantrone. In clinical trials in multiple sclerosis, concomitant short-term corticosteroid treatment for relapses was not associated with an increased incidence of infections.
Vaccination
Vaccination may be less effective during treatment with fingolimod and for up to 2 months after discontinuation of treatment. Administration of live attenuated vaccines increases the risk of infections and is therefore not recommended (see sections “Special precautions” and “Adverse reactions”).
Medicinal products causing bradycardia
The use of fingolimod in combination with atenolol and diltiazem has been studied. In interaction studies in healthy volunteers, additional reduction in heart rate (HR) by 15% was observed at the beginning of fingolimod treatment when co-administered with atenolol, but this effect was not observed with diltiazem. Initiation of fingolimod therapy should not be started in patients receiving beta-blockers or other medicinal products that may reduce HR, such as class Ia and III antiarrhythmics, calcium channel blockers such as verapamil or diltiazem, digoxin, anticholinesterase agents, or pilocarpine, due to the potential additive effect on heart rate. If fingolimod treatment is planned in such patients, cardiology consultation should be obtained regarding switching the patient to agents that do not reduce HR or appropriate monitoring should be performed at treatment initiation, at least overnight, if discontinuation of the HR-lowering agent is not feasible.
Pharmacokinetic interactions of other medicinal products with fingolimod
Fingolimod is primarily metabolized by the CYP4F2 isoenzyme. Other isoenzymes, such as CYP3A4, may also be involved in its metabolism, especially in cases of pronounced CYP3A4 induction. Significant effects of potent inhibitors of transport proteins on the pharmacokinetics of fingolimod are not expected. Concomitant administration of fingolimod with ketoconazole resulted in a 1.7-fold increase in AUC of fingolimod and fingolimod phosphate due to inhibition of CYP4F2. Caution should be exercised when using fingolimod concomitantly with medicinal products that may inhibit CYP3A4 activity (protease inhibitors, azole antifungal agents, certain macrolides such as clarithromycin or telithromycin).
Concomitant administration of carbamazepine at a dose of 600 mg twice daily at steady state and a single 2 mg dose of fingolimod reduced the AUC of fingolimod and its metabolite by approximately 40%.
Other potent inducers of CYP3A4 enzyme, such as rifampicin, phenobarbital, phenytoin, efavirenz, and St. John's wort, may similarly reduce the AUC of fingolimod and its metabolite. Since this may potentially affect efficacy, concomitant use of these agents requires caution. Concomitant use of St. John's wort is not recommended (see section “Special precautions”).
Pharmacokinetic data on potential interactions do not indicate a significant effect of fluoxetine, paroxetine (potent inhibitors of CYP2D6), or carbamazepine (potent enzyme inhibitor) on fingolimod and fingolimod phosphate. Furthermore, the following substances also had no clinically significant effect on fingolimod and fingolimod phosphate: baclofen, gabapentin, oxybutynin, amantadine, modafinil, amitriptyline, pregabalin, corticosteroids, and oral contraceptives.
Effect on laboratory tests
Since fingolimod reduces blood lymphocyte count by redistributing them into secondary lymphoid organs, peripheral blood lymphocyte count cannot be used to assess the overall lymphocyte status.
Laboratory investigations of circulating mononuclear cells may require larger blood volumes due to reduced circulating lymphocyte count.
Pharmacokinetic interactions of fingolimod with other medicinal products
Interactions between fingolimod and agents primarily metabolized by CYP450 isoenzymes or substrates of major transport proteins are unlikely.
No changes in exposure of cyclosporine or fingolimod were observed when fingolimod was administered concomitantly with cyclosporine. Therefore, changes in the pharmacokinetics of medicinal products that are substrates of the CYP3A4 isoenzyme due to fingolimod are not expected.
Concomitant administration of fingolimod and oral contraceptives (ethinylestradiol and levonorgestrel) did not alter the exposure of oral contraceptives. Despite the lack of interaction studies with oral contraceptives containing other progestogens, an effect of fingolimod on them is not expected.
Special precautions for use.
Bradialrhythmia
At the beginning of treatment with Fosfado, a temporary decrease in heart rate is observed, which may be accompanied by slowing of atrioventricular conduction, including isolated cases of transient complete atrioventricular block that resolves spontaneously.
After administration of the first dose, reduction in heart rate begins within 1 hour and reaches a maximum approximately 6 hours later. This effect persists for several subsequent days after administration of the drug, although it is usually less pronounced and typically resolves within several weeks. With continued treatment, the average heart rate (HR) returns to baseline levels within one month, although in some patients HR may not return to baseline by the end of the first month of treatment. Conduction disturbances were generally transient and clinically asymptomatic. These changes usually do not require treatment and resolve within the first 24 hours of treatment. If heart rate reduction caused by fingolimod needs to be reversed, it can be counteracted by parenteral administration of atropine or isoprenaline.
Before administration of Fosfado and 6 hours after the first dose, all patients should undergo electrocardiography (ECG) and blood pressure (BP) measurement. Continuous hourly monitoring of pulse rate and BP for 6 hours is recommended to detect symptoms of bradycardia. During this 6-hour period, continuous (real-time) ECG monitoring is recommended.
When switching patients from a daily dose of 0.25 mg to a daily dose of 0.5 mg, the same safety measures as after the first dose are recommended.
If symptoms of bradyarrhythmia occur after administration of the drug, appropriate therapeutic measures should be initiated and the patient should be monitored until symptoms resolve. If the patient requires medical treatment during the period following the first dose of Fosfado, overnight monitoring in a hospital setting is required, as well as observation after the first and second doses of fingolimod.
If 6 hours after administration the HR is at its lowest since the first dose (indicating that the maximum pharmacodynamic effect on the heart may not yet have fully manifested), monitoring should be extended for at least 2 additional hours and until HR increases again. Furthermore, if 6 hours after administration the HR is <45 beats per minute in adults, <55 beats per minute in children aged 12 years or older, or <60 beats per minute in children aged 10 to 12 years, or if ECG shows new-onset second-degree or higher atrioventricular block, or if QTc interval is ≥500 ms, extended monitoring (at least overnight) should be performed until these abnormalities resolve. The occurrence of third-degree atrioventricular block at any time also requires extended monitoring (at least overnight).
The effect of Fosfado on HR and atrioventricular conduction may reappear upon resumption of treatment and depends on the duration of the treatment interruption and time since treatment initiation. Monitoring after the first dose should be performed as at the beginning of treatment in the following cases of treatment interruption:
- for 1 day or more during the first 2 weeks of treatment;
- for more than 7 days during the 3rd or 4th week of treatment;
- for more than 2 weeks after treatment has lasted longer than 1 month.
If treatment is interrupted for a shorter period than specified above, treatment should be continued with the next scheduled dose.
Very rare cases of T-wave inversion have been reported in adult patients receiving fingolimod. In case of T-wave inversion, the physician should ensure the absence of other signs or symptoms of myocardial ischemia. If myocardial ischemia is suspected, cardiology consultation is recommended.
Due to the risk of serious cardiac arrhythmias or significant bradycardia, Fosfado should not be prescribed to patients with sinoatrial block, symptomatic bradycardia, recurrent episodes of syncope or cardiac arrest in medical history, patients with significant QT interval prolongation (adult women: QTc > 470 ms, girls: QTc > 460 ms, adult men and boys: > 450 ms), uncontrolled hypertension, or severe sleep apnea. In such cases, treatment with Fosfado may be considered only if the expected benefit outweighs the potential risk. Prior to initiating treatment, cardiology consultation should be obtained to determine the optimal method of cardiac monitoring. Extended monitoring, at least overnight, is recommended at the beginning of treatment.
The use of Fosfado in patients with arrhythmias requiring treatment with class Ia (e.g., quinidine, disopyramide) or class III (e.g., amiodarone, sotalol) antiarrhythmic agents has not been studied. Cases of torsades de pointes tachycardia have been observed in patients with bradycardia receiving class Ia and class III antiarrhythmic agents. Since initiation of Fosfado is associated with decreased HR, concomitant use of Fosfado with such agents is contraindicated.
Experience with fingolimod in patients receiving concomitant therapy with beta-blockers, calcium channel blockers that reduce HR (e.g., verapamil, diltiazem), or other agents capable of reducing HR (e.g., ivabradine, digoxin, anticholinesterase agents, pilocarpine) is limited. Since HR decreases at the beginning of Fosfado treatment, concomitant use of these agents may lead to severe bradycardia and heart block. Due to the potential additive effect on heart rate, treatment with Fosfado should not be initiated in patients receiving these agents simultaneously. Prescribing Fosfado to such patients should be considered only if the expected benefit outweighs the potential risks. If Fosfado treatment is being considered, cardiology consultation is recommended regarding switching the patient to agents that do not reduce HR. If discontinuation of HR-lowering agents is not possible, cardiology consultation is recommended regarding appropriate monitoring after the first administration of Fosfado, and extended monitoring (at least overnight) should be performed.
During the post-marketing period, isolated cases of delayed onset of action within 24 hours after the first dose of the drug have been observed, including transient asystole and a fatal case of unknown cause. Interpretation of these cases was complicated by concomitant medication use and/or underlying disease. The relationship of these events to Fosfado use remains uncertain.
Thus, all patients should be under physician supervision for 6 hours to detect signs and symptoms of bradycardia. As soon as symptoms of bradyarrhythmia occur after drug administration, appropriate treatment should be provided and monitoring continued until symptoms resolve.
QT interval
In a thorough study of the effect of fingolimod at doses of 1.25 or 2.5 mg on the QT interval after reaching steady state, when the negative chronotropic effect of fingolimod was still observed, treatment with this agent resulted in QTcI prolongation with an upper bound of the 90% confidence interval (CI) ≤13.0 ms. No relationship between the dose (exposure)/response of fingolimod and QTcI prolongation was detected. No increased frequency of QTcI interval deviations from normal (by absolute value or change from baseline) associated with fingolimod use was observed.
The clinical significance of these data is unknown. In clinical trials in multiple sclerosis, clinically significant QTc prolongation effect of the drug was not observed, but patients with increased risk of QT prolongation were not included in clinical trials.
Concomitant use of drugs that may cause QTc prolongation should be avoided in patients with significant risk factors, such as hypokalemia or congenital QT prolongation.
Immunosuppressive effect
Fingolimod has an immunosuppressive effect, increasing the risk of infections, including opportunistic infections, which may be fatal, and increasing the risk of lymphomas and other malignancies, particularly of the skin. Physicians should carefully monitor patients, especially those with comorbidities or known risk factors, such as prior immunosuppressive therapy. If such risk is suspected, the physician should consider discontinuing treatment on an individual basis.
Infections
The key pharmacodynamic effect of Fosfado is a dose-dependent reduction in the number of lymphocytes in peripheral blood to 20–30% of baseline levels. This is due to the redistribution of lymphocytes to lymphoid tissue.
Before starting treatment, a recent complete blood count (performed within the last 6 months or after completion of the previous treatment course) should be obtained. Complete blood count should also be periodically performed during treatment, at month 3 of therapy and thereafter at least once a year, and in case of signs of infectious disease. If confirmed absolute lymphocyte count is <0.2 × 10⁹/L, the drug should be discontinued until this parameter recovers, as in clinical trials patients with absolute lymphocyte count <0.2 × 10⁹/L had fingolimod therapy discontinued.
Initiation of Fosfado should be delayed in patients with active acute infectious disease until its resolution.
Before starting treatment, patients should be evaluated for immunity to varicella. Before administration of Fosfado, patients without documented history of varicella confirmed by healthcare professionals or without documented complete vaccination against varicella-zoster virus (VZV) should undergo testing for VZV antibodies. It is recommended that patients with negative VZV antibody test results receive a complete course of varicella vaccination before starting treatment. In this case, treatment initiation should be delayed by one month to allow full immune response to vaccination.
Due to the effect of Fosfado on the immune system, the risk of infections, including opportunistic infections, is increased. Therefore, during treatment, effective diagnostic and treatment methods should be used in patients with symptoms of infectious disease. When evaluating a patient suspected of infection that may be serious, consultation with a physician experienced in treating infections should be considered. Patients receiving Fosfado should be informed that if symptoms of infection occur during treatment, they should report them to their physician.
If a patient develops a serious infectious disease, temporary discontinuation of Fosfado should be considered, and resumption of therapy should only occur after evaluation of the benefit-risk ratio.
During the post-marketing surveillance period, cases of cryptococcal meningitis (fungal infection), sometimes fatal, have been reported after approximately 2–3 years of treatment, although the exact relationship with treatment duration is not established. Patients with symptoms and signs suggestive of cryptococcal meningitis (e.g., headache accompanied by changes in mental status such as confusion, hallucinations, and/or personality changes) should undergo immediate thorough diagnostic evaluation. If the diagnosis of cryptococcal meningitis is confirmed, fingolimod treatment should be discontinued and appropriate treatment initiated. If resumption of fingolimod treatment is necessary, consultations with other specialists (e.g., infectious disease specialist) should be conducted.
During post-marketing use of fingolimod, cases of progressive multifocal leukoencephalopathy (PML) have been reported. PML is an opportunistic infection caused by the John Cunningham virus (JC virus) that can lead to severe disability or death. Cases of PML occurred after 2–3 years of monotherapy in patients who had not previously received natalizumab. Despite the increasing expected risk with cumulative drug exposure over time, the relationship with treatment duration is not definitively known. Additional cases of PML have been reported in patients who previously received natalizumab, which is already known to be associated with PML. PML development is only possible with JC virus infection. When testing for JC virus, it should be remembered that the effect of lymphopenia on the reliability of JC virus antibody test results in patients receiving fingolimod has not been studied. It should also be noted that a negative JC virus antibody test result does not exclude future JC virus infection. Before starting fingolimod treatment, a baseline MRI (usually performed no earlier than 3 months before treatment initiation) should be obtained for future comparison. MRI changes may appear earlier than clinical signs and symptoms. During routine MRI scans (according to national and local recommendations), physicians should pay special attention to lesions suggestive of PML. MRI may be considered one of the preventive measures for patients at high risk of PML. Cases of asymptomatic PML detected by MRI and positive JC virus DNA in cerebrospinal fluid have been reported. In patients receiving fingolimod, if PML is suspected, diagnostic MRI should be performed immediately and fingolimod therapy suspended until PML is ruled out.
During the post-marketing period of fingolimod use, cases of human papillomavirus (HPV) infection have been observed, including development of papillomas, dysplasia, warts, and HPV-associated cancers. Due to the immunosuppressive effect of fingolimod, vaccination against HPV should be considered before starting therapy with this drug, taking into account vaccination recommendations. Oncological screening, including Pap smear, is also recommended according to standard medical care guidelines.
Elimination of fingolimod after discontinuation of treatment may take up to 2 months, so the possibility of infections should be considered during this period. Patients should be informed of the need to immediately report any symptoms of infection to their physician within 2 months after discontinuation of fingolimod.
Macular edema
Macular edema, with or without visual symptoms, occurred in 0.5% of patients receiving fingolimod 0.5 mg, most often within the first 3–4 months of treatment. Therefore, ophthalmological examination is recommended 3–4 months after starting treatment. If visual disturbances occur during treatment, fundus examination, including the macular area, should be performed.
Patients with a history of uveitis and patients with diabetes mellitus have an increased risk of macular edema. Fosfado has not been studied in patients with multiple sclerosis and concomitant diabetes. Therefore, ophthalmological examination before starting treatment and periodically during treatment is recommended for patients with multiple sclerosis and diabetes or a history of uveitis.
The consequences of continuing fingolimod in patients with macular edema have not been evaluated. In case of macular edema development, discontinuation of fingolimod treatment is recommended. When considering resumption of fingolimod therapy after resolution of macular edema, potential benefits and risks for each individual patient should be considered.
Liver function
Elevations in liver enzymes, particularly alanine aminotransferase (ALT), as well as gamma-glutamyl transferase (GGT) and aspartate aminotransferase (AST), have been reported in patients with multiple sclerosis receiving the drug. During clinical trials, 8% of adult patients receiving fingolimod 0.5 mg experienced ALT levels more than 3 times the upper limit of normal (ULN), compared to 1.9% of placebo patients. Fivefold ULN elevation was observed in 1.8% of fingolimod patients and 0.9% of placebo patients. In clinical trials, fingolimod treatment was discontinued if liver transaminase levels exceeded 5 times ULN. Recurrent elevation of liver transaminases occurred upon resumption of fingolimod treatment in some patients, confirming the association of this adverse event with fingolimod use. In clinical trials, transaminase elevations occurred at any time during treatment, although most cases occurred within the first 12 months. Normalization of serum transaminase levels occurred approximately within 2 months after discontinuation of fingolimod treatment.
Use of the drug in patients with severe hepatic impairment at treatment initiation (Child-Pugh class C) has not been studied and is therefore not recommended.
Due to the immunosuppressive properties of fingolimod, initiation of treatment in patients with active viral hepatitis should be delayed until resolution.
Before starting fingolimod treatment, recent (within the last 6 months) test results for transaminase and bilirubin levels should be available. In the absence of clinical symptoms, monitoring of liver transaminase activity should be performed at 1, 3, 6, 9, and 12 months of treatment and periodically thereafter. If transaminase levels exceed 5 times ULN, more frequent monitoring should be implemented, including measurement of bilirubin and alkaline phosphatase (ALP) in serum. If transaminase levels exceeding 5 times ULN are repeatedly confirmed, fingolimod treatment should be discontinued and resumed only after normalization of transaminase levels.
In patients with symptoms suggesting liver dysfunction, such as unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine, liver enzyme activity should be checked, and fingolimod treatment should be discontinued if significant liver injury is confirmed (e.g., if liver transaminase activity exceeds 5 times ULN and/or elevated bilirubin in serum). The decision on resuming therapy will depend on whether another cause of liver injury is identified and on the benefit-risk ratio for resuming therapy in the patient.
Although there are no data indicating a risk of increased liver test abnormalities with use of the drug in patients with pre-existing liver disease, caution should be exercised when prescribing Fosfado to patients with a history of severe liver disease.
Effect on serological test results
Since fingolimod reduces the number of lymphocytes in blood by redistributing them to secondary lymphoid organs, the peripheral blood lymphocyte count cannot be used to assess the status of lymphocyte subpopulations in patients receiving treatment. For laboratory tests using circulating mononuclear cells, a larger blood volume is required due to reduced circulating lymphocyte count.
Effect on blood pressure
Patients with uncontrolled hypertension not managed by medication were not included in pre-registration clinical trials; therefore, special caution should be exercised when using fingolimod in patients with uncontrolled hypertension.
In clinical trials of multiple sclerosis, patients receiving fingolimod 0.5 mg showed an increase in mean systolic pressure of approximately 3 mm Hg and diastolic pressure of approximately 1 mm Hg; this effect was first observed about 1 month after starting treatment and persisted during continued treatment. In a two-year placebo-controlled trial, hypertension was reported as an adverse event in 6.5% of patients receiving fingolimod 0.5 mg and 3.3% of placebo patients. Therefore, blood pressure should be regularly monitored during fingolimod treatment.
Respiratory effects
A slight dose-dependent decrease in forced expiratory volume (FEV1) and diffusing capacity of the lungs for carbon monoxide (DLCO) was observed 1 month after starting treatment with the drug, and these parameters remained stable thereafter. The drug should be used with caution in patients with severe respiratory disease, pulmonary fibrosis, and chronic obstructive pulmonary disease.
Reversible posterior leukoencephalopathy syndrome
Rare cases of reversible posterior leukoencephalopathy syndrome (RPLS) have been reported during clinical trials and in the post-marketing period with use of the drug at a dose of 0.5 mg. Symptoms included sudden onset of severe headache, nausea, vomiting, altered mental status, visual disturbances, and seizures. RPLS symptoms are usually reversible but may progress to ischemic or hemorrhagic stroke. Delay in diagnosis and treatment may lead to irreversible neurological deficits. If RPLS is suspected, the drug should be discontinued.
Prior immunosuppressive or immunomodulatory therapy
Studies evaluating the efficacy and safety of fingolimod in patients switched from teriflunomide, dimethyl fumarate, or alemtuzumab have not been conducted. When switching patients from another disease-modifying therapy to fingolimod, the half-life and mechanism of action of the drug should be considered to avoid additive effects on the immune system while minimizing the risk of disease reactivation. Complete blood count is recommended before starting fingolimod to ensure no residual effect of prior therapy on the immune system (i.e., cytopenia).
Fingolimod can usually be started immediately after discontinuation of interferon beta or glatiramer acetate.
For dimethyl fumarate, the washout period should be sufficient for blood parameters to return to normal before starting fingolimod treatment.
Due to the long half-life of natalizumab, 2–3 months are required for its elimination after discontinuation of therapy. Elimination of teriflunomide from plasma is also slow. Without accelerated elimination procedures, elimination of teriflunomide from plasma may take from several months to 2 years. It is recommended to perform the accelerated elimination procedure described in the teriflunomide product characteristics or, alternatively, a washout period of at least 3.5 months. Caution should be exercised when switching patients from natalizumab or teriflunomide to Fosfado, considering the potential for additional effects on the immune system.
Alemtuzumab has a profound and prolonged immunosuppressive effect. Since the actual duration of this effect is unknown, initiating therapy with the drug after alemtuzumab is not recommended, except when the expected benefit significantly outweighs the risks for a specific patient.
The decision on long-term concomitant use of corticosteroids should be made after careful evaluation.
Concomitant use of strong CYP450 inducers
Fingolimod should be used with caution in combination with strong CYP450 inducers. Concomitant use of St. John's wort is not recommended (see section "Interaction with other medicinal products and other forms of interaction").
Malignant neoplasms
Skin malignancies
Cases of basal cell carcinoma (BCC) and other skin tumors, including malignant melanoma, squamous cell carcinoma, Kaposi's sarcoma, and Merkel cell carcinoma, have been observed in patients receiving the drug. Skin tumors can be serious; therefore, a medical examination with skin inspection is recommended before starting treatment. Subsequent examinations are recommended every 6–12 months at the physician's discretion. If suspicious lesions are detected, the patient should be referred to a dermatologist.
Considering the potential risk of malignant tumors, patients receiving fingolimod should be informed of the need to use sun protection. Such patients are contraindicated for UV therapy or PUVA therapy (photochemotherapy) during fingolimod treatment.
Lymphomas
Cases of lymphoma have been observed in clinical trials and during the post-marketing period of the drug. The reported cases were heterogeneous in nature, predominantly non-Hodgkin's lymphoma, including B-cell and T-cell lymphomas. Cases of cutaneous T-cell lymphoma (mycosis fungoides) have occurred. A fatal case of Epstein-Barr virus (EBV)-positive B-cell lymphoma was also observed. If lymphoma is suspected, the drug should be discontinued.
Women of childbearing potential
Due to risks to the fetus, fingolimod is contraindicated during pregnancy and in women of childbearing potential who do not use effective contraception. Before starting fingolimod treatment, women of childbearing potential should be informed of the serious risk to the fetus and the need to use effective contraception during treatment and for 2 months after its completion.
Tumor-like demyelinating lesions
Rare cases of tumor-like demyelinating lesions associated with multiple sclerosis exacerbation have been identified during the post-marketing period. In case of severe exacerbation, MRI should be performed to rule out tumor-like lesions. The physician should consider discontinuing Fosfado on an individual basis, taking into account benefits and risks for the specific patient.
Return of active disease (relapse) after discontinuation of drug therapy
Severe exacerbations of the disease have been observed in the post-marketing period in patients who discontinued fingolimod. Worsening usually occurred within 12 weeks after discontinuation of the drug, but cases of worsening after 24 weeks or more have also been observed. Therefore, caution should be exercised when discontinuing fingolimod therapy. If discontinuation of the drug is necessary, the possibility of return of very high disease activity should be considered, and patients should be monitored for development of corresponding symptoms and signs, and appropriate treatment provided if necessary.
Discontinuation of therapy
If a decision is made to discontinue treatment, a 6-week interval without medication is required to eliminate fingolimod from the bloodstream. This interval is determined by the drug's half-life. In most patients, lymphocyte count usually returns to the normal range within 1–2 months after discontinuation of treatment, although for some patients, complete recovery may take significantly longer. Resuming treatment during this period will result in concomitant exposure to fingolimod. Use of immunosuppressants shortly after discontinuation of the drug may exert additional suppressive effects on the immune system, so caution is required.
Caution should also be exercised when discontinuing fingolimod therapy due to the risk of disease relapse. If discontinuation of the drug is necessary, patients should be monitored after discontinuation for signs of possible disease relapse.
Thrombocytopenia
Thrombocytopenia may develop. Blood tests should be performed before and periodically during use of this drug.
Cases of severe disease exacerbation compared to pre-treatment levels have been reported after discontinuation of treatment, usually observed within 24 weeks after discontinuation of the drug.
Paediatric population
The safety profile of the drug in paediatric patients is similar to that in adults; therefore, warnings and precautions applicable to adults also apply to paediatric patients.
Specifically, when prescribing fingolimod to paediatric patients, the following precautions should be considered:
- Precautions should be taken when administering the first dose. When switching patients from a daily dose of 0.25 mg to a daily dose of 0.5 mg, the same safety measures as for the first dose are recommended.
- In the controlled paediatric study D2311, seizures, anxiety, depressed mood, and depression occurred more frequently in patients receiving fingolimod compared to those receiving interferon beta-1a. Caution should be exercised in this patient subgroup.
- Slight isolated elevation of bilirubin levels was observed in paediatric patients receiving fingolimod.
- Before starting therapy, paediatric patients should receive all vaccinations according to the current vaccination schedule.
- Clinical trial data in children aged 10 to 12 years, children with body weight less than 40 kg, or Tanner stage <2 are very limited. Therefore, caution is required in these subgroups.
- Long-term safety data for children are lacking.
Use during pregnancy or breastfeeding.
Women of childbearing potential / contraception in women
Fosfado is contraindicated in women of childbearing potential who do not use effective contraception. Therefore, before starting treatment, women of childbearing potential should have a negative pregnancy test and should be informed of the serious risk to the fetus. Women of childbearing potential should use effective contraception during treatment and for 2 months after its completion, as elimination of Fosfado from the body after discontinuation of treatment takes about two months.
When discontinuing treatment due to planned pregnancy, the possibility of return of active disease should be considered.
Pregnancy
Available post-marketing data on the use of fingolimod in humans suggest that use of Fosfado during pregnancy may be associated with a 2-fold increase in the risk of major congenital malformations compared to the frequency in the general population (2–3%, EUROCAT).
The most frequently reported major malformations were:
- congenital heart defects, e.g., atrial and ventricular septal defects, tetralogy of Fallot;
- kidney abnormalities;
- musculoskeletal system abnormalities.
Data on the effect of fingolimod on delivery and childbirth are lacking.
Animal studies have demonstrated reproductive toxicity, including fetal death and organ developmental abnormalities, such as persistent patent ductus arteriosus and ventricular septal defect. Additionally, it is known that the receptor affected by fingolimod (sphingosine-1-phosphate receptor) is involved in vascular formation during embryogenesis.
Therefore, fingolimod is contraindicated during pregnancy. Fingolimod use should be discontinued 2 months before planned pregnancy. If a woman becomes pregnant during Fosfado treatment, it should be discontinued.
Breastfeeding period
Fingolimod penetrated into the milk of animals administered the drug during lactation. Due to the potential for serious adverse reactions to fingolimod in breastfed infants, women should discontinue breastfeeding during use of the drug.
Fertility
Preclinical study data do not indicate that fingolimod use increases the risk of reduced fertility.
Ability to affect reaction speed when driving or operating machinery.
The effect of Fosfado on the ability to drive or operate machinery is absent or negligible.
However, dizziness or somnolence may occasionally occur at the beginning of treatment with this drug. Monitoring of the patient during the 6-hour period is recommended at the beginning of treatment.
Method of Administration and Dosage
Treatment should be initiated and supervised by a physician experienced in the management of multiple sclerosis.
Method of Administration
This medicinal product is intended for oral use.
Dosage
The recommended dose of Fosfado for adult patients is 1 capsule of 0.5 mg taken orally once daily.
For pediatric patients (aged 10 years and older), the recommended dose depends on body weight:
- for children with body weight ≤ 40 kg: 1 capsule of 0.25 mg (if such a dosage strength is available) taken orally once daily;
- for children with body weight > 40 kg: 1 capsule of 0.5 mg taken orally once daily.
Pediatric patients who initiated treatment with 0.25 mg capsules (if such a dosage strength is available) and subsequently reached a stable body weight above 40 kg should be switched to treatment with 0.5 mg capsules.
When switching from a daily dose of 0.25 mg (if such a dosage strength is available) to a daily dose of 0.5 mg, the patient should be monitored after the first dose in the same manner as at treatment initiation.
The medicinal product may be administered regardless of food intake.
Capsules must always be swallowed whole and should not be opened.
Similarly to treatment initiation, monitoring after the first dose is recommended in case of treatment interruption:
- for 1 day or more during the first 2 weeks of treatment;
- for more than 7 days during the 3rd or 4th week of treatment;
- for more than 2 weeks after treatment has continued for over one month.
If treatment is interrupted for a shorter duration than specified above, treatment should be resumed with the next scheduled dose.
Dosage for Specific Patient Groups
Elderly Patients
Fosfado should be used with caution in patients aged 65 years and older, as there is insufficient data on safety and efficacy in this population.
Renal Impairment
The use of Fosfado in patients with multiple sclerosis and renal impairment has not been studied in clinical trials. However, based on clinical pharmacology studies, dose adjustment is not required for patients with mild to severe renal impairment.
Hepatic Impairment
Fosfado is contraindicated in patients with severe hepatic impairment (Child–Pugh class C). Dose adjustment is not required for patients with mild to moderate hepatic impairment; however, caution should be exercised at the beginning of treatment.
Pediatric Population
The safety and efficacy of Fosfado in children under 10 years of age have not been established. Relevant data are lacking.
Very limited data are available for children aged 10–12 years.
Children
The safety and efficacy of Fosfado in children under 10 years of age have not been established. Relevant data are lacking.
Very limited data are available for children aged 10–12 years.
Overdose
Single doses up to approximately 80 times the recommended dose (0.5 mg) have been well tolerated in healthy volunteers. At a dose of 40 mg, mild sensations of chest tightness or discomfort, clinically consistent with mild bronchial reactivity, were reported in 5 out of 6 subjects.
At the beginning of treatment, fingolimod may cause bradycardia. A decrease in heart rate is typically observed within one hour after the first dose, with the maximum reduction occurring within 6 hours. The negative chronotropic effect of the drug persists beyond 6 hours but gradually diminishes over subsequent days of treatment. Reports of slow atrioventricular conduction have been received, along with isolated cases of transient complete atrioventricular block resolving spontaneously.
In the event of overdose following the first dose, it is essential to monitor the patient with continuous ECG monitoring (in real time) and hourly measurement of pulse rate and blood pressure for at least the first 6 hours.
Additionally, if the heart rate is <45 beats per minute in adults, <55 beats per minute in children aged 12 years and older, or <60 beats per minute in children aged 10–12 years after 6 hours, or if ECG at 6 hours after the first dose shows signs of second-degree or higher atrioventricular block, or if QTc interval is ≥500 ms, extended monitoring (at least overnight) should be performed until these findings resolve. The occurrence of third-degree atrioventricular block at any time also requires extended monitoring, including overnight observation.
Dialysis or plasma exchange does not result in significant elimination of fingolimod from the body.
Adverse reactions.
The adverse reactions observed during administration of fingolimod 0.5 mg in the D2301 (FREEDOMS) and D2309 (FREEDOMS II) studies, as well as those identified during the post-marketing period, are listed in Table 1 below. The frequency of adverse reactions was defined according to the following criteria: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); frequency not known (cannot be estimated based on available data).
Table 1
List of adverse reactions
| Infections and infestations |
|
| Very common |
Influenza Sinusitis |
| Common |
Herpes virus infections Bronchitis Tinea versicolor |
| Uncommon |
Pneumonia |
| Frequency not known |
Progressive multifocal leukoencephalopathy (PML)** Cryptococcal infections** |
| Benign, malignant and unspecified neoplasms (including additional cysts and polyps) |
|
| Common |
Basal cell carcinoma |
| Uncommon |
Malignant melanoma**** |
| Rare |
Lymphoma** Squamous cell carcinoma**** |
| Very rare |
Kaposi's sarcoma**** |
| Frequency not known |
Merkel cell carcinoma*** |
| Blood and lymphatic system disorders |
|
| Common |
Lymphopenia Leukopenia |
| Serious adverse reaction |
Thrombocytopenia |
| Frequency not known |
Autoimmune hemolytic anemia*** Peripheral edema*** |
| Immune system disorders |
|
| Frequency not known |
Hypersensitivity reactions, including rash, urticaria, and angioedema after initiation of treatment*** |
| Psychiatric disorders |
|
| Common |
Depression |
| Uncommon |
Depressed mood |
| Nervous system disorders |
|
| Very common |
Headache |
| Common |
Dizziness Migraine |
| Uncommon |
Seizures |
| Rare |
Reversible posterior leukoencephalopathy syndrome (RPLS)* |
| Frequency not known |
Severe exacerbation of disease after drug discontinuation*** |
| Eye disorders |
|
| Common |
Blurred vision |
| Uncommon |
Macular edema |
| Cardiac disorders |
|
| Common |
Bradycardia Atrioventricular block |
| Very rare |
T-wave inversion*** |
| Vascular disorders |
|
| Common |
Arterial hypertension |
| Respiratory, thoracic and mediastinal disorders |
|
| Very common |
Cough |
| Common |
Dyspnea |
| Gastrointestinal disorders |
|
| Very common |
Diarrhea |
| Uncommon |
Nausea*** |
| Hepatobiliary disorders |
|
| Frequency not known |
Acute liver failure*** |
| Skin and subcutaneous tissue disorders |
|
| Common |
Atopic dermatitis Alopecia Pruritus |
| Musculoskeletal and connective tissue disorders |
|
| Very common |
Back pain |
| Common |
Myalgia Arthralgia |
| General disorders and administration site conditions |
|
| Common |
Generalized weakness |
| Investigations |
|
| Very common |
Elevated liver enzyme levels (increased ALT, GGT, AST) |
| Common |
Weight loss*** Elevated blood triglyceride levels |
| Uncommon |
Decreased neutrophil count |
| * Not observed in the FREEDOMS, FREEDOMS II, and TRANSFORMS studies. Frequency category based on data from approximately 10,000 patients treated with fingolimod in all clinical trials. ** PML and cryptococcal infections, including cases of cryptococcal meningitis, observed during the post-marketing period. *** Adverse reactions reported from spontaneous reports and scientific literature. **** Frequency category and risk assessment were based on estimated exposure to fingolimod 0.5 mg in over 24,000 patients during clinical trials. |
|
Description of individual adverse reactions
Infections
In clinical trials of multiple sclerosis, the overall incidence of infections (65.1%) with the 0.5 mg dose was similar to that observed with placebo. However, lower respiratory tract infections, primarily bronchitis, and to a lesser extent, herpes virus infections and pneumonia, were more frequently observed in patients treated with Fosdago.
Disseminated herpes virus infections, including fatal cases, have been reported with the 0.5 mg dose.
During the post-marketing period, infections caused by opportunistic microorganisms have been reported, including viral (including varicella-zoster virus [VZV], John Cunningham virus [JC virus], which causes progressive multifocal leukoencephalopathy, and herpes simplex virus [HSV]), fungal (including those caused by yeast-like fungi, such as cryptococcal meningitis), or bacterial (including those caused by atypical mycobacteria), some of which were fatal.
During the post-marketing period of fingolimod use, human papillomavirus (HPV) infections have been observed, including the development of papillomas, dysplasia, warts, and HPV-associated cancers. Since fingolimod has immunosuppressive effects, HPV vaccination should be considered before initiating therapy with this medicinal product, in accordance with vaccination guidelines. Oncological screening, including Pap smear testing, is also recommended according to standard medical care practices.
Macular edema
In clinical trials of multiple sclerosis, macular edema was observed in 0.5% of patients receiving the recommended dose of 0.5 mg and in 1.1% of patients receiving the maximum dose of 1.25 mg. Most cases occurred within the first 3–4 months of treatment. Some patients developed blurred vision or decreased visual acuity, while in others, the condition was asymptomatic and diagnosed during routine ophthalmological examination. Macular edema typically decreased or resolved spontaneously after discontinuation of Fosdago. The risk of recurrence upon re-initiation of the medicinal product has not been evaluated.
The incidence of macular edema is higher in patients with multiple sclerosis and a history of uveitis (17% compared to 0.6% in patients without a history of uveitis). The use of Fosdago in patients with multiple sclerosis and diabetes mellitus—a condition associated with an increased risk of macular edema—has not been studied. In kidney transplant studies involving patients with diabetes, the use of Fosdago at doses of 2.5 mg and 5 mg was associated with a twofold increase in the incidence of macular edema.
Bradycardia
Transient reduction in heart rate and possible slowing of atrioventricular conduction may occur upon initiation of Fosdago. In clinical trials of multiple sclerosis, the maximum decrease in heart rate occurred 6 hours after administration of the 0.5 mg dose, with a mean reduction of 12–13 beats per minute. Heart rates below 40 beats per minute in adults and below 50 beats per minute in children were rarely observed in patients receiving Fosdago at the 0.5 mg dose. Mean heart rate returned to baseline levels within 1 month of regular treatment. Bradycardia was generally asymptomatic, but some patients experienced mild to moderate symptoms, including hypotension, dizziness, weakness, and/or palpitations, which resolved within the first 24 hours after treatment initiation.
In clinical trials of multiple sclerosis in adults and pediatric patients, first-degree atrioventricular block (prolonged PR interval on ECG) occurred after treatment initiation. In adult clinical trials, this occurred in 4.7% of patients receiving Fosdago at 0.5 mg, 2.8% of patients receiving intramuscular interferon beta-1a, and 1.6% of patients in the placebo group. Second-degree atrioventricular block occurred in less than 0.2% of adult patients receiving Fosdago at 0.5 mg. During the post-marketing period, isolated cases of transient complete atrioventricular block, resolving spontaneously, were observed within the 6-hour monitoring period after the first dose. Patients recovered without symptomatic treatment. Conduction disturbances observed in clinical trials and during the post-marketing period were generally transient, asymptomatic, and resolved within the first 24 hours after treatment initiation. Although most patients did not require pharmacological treatment, one patient receiving Fosdago at 0.5 mg was administered isoprenaline for asymptomatic second-degree Mobitz type I atrioventricular block.
During the post-marketing period, isolated delayed events, including transient asystole, and one fatal case of unknown cause within 24 hours after the first dose, have been reported. In these cases, other medicinal products were co-administered and/or patients had comorbidities. A causal relationship with Fosdago has not been established.
Blood pressure
In clinical trials of multiple sclerosis, administration of Fosdago at 0.5 mg was associated with a slight increase in systolic blood pressure by approximately 3 mm Hg and diastolic blood pressure by approximately 1 mm Hg, observed about 1 month after treatment initiation. This increase persisted during continued treatment. Elevated blood pressure was observed in 6.5% of patients receiving fingolimod 0.5 mg and in 3.3% of patients receiving placebo. During the post-marketing period, cases of increased blood pressure were reported within the first month after treatment initiation and on the first day of administration, sometimes requiring antihypertensive therapy or discontinuation of the medicinal product.
Liver function
Elevated liver enzyme activity has been observed in adult and pediatric patients with multiple sclerosis receiving Fosdago. In clinical trials of multiple sclerosis, asymptomatic increases in serum ALT levels exceeding 3 times the upper limit of normal (ULN) occurred in 8.0% of adult patients and exceeding 5 times ULN in 1.8% of adult patients receiving Fosdago at 0.5 mg. Recurrent elevations in liver transaminases were observed in some cases upon re-initiation of treatment, confirming the association of this effect with the medicinal product. In clinical trials, transaminase elevations occurred at any time during treatment, although most cases occurred within the first 12 months. ALT levels returned to normal within approximately 2 months after discontinuation of the medicinal product. In a small number of patients (N = 10 for 1.25 mg, N = 2 for 0.5 mg) who had ALT elevations exceeding 5 times ULN and continued treatment, ALT levels normalized within approximately 5 months.
Disorders of the nervous system
Rare neurological disorders were observed in clinical trials in patients receiving high doses (1.25 or 5.0 mg) of the medicinal product, including ischemic and hemorrhagic stroke and atypical neurological disorders such as those resembling acute disseminated encephalomyelitis (ADEM).
Seizures, including epileptic status, have been reported in clinical trials and during the post-marketing period with fingolimod use.
Vascular disorders
Peripheral arterial occlusion was rarely observed in patients receiving higher doses of fingolimod (1.25 mg).
Respiratory system
A slight dose-dependent reduction in forced expiratory volume (FEV1) and diffusing capacity of the lungs for carbon monoxide (DLCO) was observed during the first month of treatment and persisted thereafter. At 24 months of treatment, the percentage reduction from predicted baseline FEV1 values was 2.7% in patients receiving fingolimod 0.5 mg and 1.2% in those receiving placebo; this difference was no longer apparent after treatment discontinuation. DLCO reduction at 24 months was 3.3% in patients receiving fingolimod 0.5 mg and 2.7% in those receiving placebo.
Lymphomas
Various types of lymphomas, including a fatal case of Epstein-Barr virus (EBV)-positive B-cell lymphoma, have been observed in clinical trials and during the post-marketing period. The incidence of lymphoma (B-cell and T-cell) was higher than expected in the general population in clinical trials. During the post-marketing period, several cases of T-cell lymphoma, including cutaneous T-cell lymphoma (mycosis fungoides), have also been reported.
Hemophagocytic syndrome
Very rare cases of hemophagocytic syndrome (HFS) with fatal outcomes have been reported in patients receiving fingolimod, associated with infectious diseases. HFS is a rare condition associated with infectious diseases, immunosuppression, and various autoimmune disorders.
Pediatric population
In the controlled pediatric study D2311, the safety profile of the medicinal product in pediatric patients (aged 10 to 18 years) receiving fingolimod at 0.25 mg or 0.5 mg daily was generally similar to that described in adult patients. However, neurological and psychiatric disorders were more frequently observed in this study. Caution is required in this patient subgroup due to the very limited clinical trial data available.
In the pediatric study, seizures were reported in 5.6% of patients receiving fingolimod and 0.9% of patients receiving interferon beta-1a.
Depression and anxiety are known to occur more frequently in patients with multiple sclerosis. Depression and anxiety were also observed in pediatric patients receiving fingolimod.
A slight isolated increase in bilirubin levels was observed in pediatric patients receiving fingolimod.
Shelf life.
2 years.
Storage conditions.
Store in the original packaging at a temperature not exceeding 25 °C.
Keep out of the reach of children.
Packaging.
7 capsules in a blister, 4 blisters in a cardboard box; 10 capsules in a blister, 3 blisters in a cardboard box.
Prescription status.
Prescription only.
Manufacturer.
Dr. Reddy’s Laboratories Ltd, FTO-7.
Manufacturer’s location and address of business operations.
Plot No. R1-R9, Phase-III, VSEZ, Duvvada, Visakhapatnam District, Andhra Pradesh, 530046, India.
To report an adverse reaction or lack of efficacy during the use of the medicinal product, please call (24/7):
+380 44 207 51 97 or +380 50 414 39 39; or email: [email protected]