Index of drugs

Monotherapy to modify the course of the disease in the relapsing-remitting form of multiple sclerosis with high activity in nw. groups of patients.Patients with high disease activity despite treatment with at least one drug modifying its course - these patients can be defined as those who have not responded to the full, appropriate cycle (usually at least one year) of treatment with at least one disease modifying drug; Patients should have at least one disease output within the last year of treatment and at least 9 hyperintensive T2 lesions in cranial MRI images or at least 1 change in gadolinium-enhancement; "Non-responding patient" can also be defined as a patient with an unchanged or increased relapse frequency or with severe relapses compared to the previous year.Patients with fast-growing, severe, relapsing-remitting form of sclerosissclerosis, defined as 2 or more injections causing disability in one year and 1 or more changes undergone enhancement after gandolin administration in brain MRI images or a significant increase in the number of T2 lesions compared to previous, recent MRI.

1 capsule contains 0.5 mg fingolimod (as hydrochloride).

Sphingosine phosphate receptor modulator 1. Fingolimod is metabolized by sphingosine kinase to the active metabolite fingolimod phosphate. The fingolimod phosphate binds at low nanomolar concentrations to the sphingosine 1 (S1P) phosphate receptor localized on lymphocytes and crosses the blood-brain barrier to then bind to the sphingosine 1 phosphate receptor 1 located on the CNS nerve cells. Acting as a functional antagonist of S1P receptors on lymphocytes, it blocks the ability of lymphocytes to exit the lymph nodes, resulting in their redistribution, not loss. Redistribution of lymphocytes reduces the transmission of pathogenic lymphocytes, including pro-inflammatory Th17 cells to the CNS, where they could participate in inflammation and damage to the nervous tissue. Fingolimod may also act by interacting with S1P receptors on nerve cells. A small number of lymphocytes persists during long-term daily administration of the drug. Prolonged administration of fingolimod leads to a mild reduction in the number of neutrophils to about 80% of baseline values. It does not affect the number of monocytes. Fingolimod is slowly absorbed (T_max12-16 h) and to a large extent (≥85%). Absolute oral bioavailability is 93%. Steady-state blood levels are achieved within 1-2 months of dosing once a day and are approximately 10-fold higher than after the initial dose. Fingolimod is extensively distributed in red blood cells and the percentage of distribution to blood cells is 86%. Focalolimod phosphate is characterized by a lower uptake in blood cells (<17%). Fingolimod and fingolimod phosphate are highly bound to proteins (> 99%). Fingolimod is converted in the mechanism of reversible stereoselective phosphorylation to the pharmacologically active fingolimodium (S) -antiomer. Fingolimod is eliminated in the oxidative biotransformation process catalysed mainly by the CYP4F2 isoenzyme and probably by other isoenzymes (including CYP3A4), and then decomposes into inactive metabolites. Final T_0,5 is 6-9 days. It is excreted in the urine (81%) in the form of inactive metabolites; partly with faeces in the form of fingolimod and fingolimod phosphate.

Hypersensitivity to fingolimod or to other components of the drug. Diagnosed immune deficiency syndrome. Patients with an increased risk of opportunistic infections, including immunocompromised patients (including those currently taking immunosuppressive drugs or patients with immunosuppression as a result of prior treatment). Severe active infection, active chronic infection (hepatitis, tuberculosis). Identified active neoplastic diseases, except for patients with basal cell carcinoma. Severe hepatic impairment (Child-Pugh C).

The initiation of fingolimod therapy causes a transient reduction in heart rate and may also be associated with prolonged atrioventricular conduction, including sporadic cases of transient, spontaneously resolving full atrio-ventricular block. After the first dose, the heartbeat is slowed down within 1 h and the lowest values ​​are reached within 6 h. The negative chronotropic effect of the drug persists> 6 h, gradually decreasing in the following days of treatment. During continuous use, the heart rate returns to baseline within 1 month. If necessary, a reduction in heart rate due to fingolimod can be counteracted by parenteral administration of atropine or isoprenaline. Therefore, all patients should have ECG and blood pressure measurements before and after 6 hours after the first dose. All patients should be monitored for 6 h in the direction of symptoms of bradycardia with hourly measurement of heart rate and blood pressure. Continuous (real-time) monitoring using ECG during this 6-hour period is recommended. If symptoms of bradyarrhythmias develop after administration, appropriate clinical management should be initiated and monitoring should continue until symptoms resolve. If during monitoring after the first dose the patient needs pharmacological intervention, leave the patient to the Next day in a properly equipped medical center for further monitoring, and the monitoring procedure identical to the first dose should be repeated during the second dose. If after 6 hours the heart rate is the lowest since the first dose (suggesting that the maximum pharmacological effects of the drug on the heart may not yet appear), monitoring should be prolonged for at least 2 h until the heart rate increases again. In addition, if after 6 h the heart rate is <45 beats / min or the ECG record indicates the occurrence of a new atrioventricular block at least IIst. or if the QTc interval is ≥500 ms, monitor monitoring should be prolonged (at least pausing the patient until the next day) until these symptoms disappear. The atrioventricular block IIIst. at any time during treatment should also result in prolonged monitoring (at least observation of the patient until the next day). Due to the risk of severe cardiac arrhythmia, the drug should not be used in patients with IIST atrioventricular block. Mobitz II or higher degree, syndrome of a sinus node or sinoatrial block, occurrence of symptomatic bradycardia or recurrent syncope or in patients with significant QT prolongation (QTc> 470 ms - women or> 450 ms - men). In addition, due to the risk of prolonging the QT interval during fingolimod treatment, the use of drugs that may prolong the QTc interval in patients with significant risk factors, for example hypokalaemia or congenital QT prolongation, should be avoided. Fingolimod should also not be used in patients with known ischemic heart disease (including angina pectoris), cerebrovascular disease, a history of myocardial infarction, congestive heart failure, history of cardiac arrest, uncontrolled hypertension or severe sleep apnea; in these patients, fingolimod should only be considered if the anticipated benefits outweigh the possible risks; if the treatment is taken into consideration, the cardiologist should be consulted before the start of the treatment to determine the most appropriate way to monitor the patient, at least monitoring is recommended during the initiation of treatment, leaving the patient under observation the next day. The use of the drug has not been studied in patients with cardiac arrhythmias requiring treatment with Class Ia or Class III anti-arrhythmic drugs - fingolimod should not be used concomitantly with these drugs due to the risk oftorsade de pointes. Do not initiate fingolimod treatment in patients using β-blockers, cardiac Calcium channel blockers (such as Verapamil, diltiazem or ivabradine) or other substances that may reduce heart rate (eg Digoxin, cholinesterase inhibitors or pilocarpine) that due to possible additive effects on the heart,with the risk of severe bradycardia and heart block; in these patients, fingolimod should only be considered if the expected benefit outweighs the possible risk; if you are considering starting your fingolimod treatment, please consult your cardiologist about changing the therapy for treatment with non-reduced heart before fingolimod therapy; if the administration of cardiac medication can not be interrupted, a cardiologist should be consulted to ensure that the patient is adequately monitored after the first dose, and at least the follow-up to the next day after the fingolimod dose is recommended. The same patient monitoring as the first dose when starting treatment is also recommended if fingolimod treatment has been interrupted: one day or more during the first 2 weeks of treatment; > 7 days in the 3rd and 4th week of treatment; > 2 weeks after 1 month of treatment. If treatment has been interrupted for a shorter time than the one mentioned above, you should continue with the next scheduled dose. Before starting treatment, the results of a full blood count should be available (ie performed within the last 6 months or after discontinuation of previous treatment). Assessment of blood counts is also recommended periodically during treatment, in month 3, and later at least once a year and in case of symptoms of infection. If the absolute number of lymphocytes <0.2 x10 is confirmed⁹/ l treatment should be discontinued until return to baseline. The initiation of fingolimod treatment should be postponed in patients with severe active infection until resolution. Before starting treatment, patients' resistance to varicella virus should be evaluated. In patients without chickenpox confirmed by a medical professional or with no documented full course of vaccination against smallpox, a test for antibodies against varicella zoster virus should be carried out (varicella zoster). In patients with a negative antibody test, a full course of vaccination against smallpox is recommended before beginning treatment with fingolimod. To enable the full effect of the vaccine to be developed, fingolimod should be initiated 1 month after vaccination. For patients treated with fingolimod, effective methods of diagnosis and effective therapeutic strategies should be used in the event of symptoms of infection. Consider stopping treatment if a patient develops a severe infection and the benefit-risk of treatment should be evaluated before resuming therapy. The elimination of fingolimod from the body after discontinuation of treatment may take up to 2 months, therefore caution should be exercised on the occurrence of symptoms of infection until the end of this period. Patients should be advised to report signs of infection during fingolimod treatment and after up to 2 months after its completion. Caution should be exercised due to the risk of progressive multifocal leukoencephalopathy (PML). If PML is suspected, a brain MRI scan and / or a test for JC virus DNA in the cerebrospinal fluid should be performed. If PML is confirmed, fingolimod should be discontinued permanently. Due to the risk of macular edema, an ophthalmologic examination is recommended after 3-4 months from the start of treatment. If patients report visual disturbances at any time during treatment, a fundus examination including macular examination should be performed. It is recommended that patients with multiple sclerosis and concomitant diabetes mellitus or uveitis (an increased risk of macular edema) should undergo an ophthalmologic examination prior to commencement of treatment and be subjected to ophthalmologic ophthalmological testing when fingolimod is administered. The effects of continuing treatment in patients with macular edema have not been evaluated. It is recommended to discontinue treatment if the patient develops macular edema. Before deciding whether to resume treatment after the macular edema, the potential benefits and risks of the individual patient should be taken into account. Due to the immunosuppressive properties of fingolimod, initiation of treatment should be delayed in patients with active viral hepatitis until resolution. Before starting treatment, read the last (i.e.obtained in the last 6 months) of transaminase and bilirubin test results. In the absence of clinical symptoms, hepatic transaminase levels should be monitored at 1, 3, 6, 9 and 12 months of treatment and then periodically. If hepatic transaminase increases> 5-fold GGN, follow-up should be performed more frequently, including measurement of serum bilirubin and alkaline phosphatase. With repeated confirmation of elevated liver transaminases> 5-fold GGN, treatment should be discontinued and restarted only if the hepatic transaminase activity is normalized. If symptoms suggestive of liver dysfunction (ie nausea, vomiting, abdominal pain, fatigue, lack of appetite or jaundice and / or dark urine), liver enzymes should be checked and fingolimod should be discontinued if the tests confirm significant liver damage (eg hepatic transaminase> 5-fold GGN and / or increased serum bilirubin). Resumption of treatment will depend on whether you can determine the other cause of liver damage or not and on the patient's benefit of taking treatment as compared to the risk of relapse of liver dysfunction. Caution should be exercised when using fingolimod in patients with a history of significant liver disease; in patients with severe respiratory disease, pulmonary fibrosis and chronic obstructive pulmonary disease (fingolimod may cause small, dose-related reductions in the first-second forced expiratory volume - FEV1 and diffusion capacity for carbon monoxide - DLCO); in patients ≥65 years of age; in patients with uncontrolled hypertension. Blood pressure should be monitored regularly during treatment (risk of hypertension). Treatment should be discontinued if the syndrome of reversible posterior encephalopathy (PRES) is suspected, manifested by severe headache with sudden onset, nausea, vomiting, changes in the mental state, visual disturbances and convulsions. If you decide to stop treatment, you need 6 weeks to stop treatment so that the fingolimod is removed from the body. The number of lymphocytes gradually returns to normal within 1-2 months after the end of treatment. The safety and efficacy of the medicine in children <18 years has not yet been established.

The drug may cause miscarriage (or) birth defects of the fetus, e.g. organ defects, in particular the surviving arterial trunk and ventricular septal defect, in addition, the receptor subject to the influence of fingolimod is involved in the formation of vessels during embryogenesis. Before starting treatment of women of childbearing potential, a negative pregnancy test result must be available. You should use effective contraception throughout the treatment period and for 2 months after the end of therapy. Fingolimod can be excreted in human milk (it is present in animal milk in concentrations 2-3 times higher than the plasma levels determined in the mother's plasma) - due to the risk of serious side effects in infants, women taking the drug should not breastfeed.

Very common: influenza, sinusitis, headache, cough, diarrhea, back pain, increased liver enzymes (ALT, GGT, AST). Common: herpesvirus infections, bronchitis, dandruff, lymphopenia, leukopenia, depression, dizziness, migraine, blurred vision, bradycardia, atrioventricular block, hypertension, dyspnoea, eczema, alopecia, pruritus, weakness, increased triglycerides in the blood. Uncommon: pneumonia, depressed mood, macular edema. Rare: reversible posterior encephalopathy syndrome (PRES). Not known: hypersensitivity reactions, rash, decreased neutrophil count. There have been reports of disseminated herpesvirus infections, including fatal cases, even after a 0.5 mg dose. After the introduction of the drug, transient asystole and death have been observed for unexplained reasons (the assessment of these cases was difficult due to the concurrent use of other drugs and / or coexisting disease). In clinical trials, rare events related to the nervous system occurred in patients treated with fingolimod at higher doses (1.25 or 5.0 mg), including ischemic and haemorrhagic stroke and atypical neurological disorders, such as acute dissemination of encephalitis and spleen (ADEM). Rare cases of obliterative peripheral arterial disease occurred in patients treated with fingolimod at higher doses. There have been cases of various types of lymphomas, both in clinical trials and post-marketing, including the lethal case of B-cell lymphoma associated with Epstein-Barr virus (EBV).One PML has been reported in a patient receiving fingolimod and not treated with early natalizumab or any other immunosuppressant; treatment has been discontinued and the patient has not experienced any signs or symptoms related to PML so far. The incidence of lymphomas (from B and T cells) after fingolimod was higher than expected in the general population. Very rare cases of hemophagocytic syndrome have been reported and fatal in the course of infections.

Oral: 0.5 mg once daily with or without food.Special groups of patients. No dose adjustment is necessary in patients with impaired renal function or in patients with mild or moderate hepatic impairment.