When phylogolimide was used at a dose of 0.5 mg, the following serious adverse events (AEs) were noted: infections, macular edema and transient atrioventricular blockade at the beginning of treatment. The most frequent (frequency ≥10%) when using the drug at a dose of 0.5 mg was headache, increased activity of hepatic transaminases, diarrhea, cough, flu, sinusitis, and back pain.
Below are the undesirable phenomena (AEs) in accordance with the frequency of their occurrence: very often (> 1/10 appointments); often (1 / 10-1 / 100 appointments); infrequently (1 / 100-1 / 1000 appointments); rarely (1 / 1000-1 / 10,000 appointments); very rarely (<1/10000 assignments), including individual messages. Within each frequency, the AH are arranged in decreasing order of gravity. The most frequent cause (frequency more than 1%) of discontinuation of therapy (0.5 mg dose) was an increase in activity of alanine aminotransferase (ALT) - 2.2%.
Infections and infestations: Often - Infections caused by the influenza virus, sinusitis; often - bronchitis, infections caused by the herpes virus, shingles, pityriasis; rarely - pneumonia *.
Violations of the blood and lymphatic system: often - Lymphopenia, leukopenia.
Mental disorders: often - Depression; infrequently - Depressed mood.
Disturbances from the nervous system: Often - headache; often - dizziness, migraine; rarely - a syndrome of reversible posterior encephalopathy.
Disorders from the side of the organ of vision: often - blurred vision; infrequently - macular edema.
Heart Disease: often - bradycardia, atrioventricular block.
Vascular disorders: increased blood pressure.
Disturbances from the respiratory system, chest and mediastinal organs: Often - cough, often - shortness of breath.
Disorders from the gastrointestinal tract: Often - diarrhea.
Disturbances from the skin and subcutaneous tissues: often - eczema, alopecia, itching.
Disturbances from the musculoskeletal and connective tissue: Often - backache.
General disorders: often - asthenia.
Laboratory and instrumental data: Often - increase in activity of hepatic enzymes (ALT, GGT, ACT); often - Increase in triglycerides of blood; infrequently - neutropenia.
* AE, the relationship of which with taking the drug is regarded as "probable."
Infections
When phylogolimoda was used in clinical trials at the recommended dose (0.5 mg once a day) in patients with RRS, the overall incidence of infections (65.1%) was similar to that in the placebo group.
However, in patients who received phingolimod, bronchitis, shingles and pneumonia were more common.
The incidence of serious infections in the group of patients receiving phingolimod in a dose of 0.5 mg, was 1.6%, in the placebo group 1.4%.
There are data on extremely rare deaths caused by infection with the virus Varicella Zoster, in patients who simultaneously received long-term glucocorticosteroid therapy (more than five days) in order to treat the recurrence of RRS, but the cause-and-effect relationship between treatment and death was not established.
In clinical studies with phylogolimoda in patients with RRS receiving short courses of glucocorticosteroids (within five days), there was no increase in the incidence of infections compared with the placebo group.
There are also data on other extremely rare deaths caused by infection with the herpes virus, however, there is no causal link between deaths and the use of phongolimod.
Neurological disorders
There are reports of rare cases of damage to the nervous system in patients receiving phingolimod in high doses (from 1.25 mg to 5.0 mg), with the development of ischemic and hemorrhagic attacks, as well as the syndrome of reversible posterior encephalopathy. There have also been cases of development of atypical neurologic lesions, such as ODEM (acute disseminated encephalomyelitis) -like conditions.
Vascular disorders
When treating patients with phylogolimide at a dose of 1.25 mg occlusion of peripheral arteries was noted. There are single observations on the development of the syndrome of reversible posterior encephalopathy, as well as ischemic and hemorrhagic stroke with phylogolimide in a dose of 0.5 mg.
Macular edema
When the drug was administered at the recommended dose in clinical trials in patients with RRS, the incidence of macular edema was 0.54%. In most cases, the development of macular edema was observed within 3-4 months after the start of treatment. In a number of cases, edema of the macula without clinical manifestations (revealed during routine ophthalmological examination) was observed, in some patients macular edema was accompanied by blurred vision or decreased visual acuity. At the termination of treatment with the drug, in most cases there was a decrease in severity or spontaneous resolution of the edema of the macula. The incidence of macular edema was increased with a history of uveitis.
Bradyarrhythmia
In clinical trials, at the start of treatment with the drug, a transient reduction in the number of cardiac contractions (HR) and a decrease in atrioventricular conduction were noted at the recommended dose.The maximum decrease in heart rate was observed within 6 hours after taking the medication (mean decrease by 12-13 beats per minute), and 70% of the negative chronotropic effect is achieved on the first day of use.
In clinical trials at the beginning of therapy with phygolimide at a dose of 0.5 mg in patients with RRS atrioventricular blockade (AV blockade) of the 1st degree (prolongation of the pulse time in electrocardiography, ECG) was observed in 4.7% (1.6% in the placebo group). AV block of II degree was detected in less than 0.2% of patients who received phingolimod in the recommended dose. Conduction abnormalities observed in both clinical trials and the post-marketing phase were generally transient and asymptomatic, did not require therapy, and occurred within the first 24 hours after initiation of treatment; Some patients experienced symptoms such as lowering blood pressure, dizziness, fatigue, and / or palpitations, which were also resolved on their own within 24 hours. At the postmarketing stage, individual cases of complete AV blockade after receiving the first dose of phongolimoda were carried out which were transient and spontaneously resolved.Although in most cases no medical intervention was required to relieve AEs, in one case in a clinical trial in a patient who received phingolimod in the recommended dose, the asymptomatic AV block of the II degree of the Mobitz type I was stopped with isoprenaline.
There have been cases of asystole and unexplained sudden death after the first administration of the drug, but the connection between phongolimoda and these events has not been proven.
Respiratory system
In the clinical study, after a first month of application of phylogolimide at a dose of 0.5 mg, there was a slight dose-dependent decrease in the volume of forced expiratory volume in the first second (FEV) and diffusivity of the lungs in carbon monoxide (DLCO), In the future, the achieved values of these parameters did not change. The abolition of therapy was accompanied by the normalization of indicators.
Decrease DLCO by the 24th month of the use of phylogolimidine in a dose of 0.5 mg was 3.3% compared with 2.7% in the placebo group.
Increased blood pressure
In clinical studies, the use of the drug at a dose of 0.5 mg in patients with RRS has a slight increase in blood pressure (BP) on average by 3 mm Hg. Art. systolic, by 1 mm Hg. Art. - diastolic.The increase in blood pressure was observed approximately 1 month after the start of treatment and was maintained with the continuation of therapy. Increased blood pressure was noted in 6.5% of patients who received phingolimod in the recommended dose (3.3% in the placebo group). According to post-marketing observations, hypertension was noted during the first month of treatment and in some cases required the use of antihypertensive drugs or interruption of treatment.
Impaired liver function
In clinical studies in patients treated with phylogolimide, there was an increase in activity of hepatic transaminases (predominantly ALT). At a recommended dose of 0.5 mg in 8.0% of cases, there was an asymptomatic increase in ALT activity ≥3 times higher than the upper limit of the norm (VGN) and 1.8% of cases in ≥5 VGN, compared with the placebo group, where data the rates were 1.9% and 0.9%, respectively. In most cases, an increase in ALT activity is observed during the first 6-9 months of therapy. In some patients, a second increase in ALT activity was noted after the resumption of therapy with phylogolimide.
Normalization of ALT activity in the blood plasma occurred approximately 2 months after discontinuation of the drug.
In a small number of patients with elevated ALT activity ≥5 VGN who continued treatment with the drug, the normalization of ALT activity occurred after approximately 5 months of therapy.
Lymphomas
According to clinical and post-marketing research, in patients who received phingolimod, there was a development of lymphoma in both B-cell and T-cell lymphomas.
The frequency of lymphomas is 3 cases per 10,000 person-years (versus 1.9 cases per 10,000 person-years in the general population).