There are individual buy trenbolone acetate observations about the development of reversible posterior encephalopathy syndrome, as well as ischemic and hemorrhagic stroke in the application of fingolimod 0.5 mg.Macular edema In applying the drug at the recommended dose in clinical studies in patients with macular edema PPC rate was 0.54%. In most cases of macular edema was observed within 3-4 months after initiation of treatment. In some cases, macular edema was observed without any clinical manifestations (identified on routine ophthalmologic examination), some patients have macular edema accompanied by blurred vision or decreased visual acuity.
Upon termination of treatment in the majority of cases occurred marked reduction or spontaneous resolution of macular edema. The incidence of macular edema was increased with a history of uveitis. Bradyarrhythmia In clinical studies at the beginning of treatment with the recommended dose observed transient decrease in heart rate (HR) and atrioventricular conduction slowing. The maximum decrease in heart rate was observed during 6 hours after the treatment (mean decrease of 12-13 beats per minute), and 70% of the negative chronotropic effect achieved on the first day of application. In clinical trials at the beginning of therapy fingolimod 0.5 mg in patients with RRMS atrioventricular block (AV block) I Class (lengthening the time of the pulse in electrocardiography, ECG) was observed in 4.7% (1.6% in the placebo group).
AV blockade II degree was detected in less than 0.2% of patients treated with fingolimod at the recommended dose. Conduction abnormalities observed both in clinical trials and in the post-marketing phase, were generally transient and asymptomatic, did not require treatment, and were in the first 24 hours after the start of treatment;Some patients have symptoms, such as decreased blood pressure, dizziness, fatigue and / or palpitations, which are also resolved on their own within 24 hours. In the post-marketing phase described isolated cases of complete AV block after the first dose of fingolimod which were transient in nature and resolved spontaneously. Although in most cases, for the relief of these adverse events did not require medical intervention, in buy trenbolone acetate one case in a clinical study in patients who received fingolimod at the recommended dose, asymptomatic AV block II degree type Mobitts I was eliminated with isoprenaline. Cases of asystole and unexplained sudden death after the first dose of the drug, but the association between fingolimod and these events has not been proved. The respiratory system in a clinical study after the first month of fingolimod 0.5 mg showed a slight dose-dependent decline in forced expiratory volume in the first second (FEV 1 ) and diffusion lung capacity for carbon monoxide (DLCO), later reached values of these parameters are not changed. Cancel therapy was accompanied by normalization of indicators.
No cases of overdose when using the drug to patients with RCC have been reported. Healthy volunteers satisfactorily tolerated single dose of the drug at a dose of 40 mg (dose 80 times the recommended daily), with 5 of 6 volunteers a slight airway obstruction was found, accompanied by a feeling of light tightness in the chest or a feeling of discomfort.
Fingolimod may cause the development of bradycardia. Reduced heart rate is usually observed within one hour after the first dose and reaches a maximum for 6 hours. There are reports of slowing of atrioventricular conduction and isolated reports of cases of transient AV block with spontaneous resolution.
In case of overdose with the first dose of the drug buy trenbolone acetate is important to identify the manifestation of bradycardia while monitoring may be required until the next morning. It is necessary to regularly measure the heart rate and blood pressure, as well as to make shooting electrocardiogram. If after 6 hours after the first dose heart rate was <45 beats / min or manifested electrocardiographic signs of II and higher degrees of AV block, or QT-interval was > 500 msec, you should extend the monitoring over night before the disappearance of signs of cardiac arrhythmia. When an AV block III level at any time is necessary to ensure monitoring during the night.
Fingolimod is not removed from the body by dialysis and plasmapheresis.
Signs of overdose correction is the disappearance of the above symptoms, including bradycardia.
Interaction with other drugs pharmacodynamic interaction Given the possibility of an additional inhibitory effect on the immune system, caution should be exercised when used in conjunction with anti fingolimod immunosuppressants (including corticosteroids) or immunomodulators. Since glucocorticosteroids have immunosuppressive action, duration of treatment and the dose at odnovremennomprimenenii with fingolimod should be adjusted based on clinical data. In clinical studies, when the use of fingolimod in patients with RRMS treated with short courses of corticosteroids (for five days), there was no increase of infection frequency . It should be used with caution fingolimod in patients treated previously for a long time drugs such as natalizumab or mitoxantrone. Limited experience in the use of fingolimod in patients receiving concomitant therapy with beta-blockers, calcium channel blockers, which reduce heart rate (such as verapamil, diltiazem or ivabradine), or other drugs that can reduce the heart rate (eg, digoxin). The use of these drugs in combination with the drug Neskler may be accompanied by the development of bradycardia and heart block. When taken in combination with fingolimod atenolol heart rate is further reduced to 15% (when taken with diltiazem no such effect is observed). In view of the powerful combined effect on heart rate, is not recommended for use in patients who are currently receiving these drugs. If you intend to treatment with , need to consult a cardiologist about the possibility of switching to drugs that do not reduce heart rate, as well as monitoring.
In connection with the above, the effect of fingolimod and fingolimodfosfata on drug clearance is metabolized via the major isoenzymes of CYP, is unlikely. The effect of fingolimod and fingolimodfosfata metabolism jointly prescribed drugs: Studies in vitro showed that fingolimod and fingolimodfosfat little or not at all able to inhibit the activity of cytochrome isoenzymes human P450 (1A2, 2A6, 2B6, 2S8, 2C9, 2C19, 2D6, 2E1, ZA4 / 5 or 4A9 / 11). Thus, the decrease in clearance of drugs metabolized mainly major cytochrome P450 isoenzymes, in the presence of fingolimod and fingolimodfosfata clinically unlikely. Transport proteins drug probably does not violate the absorption and excretion of the drug cell vehicles and other substances that are substrates of the main transporter proteins. Cyclosporine pharmacokinetics of fingolimod and cyclosporine in the case of single or repeated use did not change. oral contraceptives Concomitant use of fingolimod at a dose of 0.5 mg daily and oral contraceptives (ethinyl estradiol and levonorgestrel) does not alter the effects of oral contraceptives. Despite the lack of studies, the effects of oral contraceptives containing progestogens on fingolimod expected. Ketoconazole In the case of simultaneous use of ketoconazole (200 mg two times a day to reach equilibrium) and fingolimod (at a dose of 5 mg single dose) indicated a moderate increase in AUC fingolimod and fingolimodfosfata (1.7 times). isoprenaline, atropine, atenolol and diltiazem on fingolimod exposure and fingolimodfosfata not influenced simultaneous use with isoprenaline or atropine. Concomitant use of atenolol, diltiazem and cyclosporine did not affect the pharmacokinetics of fingolimod or fingolimodfosfata. Carbamazepine Concomitant use of carbamazepine at a dose of 600 mg 2 times a day and 2 mg of fingolimod once did not significantly affect the AUC and fingolimod fingolimodfosfata, reducing them by approximately 40%. Concomitant use of carbamazepine with fingolimod could reduce the effectiveness of the latter. Potential drug interactions in clinical studies in patients with RRMS were observed significant effect of fluoxetine and paroxetine (potent inhibitors of CYP2D6 isoenzyme) the concentration of fingolimod or fingolimodfosfata. Baclofen, gabapentin, oxybutynin, amantadine, modafinil, amitriptyline, pregabalin, steroids and oral contraceptives has no clinically significant effect on concentration ( < 20%) fingolimod and fingolimodfosfata.Vaccination As the use of live attenuated vaccines may increase buy trenbolone acetate the risk of infection, the application of the preparation does not It should be immunized with live attenuated vaccines. While drug therapy and for 2 months after discontinuation of fingolimod treatment vaccination may be less effective.