Before Initiation of Therapy :
- Immunization status of VZV must be confirmed with serology levels prior to starting therapy. If negative then vaccination must be completed at least 4 to 6 weeks prior to starting Gilenya.
- Immunization should be brought to date and vaccination for pneumococcus and haemophilus influenza type B done.
- ECG, pregnancy test, chest X-ray.
- CBC,liver enzymes, bilirubin,TSH, creatinine.
- Resting blood pressure.
- Patients with diabetes mellitus or a history of uveitis are at increased risk of macular edema and should undergo an ophthalmic evaluation prior to initiating GILENYA® therapy.
- No wash out period is necessary when switching from interferons or glatiramer acetate.
- The wash out period should be less than 2 months when switching from natalizumab.
- Questran should be used to fully eliminate teriflunamide when switching from it to Gilenya.
- Negative pregnancy test and counsel with regards to contraception
First Dose :
- The first dose must be administered at a first dose clinic where ECG, electrocardiographic and vital signs monitoring will be done prior and for least 6 hours immediately after the first dose.
- Overnight monitoring should occur in patients with pre-existing cardiac conditions ,prolonged QTc interval, those that require pharmacological intervention for bradyarrythmia during the monitoring period or at the end of the 6 hrs period the QTc is >500ms
- First dose monitoring should be repeated if the therapy is interrupted for more than 1 day during the first 2 weeks, more than 7 days during the weeks 3 and 4 and more than 2 weeks any time after 1 month of therapy.
Monitoring During Therapy :
- Regular blood pressure monitoring
- All patients should undergo an ophthalmological examination at month 3 or 4 for possible macular edema
- Diabetic patients should undergo regular ophthalmological examinations while on Gilenya therapy
- CBC,creatinine,TSH bilirubin,liver enzymes Q1 months X6 then Q4 months
- Annual influenza vaccination of patient and his/her family members
- Ophthalmological examination if there is visual symptoms
- Spirometric evaluation if there is respiratory symptoms (can occur within 1 month of initiation)
Discontine Therapy :
- There is evidence of a serious infection such as disseminated VZV or herpetic infection or cryptococcal meningitis
- PML is suspected
- There is a sustained 5X ULN increase in the transaminases level
- Evidence of PRES, macular edema
- There is a reduction in spirometric values
- Immunocomprised, baseline lymphopenia, severe hepatic impairment, active malignancy, active infection, not immunized against varicella zoster virus.
- History or currently experiencing second degree Mobitz type II or higher AV block, sick-sinus syndrome, sino-atrial heart block.
- History of recurrent syncope or symptomatic bradycardia.
- Significant QT prolongation (QTc >470 msec in females or >450 msec in males) or in patients with relevant risk factors for QTprolongation (e.g. hypokalemia, hypomagnesemia or congenital QT prolongation), due to the risk of serious cardiac rhythm disturbances.
- Known ischemic heart disease (including angina pectoris), history of myocardial infarction, congestive heart failure, history of cardiac arrest, cerebrovascular disease.
- Uncontrolled hypertension.
- Severe untreated sleep apnea.
- Taking Class Ia and Class III anti-arrhythmic drugs, beta-blockers, calcium channel blockers or any other substances that may decrease heart rate.
- COPD, moderate or severe asthma.
- Severe renal impairment.
- Who have received a live vaccine within the past 6 weeks
Gilenya is teratogenic. Women of childbearing potential should be counseled on the potential for serious risk to the fetus and the need for effective contraception during, and for 2 months after treatment. Breastfeeding is discouraged while receiving and for two months after stopping Gilenya.
Live vaccines should be avoided during Gilenya therapy and for 2 months after cessation. Vaccination may be less effective during and for up to two months after discontinuing treatment
Adverse Events :
- The most frequent AEs (incidence ≥10% and more frequent than with placebo) were headache, influenza, diarrhea, back pain, liver enzyme elevations and cough.
- The most serious adverse events (AEs) were infections, macular edema, and bradycardia or atrioventricular blocks on treatment initiation.
- The most common adverse event leading to treatment discontinuation was ALT elevation (3.8%).
- Increased levels of baseline total cholesterol, LDL cholesterol, and triglycerides tend to occur in the first 6 months of treatment.
- Hypertension was reported in 5% of patients.
- 4% developped persistent lymphopenia < 0.2.
- After the first 0.5mg dose, the heart rate decrease is maximal within 6 hours post-dosing. The heart rate returns to baseline progressively over approximately one month during chronic treatment. During first dose 0.5% of patients experienced mild to moderate symptoms which resolved within the first 24 hours of treatment. The incidence of first degree AV block on ECG at 6 h after the first dose was 4.7% while the incidence of 2nd-degree AV block Mobitz type 1 was 0.2% and 2:1 AV block was 1.7%. These tended to be asymptomatic and resolved within 24hrs. Isolated delayed onset events however have been reported in the post marketing surveillance, including transient asystole and unexplained death within 24 hours of the first dose of Gilenya.
- Dose-dependent reductions in forced expiratory volume over 1 second (FEV1) and diffusion lung capacity for carbon monoxide (DLCO) were observed in patients treated with Gilenya as early as 1 month after treatment initiation. Dyspnea was reported in 7.1% vs 4.5% in the placebo group.
- Macular edema occured in 0.4% of patients and tended to occur before 3-4 months of treatment. Patients with diabetes or uveitis were associated with an increased risk of macular edema.
- Liver enzyme elevation of >5X ULN occured in 2% and tended to resolve 2 months after discontinuing therapy
- Cases of lymphoma, skin cancers, posterior reversible encephalopathy syndrome (PRES), have been reported.
- Hemophagocytic syndrome with fatal outcome has been reported with fingolimod treatment in the context of infection.
- Cases of infections with opportunistic viral (e.g. VZV, JCV causing PML, HSV), fungal (e.g.cryptococci including cryptococcal meningitis), or bacterial (e.g. atypical mycobacterium) pathogens, have been reported.
- Cases of PML have occurred after approximately 2-3 years of treatment in patients who had not previously taken or were not concomitantly taking any immunosuppressive or immunomodulatory medications.
- Hypersensitivity reactions, including rash, urticaria and angioedema upon treatment initiation have been reported.
Drug Interactions :
- Ketoconazole may increase serum levels of Gilenya while carbamazepine may decrease it.
- Co-administration of anti-neoplastic, immunosuppressive or immunemodulating therapies is not recommended.