Domilo 0,5 mg Capsule

Domilo is indicated as a disease modifying therapy for the treatment of patients with relapsing multiple sclerosis to reduce the frequency of relapses and to delay the progression of disability.

Posology
Do not exceed the recommended dosage.
The recommended dose of Domilo is one 0,5 mg capsule taken once daily. If a dose is missed treatment should be continued with the next dose as planned. On initiation of Domilo treatment, after the first dose, all patients should be observed, with hourly pulse and blood pressure measurement, for a period of at least 6 hours for signs and symptoms of bradycardia. All patients should have an electrocardiogram performed prior to dosing and at the end of 6-hour monitoring period (see section 4.4, bradydysrhythmia subsection). For recommendations related to switching patients from other disease modifying therapies to Domilo, see section 4.4: Prior treatment with immunosuppressive or immune-modulating therapies.
Dosing in special populations
Renal impairment
No Domilo dose adjustments are needed in patients with renal impairment (see section 5.2).
Hepatic Impairment
No Domilo dose adjustments are needed in patients with mild to moderate hepatic impairment. Domilo should be used with caution in patients with severe hepatic impairment (Child-Pugh class C) (see section 5.2).
Elderly patients
Domilo should be used with caution in patients aged 65 years and over (see section 5.2).
Diabetic patients
Domilo should be used with caution in patients with diabetes mellitus due to a potential increased risk of macular oedema (see section 4.4).
Paediatric patients
Domilo is not indicated for use in paediatric patients (see section 5.2).
Method of administration
For oral use, with or without food.

• Hypersensitivity to fingolimod or to any of the excipients listed in section 6.1 (see sections 4.4 and 4.8).
• Concomitant administration with anti-dysrhythmic medicines; Class 1a (e.g. quinidine, procainamide), Class III (e.g. amiodarone, sotalol) (see section 4.4.).
• Pregnancy and lactation.
• Immunodeficiency syndrome.
• Severe active infections, active chronic infections (hepatitis, tuberculosis).
• Active malignancies.
• Patients who in the last 6 months had myocardial infarction (MI), unstable angina pectoris, stroke/transient ischaemic attack (TIA), decompensated heart failure (requiring inpatient treatment), or New York Heart Association (NYHA) class III/IV heart failure (see section 4.4).
• Patients with severe cardiac dysrhythmias requiring anti-dysrhythmic treatment with class Ia or class III anti-dysrhythmic medicines (see section 4.4).
• Patients with second-degree Mobitz type II atrioventricular (AV) block or third-degree AV block, or sick-sinus syndrome, if they do not wear a pacemaker (see section 4.4).
• Patients with a baseline QTc interval u2265 500 msec (see section 4.4).

Bradydysrhythmia
Initiation of Domilo treatment results in a decrease in heart rate and may also be associated with atrioventricular conduction delays, including the occurrence of isolated reports of transient, spontaneously resolving complete AV block (see sections 4.8 and 5.1). After the first dose, the decline in heart rate starts within one hour, and is maximal within 6 hours and usually normalises by one month. However individual patients may not return to baseline heart rate by the end of the first month. Conduction abnormalities were typically transient and asymptomatic. They usually did not require treatment and resolved within the first 24 hours on treatment. If necessary, the decrease in heart rate induced by Domilo can be reversed by parenteral doses of atropine or isoprenaline.
All patients should have an ECG and blood pressure measurement performed prior to and 6 hours after the first dose of Domilo. All patients should be monitored for a period of 6 hours for signs and symptoms of bradycardia with hourly heart rate and blood pressure measurement. Continuous (real time) ECG monitoring during this 6-hour period is recommended. Should post-dose bradydysrhythmia-related symptoms occur, appropriate clinical management should be initiated, and monitoring should be continued until the symptoms have resolved. Should a patient require pharmacological intervention during the first-dose monitoring, overnight monitoring in a medical facility should be instituted and the first-dose monitoring should be repeated after the second dose of Domilo. If the heart rate at 6 hours is the lowest since the first dose was administered (suggesting that the maximum pharmacodynamic effect on the heart may not yet be manifest), monitoring should be extended by at least 2 hours and until heart rate increases again. Additionally, if after 6 hours, the heart rate is <45 bpm in adults, <55 bpm in paediatric patients aged 12 years and above, or <60 bpm in paediatric patients aged 10 to below 12 years, or the ECG shows new onset second degree or higher grade AV block or a QTc interval u2265500 msec, extended monitoring (at least overnight monitoring), should be performed, and until the findings have resolved. The occurrence at any time of third degree AV block should also lead to extended monitoring (at least overnight monitoring).

The effects on heart rate and atrioventricular conduction may recur on re-introduction of Domilo treatment depending on duration of the interruption and time since start of Domilo treatment. The same first dose monitoring as for treatment initiation is recommended when treatment is interrupted for:
u2212 1 day or more during the first 2 weeks of treatment.
u2212 more than 7 days during weeks 3 and 4 of treatment.
u2212 more than 2 weeks after one month of treatment.
If the treatment interruption is of shorter duration than the above, the treatment should be continued with the next dose as planned.
Cases of T-wave inversion have been reported in adult patients treated with fingolimod as contained in Domilo. In case of T-wave inversion, the medical practitioner should ensure that there are no associated myocardial ischaemia signs or symptoms. If myocardial ischaemia is suspected, it is recommended to seek advice from a cardiologist.
Due to the risk of serious rhythm disturbances or significant bradycardia, Domilo should not be used in patients with sino-atrial heart block, a history of symptomatic bradycardia, recurrent syncope or cardiac arrest, or in patients with significant QT prolongation (QTc>470 msec [adult female], QTc >460 msec [paediatric female] or >450 msec [adult and paediatric male]), uncontrolled hypertension or severe sleep apnoea (see also section 4.3). If treatment is considered in patients for whom Domilo is not contradicted, advice from a cardiologist should be sought prior to initiation of treatment in order to determine the most appropriate monitoring strategy. At least overnight extended monitoring is recommended for treatment initiation (see also section 4.5).

Anti-neoplastic, immunomodulatory or immunosuppressive therapies
Anti-neoplastic, immunomodulatory or immunosuppressive therapies should be co-administered with caution due to the risk of additive immune system effects (see sections 4.4).
Caution should also be exercised when switching patients from long-acting therapies with immune effects such as natalizumab, teriflunomide or mitoxantrone (see section 4.4). In multiple sclerosis clinical studies the concomitant treatment of relapses with a short course of corticosteroids was not associated with an increased rate of infection.
Vaccination
During and for up to two months after treatment with Domilo vaccination may be less effective. The use of live attenuated vaccines may carry a risk of infections and should therefore be avoided (see sections 4.4 and 4.8).
Bradycardia-inducing medicines
Treatment with Domilo should not be initiated in patients receiving beta blockers, or other medicines which may decrease heart rate, such as class Ia and III anti-dysrhythmics, calcium channel blockers (such as verapamil or diltiazem), ivabradine, digoxin, anti-cholinesteratic medicines or pilocarpine because of the potential additive effects on heart rate (see sections 4.4 and 4.8). If treatment with Domilo is considered in such patients, advice from a cardiologist should be sought regarding the switch to non-heart rate lowering medicines or appropriate monitoring for treatment initiation, at least overnight monitoring is recommended.

Women of childbearing potential / Contraception in females
Due to risk to the foetus, Domilo is contraindicated during pregnancy and in women of childbearing potential not using effective contraception. Before initiation of treatment in women of childbearing potential, a negative pregnancy test result needs to be available and counselling should be provided regarding the potential for serious risk to the foetus and the need for effective contraception during treatment with Domilo. Since it takes approximately two months to eliminate fingolimod from the body on stopping treatment (see section 4.4), the potential risk to the foetus may persist and contraception should be continued during that period.
Pregnancy
Domilo should not be used in pregnancy (see section 4.3). Animal studies have shown reproductive toxicity including foetal loss and organ defects, notably persistent truncus arteriosus and ventricular septal defect (see section 5.3). Furthermore, the receptor affected by fingolimod (sphingosine 1- phosphate receptor) is known to be involved in vascular formation during embryogenesis. Safety in pregnancy and lactation has not been established.
Breastfeeding
Fingolimod is excreted in milk of treated animals during lactation (see section 5.3). Women receiving Domilo should not breastfeed.
Fertility
Fingolimod is present in seminal ejaculate. Safety regarding an increased risk of male mediated foetal toxicity has not been demonstrated.

The clinical status of the patient and adverse event profile of Domilo should be borne in mind when considering the patients ability to perform tasks that require judgement, motor and cognitive skills. Driving may be impaired by such adverse events.

a. Summary of the safety profile
Adverse reactions reported with fingolimod in clinical studies are shown below. Adverse reactions derived from post-marketing experience with fingolimod via spontaneous case reports or literature cases are also reported in table below.
b. Tabulated list of adverse reactions
MedDRA SOC
Infections and infestations
Frequent Influenza, sinusitis, Herpes viral infections, bronchitis, tinea versicolor
Less frequent Pneumonia
Unknown frequency Progressive multifocal leukoencephalopathy (PML)**, cryptococcal infections**
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Frequent Basal cell carcinoma
Less frequent Malignant melanoma****, lymphoma***, squamous cell carcinoma****, kaposi's sarcoma****
Unknown frequency Merkel cell carcinoma***
Blood and lymphatic system disorders
Frequent Lymphopenia, leucopenia
Less frequent Thrombocytopenia
Unknown frequency Autoimmune haemolytic anaemia***, peripheral oedema***
Immune system disorders
Unknown frequency Hypersensitivity reactions, including rash, urticaria and angioedema upon treatment initiation***
Psychiatric disorders
Frequent Depression
Less frequent Depressed mood
Nervous system disorders
Frequent Headache, dizziness, migraine
Less frequent Seizure, posterior reversible encephalopathy syndrome (PRES)*
Unknown frequency Severe exacerbation of disease after Domilo discontinuation***
Eye disorders
Frequent Blurred vision
Less frequent Macular oedema
Cardiac disorders
Frequent Bradycardia, atrioventricular block
Less frequent T-wave inversion***
Vascular disorders
Frequent Hypertension
Respiratory, thoracic and mediastinal disorders
Frequent Cough, dyspnoea
Gastrointestinal disorders
Frequent Diarrhoea
Less frequent Nausea***
Skin and subcutaneous tissue disorders
Frequent Eczema, alopecia, pruritus
Musculoskeletal and connective tissue disorders
Frequent Back pain, myalgia, arthralgia
General disorders and administration site conditions
Frequent Asthenia
Investigations
Frequent Increased hepatic enzyme (increased ALT, Gamma glutamyltransferase, Aspartate transaminase), decreased weight***, increased blood triglycerides
Less frequent Decreased neutrophil count
* Not reported in reports from studies FREEDOMS, FREEDOMS II and TRANSFORMS. The frequency category was based on an estimated exposure of approximately 10 000 patients to fingolimod in all clinical trials.
** PML and cryptococcal infections (including cases of cryptococcal meningitis) have been reported in the post-marketing setting (see section 4.4).
*** Adverse drug reactions from spontaneous reports and literature.
**** The frequency category and risk assessment were based on an estimated exposure of more than 24 000 patients to fingolimod 0,5 mg in all reported clinical trials.
c. Description of selected adverse reactions
Infections
In multiple sclerosis clinical studies the rates of lower respiratory tract infections, primarily bronchitis and to a lesser extent herpes infection and pneumonia were more frequent in Domilo-treated patients than in placebo treated patients. Some cases of disseminated herpes infection, including fatal cases, have been reported even at the 0,5 mg dose. In the post-marketing setting, cases of infections with opportunistic pathogens, such as viral (e.g. varicella zoster virus [VZV], John Cunningham virus [JCV] causing Progressive Multifocal Leukoencephalopathy, herpes simplex virus [HSV]), fungal (e.g. cryptococci including cryptococcal meningitis) or bacterial (e.g. atypical mycobacterium), have been reported, some of which have been fatal (see section 4.4). Human papilloma virus (HPV) infection, including papilloma, dysplasia, warts and HPV-related cancer, has been reported under treatment with fingolimod in the post-marketing setting. Due to the immunosuppressive properties of fingolimod, vaccination against HPV should be considered prior to treatment initiation with fingolimod taking into account vaccination recommendations. Cancer screening, including Pap test, is recommended as per standard of care.
Macular oedema
Reports from multiple sclerosis clinical studies have shown that macular oedema occurred in 0,5 % of patients treated with the recommended dose of 0,5 mg and 1,1 % of patients treated with the higher dose of 1,25 mg. The majority of cases occurred within the first 3-4 months of therapy. Some patients presented with blurred vision or decreased visual acuity, but others were asymptomatic and diagnosed on routine ophthalmological examination. The macular oedema generally improved or resolved spontaneously after discontinuation of Domilo. The risk of recurrence after re-challenge has not been evaluated. Macular oedema incidence is increased in multiple sclerosis patients with a history of uveitis (17 % with a history of uveitis vs. 0,6 % without a history of uveitis). Domilo has not been studied in multiple sclerosis patients with diabetes mellitus, a disease which is associated with an increased risk for macular oedema (see section 4.4). In renal transplant clinical studies in which patients with diabetes mellitus were included, therapy with fingolimod 2,5 mg and 5 mg resulted in a 2-fold increase in the incidence of macular oedema.
Bradydysrhythmia
Initiation of Domilo treatment results in a transient decrease in heart rate and may also be associated with atrioventricular conduction delays. It has been reported that in multiple sclerosis clinical studies the maximal decline in heart rate was seen within 6 hours after treatment initiation, with declines in mean heart rate of 12-13 beats per minute for Domilo. Heart rate below 40 beats per minute in adults, and below 50 beats per minute in paediatric patients, was observed in patients on Domilo. The average heart rate returned towards baseline within 1 month of chronic treatment. Bradycardia was generally asymptomatic, but some patients experienced mild to moderate symptoms, including hypotension, dizziness, fatigue and/or palpitations, which resolved within the first 24 hours after treatment initiation (see sections 4.4 and 5.1). Reports from multiple sclerosis clinical studies have shown first-degree atrioventricular block (prolonged PR interval on ECG) after treatment initiation in adult and paediatric patients. It has been reported that in clinical trials involving adults it occurred in 4,7 % of patients on fingolimod 0,5 mg, in 2,8 % of patients on intramuscular interferon beta-1a, and in 1,6 % of patients on placebo. Second-degree atrioventricular block was detected in less than 0,2 % adult patients on Domilo. In the post-marketing setting, reports of transient, spontaneously resolving complete AV block have been observed during the six-hour monitoring period following the first dose of Domilo. The patients recovered spontaneously. The conduction abnormalities observed both in clinical trials and post-marketing were typically transient, asymptomatic and resolved within the first 24 hours after treatment initiation. Although most patients did not require medical intervention, one patient on fingolimod 0,5 mg received isoprenaline for asymptomatic second-degree Mobitz I atrioventricular block. In the post-marketing setting, delayed onset events including transient asystole and unexplained death, have occurred within 24 hours of the first dose. These cases have been confounded by concomitant medications and/or pre-existing disease. The relationship of such events to Domilo is uncertain.
Blood pressure
It has been reported that in multiple sclerosis clinical trials Domilo was associated with an average increase of approximately 3 mmHg in systolic pressure and approximately 1 mmHg in diastolic pressure, manifesting approximately 1 month after treatment initiation. This increase persisted with continued treatment. Hypertension was reported in 6,5 % of patients on treatment and in 3,3 % of patients on placebo.
Liver function
Increased hepatic enzymes have been reported in adult and paediatric multiple sclerosis patients treated with Domilo. In clinical studies 8,0 % and 1,8 % of adult patients treated with Domilo experienced an asymptomatic elevation in serum levels of ALT of u22653x ULN (upper limit of normal) and u22655x ULN, respectively. Recurrence of liver transaminase elevations has occurred upon re-challenge in some patients, supporting a relationship to the medicine. In clinical studies, transaminase elevations occurred at any time during treatment although the majority occurred within the first 12 months. ALT levels returned to normal within approximately 2 months after discontinuation of Domilo. In a small number of patients (N=10 on 1,25 mg, N=2 on 0, 5 mg) who experienced ALT elevations u22655x ULN and who continued on Domilo therapy, the ALT levels returned to normal within approximately 5 months (see section 4.4, Liver function).

At 40 mg, 5 of 6 subjects reported mild chest tightness or discomfort which was clinically consistent with bronchoconstriction. Domilo can induce bradycardia. The decline in heart rate usually starts within one hour of the first dose and is maximal within 6 hours. There have been reports of slow atrioventricular conduction with isolated reports of transient, spontaneously resolving complete AV block (see sections 4.4 and 4.8). If the overdose constitutes first exposure to Domilo it is important to observe for signs and symptoms of bradycardia, which could include overnight monitoring. Regular measurements of pulse rate and blood pressure are required and electrocardiograms should be performed. Neither dialysis nor plasma exchange would result in meaningful removal of Domilo from the body.