FINGOLIMOD ZENTIVA

The treatment should be initiated and supervised by a physician experienced in multiple sclerosis. 5 mg capsule taken orally once daily. 5 mg capsule taken orally once daily. 25 mg taken orally once daily. 5 mg capsules, it is not suitable for the use in paediatric patients with body weight ≤ 40 kg.

Other suitable formulations are available. 5 mg capsules. 5 mg daily dose, it is recommended to repeat the same first dose monitoring as for treatment initiation. The same first dose monitoring as for treatment initiation is recommended when treatment is interrupted for: • 1 day or more during the first 2 weeks of treatment.

• More than 7 days during weeks 3 and 4 of treatment. • More than 2 weeks after 1 month of treatment. 4). 2). Renal impairment Fingolimod was not studied in patients with renal impairment in the multiple sclerosis pivotal studies. Based on clinical pharmacology studies, no dose adjustments are needed in patients with mild to severe renal impairment.

3). 2). Paediatric population The safety and efficacy of fingolimod in children aged below 10 years have not yet been established. No data are available. 1). Method of administration This medicinal product is for oral use. 2). The capsules should always be swallowed intact, without opening them.

0%). Tabulated list of adverse reactions Adverse reactions reported in clinical trials and derived from post-marketing experience via spontaneous case reports or literature cases are shown below.

Frequencies were defined using the following convention:

Very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.

MedDRA system organ class Frequency Adverse reaction Very common Influenza, sinusitis Common Herpes viral infections, bronchitis, tinea versicolor Uncommon Pneumonia Infections and infestations Not known Progressive multifocal leukoencephalopathy (PML)**, cryptococcal infections** Common Basal cell carcinoma Uncommon Malignant melanoma**** Rare Lymphoma***, squamous cell carcinoma**** Very rare Kaposi’s sarcoma**** Neoplasms benign, malignant and unspecified (incl.

cysts and polyps) Not known Merkel cell carcinoma*** Blood and lymphatic system Common Lymphopaenia, leucopaenia Uncommon Thrombocytopaeniadisorders Not known Autoimmune haemolytic anaemia***, peripheral oedema*** Immune system disorders Not known Hypersensitivity reactions, including rash, urticaria and angioedema upon treatment initiation*** Immune reconstitution inflammatory syndrome (IRIS)** Common DepressionPsychiatric disorders Uncommon Depressed mood Very common Headache Common Dizziness, migraine Uncommon Seizure Rare Posterior reversible encephalopathy syndrome (PRES)* Nervous system disorders Not known Severe exacerbation of disease after fingolimod discontinuation*** Common Vision blurredEye disorders Uncommon Macular oedema Cardiac disorders Common Bradycardia, AV block Very rare T-wave inversion*** Vascular disorders Common Hypertension Very common CoughRespiratory, thoracic and mediastinal disorders Common Dyspnoea Gastrointestinal disorders Very common Diarrhoea Uncommon Nausea*** Hepatobiliary disorders Not known Acute hepatic failure*** Skin and subcutaneous tissue disorders Common Eczema, alopecia, pruritus Very common Back painMusculoskeletal and connective tissue disorders Common Myalgia, arthralgia General disorders and administration site conditions Common Asthenia Very common Hepatic enzyme increased (increased ALT, GGT, AST) Common Weight decreased***, Blood triglycerides increased Investigations Uncommon Neutrophil count decreased * Not reported in 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. 4). *** Adverse drug reactions from spontaneous reports and literature. 5 mg in all clinical trials. 5 mg dose was similar to placebo.

However, lower respiratory tract infections, primarily bronchitis and to a lesser extent herpes infection and pneumonia were more common in fingolimod-treated patients. 5 mg dose. g. g. 4). 4). 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. 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 treatment. 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.

6% without a history of uveitis). 4). 5 mg and 5 mg resulted in a 2-fold increase in the incidence of macular oedema. Bradyarrhythmia Initiation of treatment results in a transient decrease in heart-rate and may also be associated with AV conduction delays.

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 […]

1). After the first dose, the decline in heart-rate starts within 1 hour, and is maximal within 6 hours. This post-dose effect persists over the following days, although usually to a milder extent, and usually abates over the next weeks.

With continued administration, the average heart-rate returns towards baseline within 1 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 fingolimod 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 fingolimod.

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. 5 mg daily dose.

Should post-dose bradyarrhythmia-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 fingolimod.

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 beats per minute (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 ≥ 500 ms, 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 AV conduction may recur on re-introduction of fingolimod treatment depending on duration of the interruption and time since start of treatment.

2). Very rare cases of T-wave inversion have been reported in adult patients treated with fingolimod. In case of T-wave inversion, the prescriber 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.

3). In such patients, treatment with fingolimod should be considered only if the anticipated benefits outweigh the potential risks, and advice from a cardiologist sought prior to initiation of treatment in order to determine the most appropriate monitoring.

5). g. g. amiodarone, sotalol) antiarrhythmic medicinal products. 3). g. ivabradine, digoxin, anticholinesteratic agents or pilocarpine). 8 “Bradyarrhythmia”), concomitant use of these substances during treatment initiation may be associated with severe bradycardia and heart block.

5). In such patients, treatment with fingolimod should be considered only if the anticipated benefits outweigh the potential risks. If treatment with fingolimod is considered, advice from a cardiologist should be sought regarding the switch to non-heart-rate- lowering medicinal products prior to initiation of treatment.

5). 0 […]

1. • Immunodeficiency syndrome. • Patients with increased risk for opportunistic infections, including immunocompromised patients (including those currently receiving immunosuppressive therapies or those immunocompromised by prior therapies).

4). • Severe active infections, active chronic infections (hepatitis, tuberculosis). • Active malignancies. • Severe liver impairment (Child-Pugh class C). 4). 4). 4). 4). 6).