FINGOLIMOD FRESENIUS KABI

The treatment should be initiated and supervised by a physician experienced in multiple sclerosis. 5 mg capsule taken orally once daily. Fingolimod Fresenius Kabi can be taken with or without food. The capsules should always be swallowed intact, without opening them.

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 one month of treatment.

4). 2). Renal impairment Fingolimod Fresenius Kabi 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). Method of administration This medicinal product is for oral use.

5 mg in Studies D2301 (FREEDOMS) and D2309 (FREEDOMS II) are shown below. Adverse reactions derived from post- marketing experience with fingolimod via spontaneous case reports or literature cases are also reported. 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).

Tabulated list of adverse reactions Infections and infestations Very common:

Influenza Sinusitis Common: Herpes viral infections Bronchitis Tinea versicolor Uncommon: Pneumonia Not known: Progressive multifocal leukoencephalopathy (PML)** Cryptococcal infections** Neoplasms benign, malignant and unspecified (incl cysts and polyps) Common: Basal cell carcinoma Uncommon: Malignant melanoma**** Rare: Lymphoma*** Squamous cell carcinoma**** Very rare: Kaposi’s sarcoma**** Not known: Merkel cell carcinoma*** Blood and lymphatic system disorders Common: Lymphopenia Leucopenia Uncommon: Thrombocytopenia Not known: Autoimmune haemolytic anaemia*** Peripheral oedema*** Immune system disorders Not known: Hypersensitivity reactions, including rash, urticaria and angioedema upon treatment initiation*** Psychiatric disorders Common: Depression Uncommon: Depressed mood Nervous system disorders Very common: Headache Common: Dizziness Migraine Uncommon: Seizure Rare: Posterior reversible encephalopathy syndrome (PRES)* Not known: Severe exacerbation of disease after fingolimod discontinuation*** Eye disorders Common: Vision blurred Uncommon: Macular oedema Cardiac disorders Common: Bradycardia Atrioventricular block Very rare: T-wave inversion*** Vascular disorders Common: Hypertension Respiratory, thoracic and mediastinal disorders Very common: Cough 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 Musculoskeletal and connective tissue disorders Very common: Back pain Common: Myalgia Arthralgia General disorders and administration site conditions Common: Asthenia Investigations Very common: Hepatic enzyme increased (increased ALT, Gamma glutamyltransferase, Aspartate transaminase) Common: Weight decreased*** Blood triglycerides increased 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). 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 Fresenius Kabi -treated patients.

5 mg dose. g. g. g. 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. 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 Fingolimod Fresenius Kabi. 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 Fingolimod Fresenius Kabi treatment results in a transient decrease in heart rate and may also be associated with atrioventricular conduction delays.

5 mg. Heart rate below 40 […]

1). After the first dose, the decline in heart rate starts within one 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 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 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 Fresenius Kabi.

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 Fresenius Kabi.

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, or the ECG shows new onset second degree or higher grade AV block or a QTc interval >500 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 Fingolimod Fresenius Kabi treatment depending on duration of the interruption and time since start of Fingolimod Fresenius Kabi treatment.

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 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. 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 Fresenius Kabi 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 Fingolimod Fresenius Kabi initiation may be associated with severe bradycardia and heart block.

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

If the heart-rate-lowering medication cannot be stopped, cardiologist’s advice should be sought to determine […]

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

- Severe active infections, active chronic infections (hepatitis, tuberculosis). - Active malignancies. - Severe liver impairment (Child-Pugh class C). 4). 4). 4). 4). 6). 1.