decentralised procedure

Decentralised Procedure

Public Assessment Report

Fingolimod Hormosan 0,5 mg Hartkapseln

Fingolimod Lupin 0,5 mg Hartkapseln

Fingolimod hydrochloride

DE/H/6331+6332/001/DC

Applicants:

Lupin Healthcare (UK) Limited, United Kingdom

Lupin Europe GmbH, Germany

Date: 28th September 2020

This module reflects the scientific discussion for the approval of the above-mentioned products.

The procedure was finalised on 11th March 2020.

Fingolimod Hormosan / Lupin 0,5 mg Hartkapseln DE/H/6331+6332/001/DC Public AR 2/15

TABLE OF CONTENTS

I INTRODUCTION ......................................................................................................................... 4

II EXECUTIVE SUMMARY .......................................................................................................... 4

II.1 Problem statement..................................................................................................................... 4

II.2 About the product ..................................................................................................................... 4

II.3 General comments on the submitted dossier .......................................................................... 4

II.4 General comments on compliance with GMP, GLP, GCP and agreed ethical principles .. 5

III SCIENTIFIC OVERVIEW AND DISCUSSION .................................................................... 5

III.1 Quality aspects ......................................................................................................................... 5

III.2 Non clinical aspects .................................................................................................................. 6

III.3 Clinical aspects ......................................................................................................................... 7

Proposed list of conditions pursuant to Article 21a or specific obligations pursuant to article 22

of Directive 2001/83/EC .................................................................................................................... 10

IV BENEFIT RISK ASSESSMENT ............................................................................................. 15


ADMINISTRATIVE INFORMATION

Proposed name of the medicinal

product in the RMS

Fingolimod Hormosan 0,5 mg Hartkapseln

Fingolimod Lupin 0,5 mg Hartkapseln

Name of the drug substance (INN

name): Fingolimod hydrochloride

Pharmaco-therapeutic group

(ATC Code): L04AA27

Pharmaceutical form(s) and

strength(s): Capsule, hard; 0,5 mg

Reference Number(s) for the

Decentralised Procedure

DE/H/6331/001/DC

DE/H/6332/001/DC

Reference Member State: DE

Concerned Member States: DE 6331: LU

DE 6332: AT, DK, ES, IT, NL, NO, PL, SE

Legal basis of application: Article 10(1) Generic application

Applicants (name and address) Lupin Healthcare (UK) Limited

2nd Floor

The Urban Building

3-9 Albert Street

SL1 2BE Slough

United Kingdom

Lupin Europe GmbH

Hanauer Landstr. 139 - 143

60314 Frankfurt Am Main

Germany

Names and addresses of all proposed

manufacturer(s) responsible for

batch release in the EEA

Lupin Europe GmbH

Hanauer Landstr. 139 - 143

60314 Frankfurt Am Main

Germany


I INTRODUCTION Based on the review of the data on quality, safety and efficacy, the application for “Fingolimod

Hormosan / Lupin 0,5 mg Hartkapseln” with the following indication:

[Product name] is indicated as single disease modifying therapy in highly active relapsing

remitting multiple sclerosis for the following groups of adult patients and paediatric patients

aged 10 years and older:

Patients with highly active disease despite a full and adequate course of treatment with at

least one disease modifying therapy (for exceptions and information about washout periods

see SmPC sections 4.4 and 5.1).

or

Patients with rapidly evolving severe relapsing remitting multiple sclerosis defined by 2 or

more disabling relapses in one year, and with 1 or more Gadolinium enhancing lesions on

brain MRI or a significant increase in T2 lesion load as compared to a previous recent MRI.

is approved.

II EXECUTIVE SUMMARY II.1 Problem statement N/A

II.2 About the product The active substance, fingolimod hydrochloride or FTY720 (hereinafter referred to as fingolimod) is a

sphingosine 1-phosphate (S1P) receptor modulator that inhibits the exit of lymphocytes from lymph

nodes and their recirculation. This results in a reduced egress of lymphocytes from the lymph nodes;

in particular, auto-aggressive T-cells that perform a central role in the multiple sclerosis (MS)

inflammatory disease process are prevented from recirculating to the central nervous system (CNS). In

addition, fingolimod may also directly target glial cells and neurons.

Fingolimod is indicated as single disease modifying therapy in highly active relapsing remitting

multiple sclerosis for the following groups of adult patients and paediatric patients aged 10 years and

older:

- Patients with highly active disease despite a full and adequate course of treatment with at

least one disease modifying therapy (for exceptions and information about washout

periods see sections 4.4 and 5.1).

or

- Patients with rapidly evolving severe relapsing remitting multiple sclerosis defined by 2

or more disabling relapses in one year, and with 1 or more Gadolinium enhancing lesions

on brain MRI or a significant increase in T2 lesion load as compared to a previous recent

MRI.

The approved dosing of 0.5 mg once daily (or 0.25 mg once daily in pediatric patients 10 years of age

and above with a body weight of ≤40 kg) when restarting fingolimod should be administered. Other

dosing regimens have not been approved.

In adults and paediatric patients with body weight > 40 kg the recommended dose is one 0.5 mg

fingolimod taken orally once daily. The capsule can be taken with or without food. The capsules should

always be swallowed intact, without opening them.

II.3 General comments on the submitted dossier This decentralised application concerns a generic version of fingolimod hydrochloride or FTY720

under the trade name Fingolimod Hormosan / Lupin 0,5 mg Hartkapseln. In this Assessment Report,

the name fingolimod is used.

The originator product is Gilenya 0.5 mg hard capsules by Novartis Pharma GmbH, Germany,

registered since September 2010 by the FDA and subsequently since March 2011 by the EMA. The


original product Gilenya has been authorized within the Community in accordance with Community

provisions in force for not less than ten years. Consequently, this application is made according to

Article 10(1) of Directive 2001/83/EC.

Fingolimod (trade name Gilenya, Novartis) received its first marketing authorization by the FDA in

September 2010 and subsequently by the EMA in March 2011, meeting the requirements of a well-

documented medicinal product in terms of safety and recognized efficacy. Gilenya was also approved

in Switzerland in January 2011. Since its first authorization, fingolimod has been licensed in many

countries worldwide.

With Germany as the Reference Member State in this Decentralized Procedure, Lupin Healthcare (UK)

Limited, United Kingdom, and Lupin Europe GmbH, Germany, is applying for the Marketing

Authorisations for “Fingolimod Hormosan / Lupin 0,5 mg Hartkapseln” in LU.

II.4 General comments on compliance with GMP, GLP, GCP and agreed ethical

principles A statement on the application of appropriate GCP standards in the submitted study has been provided.

The conduct of the study and the data generated during the study, together with the report which reflect

the raw data were inspected and audited by the Quality Assurance Unit of Veeda Clinical Research

Pvt. Ltd., Ahmedabad, Lupin Bioresearch Center, Pune and In Vitro Research Solutions Private Ltd.,

Bangalore for conformance to study protocol, in house SOPs, GCP and GLP.

The RMS has been assured that acceptable standards of GMP are in place for these product types at all

sites responsible for the manufacture and assembly of this product

For manufacturing sites within the Community, the RMS has accepted copies of current manufacturer

authorisations issued by inspection services of the competent authorities as certification that acceptable

standards of GMP are in place at those sites.

For manufacturing sites outside the Community, the RMS has accepted copies of current GMP

Certificates of satisfactory inspection summary reports, ‘close-out letters’ or ‘exchange of information’

issued by the inspection services of the competent authorities (or those countries with which the EEA

has a Mutual Recognition Agreement for their own territories) as certification that acceptable standards

of GMP are in place at those non-Community sites.

GMP active substance

Regarding the statement on GMP for the active substance a statement/declaration is provided from the

manufacturer(s) responsible for manufacture of the finished product and batch release situated in the

EU.

The GMP certificate of the manufacturer of the drug product is older than three years, however the

authority which conducted the most recent GMP inspection confirms the validity of the certificate.

III SCIENTIFIC OVERVIEW AND DISCUSSION III.1 Quality aspects Drug substance

Module 3.S is presented as an EU-ASMF.

The chemical-pharmaceutical documentation and Quality Overall Summary in relation to Fingolimod

0,5 mg Hartkapseln are of sufficient quality in view of the present European regulatory requirements.

Basically the control tests and specifications for drug substance product are adequately drawn up.

Stability studies have been performed with the drug substance. No significant changes in any

parameters were observed. The proposed retest period of 60 months when stored at 5°C is acceptable.

Drug Product

Composition

The drug product is an immediate-release solid oral dosage form in a hard gelatin capsule. Excipients

are Magnesium alumina metasilicate and Sodium stearyl fumarate. The drug product is packed in


PVC/Aclar – Al blisters.

Excipients and container closure system are usual for this type of dosage form.

Pharmaceutical development

The development of the product has been described, the choice of excipients is justified and their

functions explained. Sufficient information has been provided on manufacturing process development,

which is dry mixing followed by encapsulation.

The development of the proposed routine dissolution method has been adequately described.

The proposed dissolution limit is considered too wide in view of the dissolution profile of the biobatch

of the test product.

Manufacturing process

The manufacturing process of the drug product comprises a dry mixing process followed by

encapsulation. Although the manufacturing is not a complex manufacturing process, due to the low

content of the drug substance in the drug product (≤ 2%), it is considered a non-standard process.

The information provided on the manufacturing process is sufficiently detailed. A flow-chart and

narrative description are provided, IPCs have been indicated. Several process parameters (e.g. mixing

speeds, mixing times), and equipment are provided.

The manufacturing process has been validated with three batches at proposed batch size of 120,000

capsules. The presented validation results on the lubrication and filling process comply with the

predefined acceptance criteria.

Excipients

The excipients comply with the Ph.Eur. Acceptable in house specification has been provided for the

empty gelatin capsules.

Quality control of drug product

The drug product specifications include tests for description, identification by HPLC and UV, water,

assay, uniformity of dosage units by content uniformity, dissolution, related substances, and

microbiological controls.

The proposed drug product specifications are yet acceptable.

Analytical methods were adequately described and validated.

Batch analysis data of three batches demonstrate compliance with the proposed release specification.

An acceptable risk assessment for elemental impurities based on ICH guideline Q3D as well a risk

assessment relating to nitrosamine impurities have been provided. No additional control strategies for

elemental impurities are required.

Stability of drug product

Stability data on the product has been provided for three batches stored at 25°C/60% RH (six months)

and 40°C/75% RH (six months). The conditions used in the stability studies are according to the ICH

stability guideline. The batches were stored in PVC/ /Aclar – Al blisters.

Photostability studies are provided.

No significant changes have been observed. Slight trends for water content and assay are seen but

results are within specifications.

The proposed shelf life of 24 months is supported by long term /intermediate data and storage under

accelarated conditions

Other information

The gelatin capsules are sourced from pure bovine origin. No other materials of human or animal origin

are present in the drug product.

III.2 Non clinical aspects The pharmacological properties of fingolimod are well known and have been satisfactorily summarised

in the non-clinical overview. Module 2.4 is appropriate and reflects the current scientific knowledge

on fingolimod.

The instructions on use of the active substance during pregnancy and lactation and the preclinical safety


data contained in the proposed SmPC and PL, respectively, essentially reflect the characteristics of

fingolimod and have been harmonised with the most recent version of the texts approved for the

reference product “Gilenya” (03/09/2019 Gilenya - EMEA/H/C/002202 - IB/0053).

In the light of the nonclinical data available from the literature, it can be assumed that the toxico-

pharmacological properties of Fingolimod 0.5 mg hard capsules have been well defined through its

active substance. According to this knowledge, combined with the extensive clinical experience over

the years, the product can be safely and efficaciously used in patients for the proposed indications.

There are no objections to approval of Fingolimod 0,5 mg Hartkapseln from a non-clinical point of

view.

Environmental Risk Assessment (ERA)

Since “Fingolimod 0,5 mg Hartkapseln” is intended for generic substitution, this will not lead to an

increased exposure to the environment. An environmental risk assessment is therefore not deemed

necessary.

III.3 Clinical aspects Pharmacokinetics

To support the application, the applicant has submitted one bioequivalence study:

Study Number: 18-VIN-0263 / LBC-18-131

Study Title: A randomized, open label, balanced two-treatment, single-period, single dose, parallel,

oral bioequivalence study comparing Fingolimod Capsules, 0.5 mg manufactured by Lupin Limited,

India with Gilenya® 0.5 mg hard capsules (Fingolimod) manufactured by Novartis Pharma GmbH,

Roonstrasse 25 D-90429 Nuremberg, Germany and marketed by Novartis Europharm Limited, Firmly

Business park, Camberley GUI6 7SR, United kingdom in healthy, adult, human subjects under fasting

conditions.

As fingolimod may be administered with or without food (Gilenya - SmPC) the study was carried out

only in fasting conditions in accordance with the “Guideline on the Investigation of Bioequivalence”

(CPMP/EWP/QWP/1401/98 Rev. 1/ Corr **, 2010). This dose is assumed to be well tolerated by

healthy adult volunteers. This is acceptable.

Based on the submitted bioequivalence study Fingolimod Capsules 0.5 mg is considered bioequivalent

with Gilenya 0.5 mg hard capsules.

The 90% confidence intervals for the ratios of Test (T) and Reference (R) product averages (least

squares means) derived from the analysis of log transformed pharmacokinetic parameters Cmax and

AUC0-72 of Fingolimod were within the limit of 80.00% and 125.00%.

Thus, it can be concluded that single oral dose of Fingolimod Capsules 0.5 mg manufactured by Lupin

Limited, India, with Gilenya® 0.5 mg hard capsules (Fingolimod) manufactured by Novartis Pharma

GmbH, Roonstrasse 25 90429 Nuremberg, Germany, are bioequivalent in healthy adult human male

subjects under fasting conditions.

The efficacy and safety of once-daily doses of fingolimod 0.25 mg or 0.5 mg (dose selected based on

body weight and exposure measurements) have been established in paediatric patients aged 10 to

<18 years with relapsing-remitting multiple sclerosis.

Only capsules with a dose strength of 0.5 mg are being applied for, but not for an additional 0.25 mg

dose strength. According to the SmPC, the applicant requests approval not only for the adult indication,

but also for paediatric patients with 10 years of age and above. In these patients the recommended dose

is dependent on body weight.

According to the dosage information (posology, section 4.2 SmPC) paediatric patients with a body

weight ≤ 40 kg should take one 0.25 mg capsule orally once daily.


The applied 0.5 mg hard capsules are not suitable for paediatric patients with a body weight ≤40 kg.

Other fingolimod-containing medicinal products are available in a lower strength (as 0.25 mg

capsules).

The product information (SmPC and PL) has been updated accordingly.

Pharmacodynamics

N/A

Clinical efficacy

N/A

Clinical safety

N/A

Legal Status The medicinal product is subject to medical prescription.

User Testing

The leaflet has been objectively validated as legible, clear and easy to understand. It is therefore

recommended as an appropriate patient information leaflet to accompany FINGOLIMOD HARD

CAPSULES. No further testing is considered necessary.

Summary Pharmacovigilance system

The Applicant has submitted a signed Summary of the Applicant's and/or Proposed Future MAH's

Pharmacovigilance System. Provided that the Pharmacovigilance System Master File fully complies

with the new legal requirements as set out in the Commission Implementing Regulation and as detailed

in the GVP module, the RMS considers the Summary acceptable.

Risk Management Plan

The MAH has submitted a risk management plan, in accordance with the requirements of Directive

2001/83/EC as amended, describing the pharmacovigilance activities and interventions designed to

identify, characterise, prevent or minimise risks relating to Fingolimod 0.5 mg hard capsules.

The RMP was aligned to the EU RMP of the originator product Gilenya (by Novartis) in accordance

with the EPAR Risk-management-plan summary as published on the EMA website on 13 September

2019.

Safety specification

The applicant proposes the following safety concerns in RMP version 0.4, signed on 13 February 2020,

which are in line with the ones for the reference product Gilenya.

Summary of safety concerns

Important identified

risks

1. Bradyarrhythmia (including conduction defects and bradycardia

complicated by hypotension) occurring post-first dose

2. Hypertension

3. Liver transaminase elevation

4. Posterior Reversible Encephalopathy Syndrome (PRES)

5. Macular oedema

6. Infections, including opportunistic infections (PML, VZV, herpes

viral infections other than VZV, fungal infection)

7. Reproductive toxicity

8. Bronchoconstriction

9. Skin cancer (Basal cell carcinoma, Kaposi’s sarcoma, Malignant

melanoma, Merkel cell carcinoma, Squamous cell carcinoma)

10. Convulsions


Important potential risks 1. Acute disseminated encephalomyelitis-like (ADEM-like) events

2. Lymphoma

3. Other malignant neoplasms

4. Thrombo-embolic events

5. QT interval prolongation

Missing information 1. Long-term use in paediatric patients, including impact on growth

and development (including cognitive development)

2. Elderly patients (≥ 65 years)

3. Lactating women

4. Patients with diabetes mellitus

5. Patients with cardiovascular conditions including myocardial

infarction, angina pectoris, Raynaud’s phenomenon, cardiac failure

or severe cardiac disease, increased QTc interval, uncontrolled

hypertension, patients at risk for bradyarrhythmia and who may not

tolerate bradycardia, patients with second degree Mobitz type 2 or

higher AV block, sick-sinus syndrome, sino-atrial heart block,

history of cardiac arrest, cerebrovascular disease and severe sleep

apnoea

6. Long-term risk of cardiovascular morbidity/mortality

7. Long-term risk of malignant neoplasms

8. Unexplained death

9. Switch from other disease modifying therapy

Pharmacovigilance Plan

Routine pharmacovigilance is suggested and no additional pharmacovigilance activities are proposed

by the applicant, which is endorsed. There are targeted questionnaires available to gain structured

information about the following safety concerns:

Bradyarrhythmia, Bronchoconstriction, Liver transaminase elevation, Macular edema, Infections, Skin

cancer, Reproductive toxicity, Convulsions, Lymphoma and other malignant neoplasms,

Thromboembolic events, Unexplained death.

In addition, the applicant will review all pregnancy cases in the PSUR submissions as part of routine

pharmacovigilance, which is adequately reflected in the RMP.

Risk minimisation measures

Routine risk minimisation activities as described above are considered sufficient to manage the safety

concerns of the medicinal product except for following risks:

Important Identified risks:

1. Bradyarrhythmia (including conduction defects and bradycardia complicated by hypotension)

occurring post-first dose

2. Liver transaminase elevation

3. Macular edema

4. Infections, including opportunistic infections (PML, VZV, herpes viral infections other than

VZV, fungal infection)

5. Reproductive toxicity

6. Skin cancer (Basal cell carcinoma, Kaposi’s sarcoma, Malignant melanoma, Merkel cell

carcinoma, Squamous cell carcinoma)

7. Convulsions

Missing information:

1. Long-term use in paediatric patients, including impact on growth and development (including

cognitive development)

for which additional risk minimisation measures are proposed and detailed below.

Educational Materials (Annex 6):

Physician’s checklist

Patient/Parent/Caregiver guide


Pregnancy-specific patient reminder card

The key elements are aligned to the ones for the reference product.

Proposed list of conditions pursuant to Article 21a or specific obligations pursuant to

article 22 of Directive 2001/83/EC

Additional risk minimisation measures (including educational material)

The educational material should contain the following key elements:

Physician’s checklist

Monitoring requirements at treatment initiation

Before first dose

o Perform baseline ECG prior to the first dose of Fingolimod 0.5mg hard capsules.

o Perform blood pressure measurement prior to the first dose of Fingolimod 0.5mg

hard capsules.

o Perform a liver function test (within 6 months) prior to treatment initiation.

o Arrange ophthalmological assessment prior to initiation with Fingolimod 0.5mg hard

capsules in patients with diabetes mellitus or with a history of uveitis.

o A negative pregnancy test result must be confirmed prior to starting treatment.

Until 6 hours after first dose

o Monitor the patient for 6 hours after the first dose of Fingolimod 0.5mg hard

capsules A has been administered for signs and symptoms of bradycardia, including

hourly pulse and blood pressure checks. Continuous (real time) ECG monitoring is

recommended.

o Perform an ECG at the end of the 6-hour monitoring period.

>6 to 8 hours after first dose

o If, at the 6-hour time point, the heart rate is at the lowest value following the first

dose, extend heart rate monitoring for at least 2 more hours and until the heart rate

increases again.

Recommendation for re-initiating Fingolimod 0.5 mg hard capsules therapy after treatment

interruption

The same first dose monitoring as for treatment initiation is recommended when treatment is

interrupted for

o One day or more during the first 2 weeks of treatment;

o More than 7 days during weeks 3 and 4 of treatment;

o More than 2 weeks after at least 1 month of treatment.

Recommendation for overnight monitoring after the first dose.

Extend heart rate monitoring for at least overnight in a medical facility and until resolution of

findings in patients:

o Requiring pharmacological intervention during monitoring at treatment initiation/re-

initiation. Also repeat the first dose monitoring after the second dose of Fingolimod

0.5 mg hard capsules for these patients.

o With third degree AV block occurring at any time.

o Where at the 6-hour time point:

- Heart rate <45 bpm, <55 bpm in pediatric patients aged 12 years old and above,

or <60 bpm in pediatric patients 10 to below 12 years of age;

- New onset second degree or higher AV block.

- QTc interval ≥500 msec.

Fingolimod 0.5 mg hard capsules is contraindicated in patients with:

o Immunodeficiency syndrome;

o Increased risk for opportunistic infections, including immunocompromised patients

(including those currently receiving immunosuppressive therapies or those

immunocompromised by prior therapies);


o Severe active infections, active chronic infections (hepatitis, tuberculosis);

o Active malignancies;

o Severe liver impairment (Child-Pugh class C);

o In the previous 6 months, 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;

o Severe cardiac arrhythmias requiring anti-arrhythmic treatment with class Ia or class

III anti-arrhythmic drugs;

o Second-degree Mobitz type II atrioventricular (AV) block or third-degree AV block,

or sick-sinus syndrome, if they do not wear a pacemaker;

o A baseline QTc interval ≥500 msec;

o Hypersensitivity to the active substance or to any of the excipients

And

o During pregnancy and in women of childbearing potential not using effective

contraception.

That Fingolimod 0.5mg hard capsules is not recommended in patients with:

o Sino-atrial heart block;

o QTc prolongation >470 msec (adult females), >460 msec (paediatric females) or

>450 msec (adult and paediatric males);

o History of cardiac arrest;

o Severe sleep apnoea;

o History of symptomatic bradycardia;

o History of recurrent syncope;

o Uncontrolled hypertension.

If Fingolimod 0.5mg hard capsules treatment is considered in these patients anticipated benefits must

outweigh potential risks and a cardiologist must be consulted to determine appropriate monitoring, at

least overnight extended monitoring is recommended.

Fingolimod 0.5mg hard capsules is not recommended in patients concomitantly taking

medicines which are known to decrease the heart rate. If Fingolimod 0.5mg hard capsules

treatment is considered in these patients anticipated benefits must outweigh potential risks

and a cardiologist must be consulted to switch to non heart-rate-lowering therapy or, if not

possible, to determine appropriate monitoring. At least overnight extended monitoring is

recommended.

Fingolimod 0.5mg hard capsules reduces peripheral blood lymphocyte counts. Peripheral

lymphocyte count (CBC) should be checked in all patients prior to initiation (within 6

months or after discontinuation of prior therapy) and monitored during treatment with

Fingolimod 0.5mg hard capsules. Treatment should be interrupted if lymphocyte count is

confirmed as <0.2x109/L. The approved dosing of 0.5 mg once daily (or 0.25 mg once daily

in pediatric patients 10 years

of age and above with a body weight of ≤ 40 kg) should be administered when restarting

Fingolimod 0.5 mg hard capsules. Other dosing regimens have not been approved.

Fingolimod 0.5mg hard capsules have an immunosuppressive effect that predisposes patients

to an infection risk, including opportunistic infections that can be fatal, and increases the risk

of developing lymphomas (including mycosis fungoides) and other malignancies,

particularly those of the skin. Surveillance should include vigilance for both skin

malignancies and mycosis fungoides. Physicians should carefully monitor patients, especially

those with concurrent conditions or known factors, such as previous immunosuppressive

therapy. If this risk is suspected, discontinuation of treatment should be considered by the

physician on a case-by-case basis.

o Treatment initiation in patients with severe active infection should be delayed until

the infection is resolved. Suspension of treatment during serious infections should be

considered. Anti-neoplastic, immunomodulatory or immunosuppressive therapies

should not be co-administered due to the risk of additive immune system effects. For

the same reason, a decision to use prolonged concomitant treatment with

corticosteroids should be taken after careful consideration.


o Vigilance for basal cell carcinoma and other cutaneous neoplasms including

malignant melanoma, squamous cell carcinoma, Kaposi’s sarcoma and Merkel cell

carcinoma is recommended, with skin examination prior to treatment initiation and

then every 6 to 12 months taking into consideration clinical judgement. Patients

should be referred to a dermatologist if suspicious lesions are detected. Caution

patients against exposure to sunlight without protection. These patients should not

receive concomitant phototherapy with UV-B-radiation or PUVA-

photochemotherapy.

The need to instruct patients to report signs and symptoms of infections immediately to their

prescriber during and for up to two months after treatment with Fingolimod 0.5mg hard

capsules.

o Prompt diagnostic evaluation should be performed in patient with symptoms and

signs consistent with cryptococcal meningitis; appropriate treatment, if diagnosed,

should be initiated.

o Reports of cryptococcal meningitis (sometimes fatal) have been received after

approximately 2-3 years of treatment, although an exact relationship with the

duration of treatment is unknown.

o Physicians should be vigilant for clinical symptoms or MRI findings suggestive of

PML. If PML is suspected, treatment with Fingolimod 0.5 mg hard capsules should

be suspended until PML has been excluded

o Cases of PML have occurred after approximately 2-3 years of monotherapy

treatment although an exact relationship with the duration of treatment is unknown.

o Specific recommendations regarding vaccination for patients initiating Fingolimod

0.5 mg hard capsules treatment. Check varicella zoster virus (VZV) antibody status

in patients without a healthcare professional confirmed history of chickenpox or

documentation of a full course of varicella vaccination. If negative, a full course of

vaccination with varicella vaccine is recommended and treatment initiation should be

delayed for 1 month to allow full effect of vaccination to occur.

o Human papilloma virus (HPV) infection, including papilloma, dysplasia, warts and

HPV-related cancer, has been reported in the post-marketing setting. Cancer

screening, including Pap test, and vaccination for HPV-related cancer is

recommended for patients, as per standard of care.

The need for a full ophthalmological assessment 3-4 months after starting Fingolimod 0.5mg

hard capsules therapy for the early detection of visual impairment due to drug-induced

macular oedema.

The need for ophthalmological assessment during treatment with Fingolimod 0.5mg hard

capsules in patients with diabetes mellitus or with a history of uveitis.

The teratogenic risk of Fingolimod 0.5mg hard capsules: It is contraindicated in women of

childbearing potential (including female adolescents) not using effective contraception and in

pregnant women;

o A negative pregnancy test result must be confirmed prior to starting treatment, and it

must be repeated at suitable intervals.

o Women of child-bearing potential, including adolescent females, their parents (or

legal representatives), and caregivers, should be counselled before treatment

initiation and regularly thereafter about the serious risks of Fingolimod to the foetus,

facilitated by the pregnancy-specific patient reminder card.

o Women of childbearing potential must use effective contraception during treatment

and for two months following treatment discontinuation.

o While on treatment, women must not become pregnant. If a woman becomes

pregnant while on treatment, Fingolimod 0.5 mg hard capsules must be discontinued.

When stopping Fingolimod therapy due to pregnancy or for planning a pregnancy,

the possible return of disease activity should be considered. Medical advice should

be given regarding the risk of harmful effects to the foetus associated with

Fingolimod treatment and follow-up medical examinations (e.g. ultrasonography

examination) should be performed.


o Fingolimod 0.5 mg hard capsules must be stopped 2 months before planning a

pregnancy.

The need for liver function monitoring at months 1, 3, 6, 9 and 12 during Fingolimod 0.5 mg

hard capsules therapy and periodically thereafter; the approved dosing of 0.5 mg daily (or

0.25 mg once daily in pediatric patients 10 years of age and above with a body weight of ≤40

kg) should be administered. Other dosing regimens have not been approved.

In the post-marketing setting, severe exacerbation of disease has been observed rarely in

some patients stopping Fingolimod. The possibility of recurrence of exceptionally high

disease activity should be considered.

Cases of seizure, including status epilepticus, have been reported. Physicians should be

vigilant for seizures and especially in those patients with underlying conditions or with a pre-

existing history or family history of epilepsy.

Physicians should reassess on an annual basis the benefit of Fingolimod treatment versus

risk in each patient, especially pediatric patients.

The need to provide patients/parents/caregivers with the patient/parent/caregiver’s guide and

with the pregnancy-specific reminder card.

The safety profile in pediatric patients is similar to adults and therefore the warnings and precautions

in adults also apply for pediatric patients.

Specifically, with pediatric patients, physicians should also:

Assess Tanner staging and measure height and weight as per standard of care;

Perform cardiovascular monitoring;

Take precautions when the first dose is administered / patients are switched from 0.25 to 0.5

mg daily, due to the potential for bradyarrhythmia;

Monitor the patient for signs and symptoms of depression and anxiety;

Emphasize treatment compliance and misuse to patients, especially about treatment

interruption and the importance of repeating cardiovascular monitoring;

Emphasize Fingolimod 0.5 mg hard capsules immunosuppressive effects;

Consider a complete vaccination schedule before starting Fingolimod;

Provide guidance on seizure monitoring.

Patient/Parent/Caregiver’s guide

What Fingolimod 0.5 mg hard capsules is and how it works;

What multiple sclerosis is;

Patients should read the package leaflet thoroughly before starting treatment and should keep

it in case they need to refer to it again during treatment;

Importance to report adverse reactions;

Patients will have a baseline ECG and blood pressure measurement prior to the first dose of

Fingolimod 0.5mg hard capsules.

Their heart rate will need to be monitored for 6 or more hours after the first dose of

Fingolimod 0.5mg hard capsules, including hourly pulse and blood pressure checks. Patients

may be monitored with a continuous ECG during the first 6 hours. They will need an ECG at

6 hours and in some circumstances monitoring may involve an overnight stay.

Patients should call their doctor in case of treatment interruption as the 1st dose monitoring

may need to be repeated, depending on duration of interruption and time since starting of

Fingolimod 0.5 mg hard capsules treatment.

Patients should report immediately symptoms indicating low heart rate (such as dizziness,

vertigo, nausea or palpitations) after the first dose of Fingolimod 0.5mg hard capsules.

Fingolimod 0.5 mg hard capsules is not recommended in patients with cardiac disease or

those taking medicines concomitantly known to decrease heart rate and they should tell any

doctor they see that they are being treated with Fingolimod 0.5mg hard capsules.

Signs and symptoms of infection and the need to report these immediately to the prescriber

physician during and up to two months after treatment with Fingolimod 0.5 mg hard

capsules.


The need to undergo cancer screening, including Pap test, and vaccination for HPV-related

cancer, as per standard of care, will be assessed by the prescriber physician.

The need to report any symptoms of visual impairment immediately to the prescriber during

and for up to two months after the end of treatment with Fingolimod 0.5 mg hard capsules.

That Fingolimod 0.5 mg hard capsules is teratogenic so women of childbearing potential,

including adolescent females, must:

o Be informed before treatment initiation and regularly thereafter by their physician

about Fingolimod 0.5 mg hard capsules’ serious risks to the foetus and about the

contraindication in pregnant women and women of childbearing potential not using

effective contraception, facilitated by the pregnancy-specific reminder card;

o Have a negative pregnancy test before starting Fingolimod 0.5 mg hard capsules;

o Be using effective contraception during and for at least two months following

discontinuation of treatment with Fingolimod.

o Immediately report any (intended or unintended) pregnancy during and two months

following discontinuation of Fingolimod treatment to the prescriber.

The need for a liver function test prior to treatment initiation and for liver function

monitoring at months 1, 3, 6, 9 and 12 during Fingolimod 0.5 mg hard capsules therapy and

periodically thereafter.

Skin cancers have been reported in multiple sclerosis patients treated with Fingolimod.

Patients should inform their doctor immediately if any skin nodules (e.g., shiny, pearly

nodules), patches or open sores that do not heal within weeks are noted. Symptoms of skin

cancer may include abnormal growth or changes of skin tissue (e.g., unusual moles) with a

change in colour, shape or size over time.

Seizure may occur. The doctor should be informed about a pre-existing history or family

history of epilepsy.

Stopping Fingolimod 0.5 mg hard capsules therapy may result in return of disease activity.

The prescribing physician should decide whether and how the patient should be monitored

after stopping Fingolimod 0.5 mg hard capsules.

Specifically for Pediatric patients:

The following should be considered:

Physicians should assess Tanner staging and measure height and weight as per standard of

care;

Precautions should be taken during the first dose of Fingolimod 0.5 mg hard capsules and

when patients are switched from 0.25 mg Fingolimod to 0.5 mg daily;

Depression and anxiety are known to occur with increased frequency in the multiple sclerosis

population and have been reported also in pediatric patients treated with Fingolimod;

Cardiac monitoring guidance;

Patients should ensure medication compliance and avoid misuse, especially treatment

interruption, and repeat cardiac monitoring;

Signs and symptoms of infection;

Seizure monitoring guidance.

Pregnancy-specific reminder card

Fingolimod 0.5 mg hard capsules is contraindicated during pregnancy and in women of

childbearing potential not using effective contraception;

Doctors will provide counselling before treatment initiation and regularly thereafter

regarding the teratogenic risk of Fingolimod 0.5 mg hard capsules and required actions to

minimise this risk.

Patients must use effective contraception while taking Fingolimod 0.5 mg hard capsules;

A pregnancy test must be carried out and negative results verified by the doctor before

starting treatment. It must be repeated at suitable intervals;

Patients will be informed by their doctor of the need for effective contraception while on

treatment and for 2 months after discontinuation;

Doctors will provide counselling in the event of pregnancy and evaluation of the outcome of

any pregnancy;


While on treatment, women must not become pregnant. If a woman becomes pregnant or

wants to become pregnant, Fingolimod must be discontinued;

Patients should inform their doctor straight away if there is worsening of multiple sclerosis

after stopping treatment with Fingolimod;

Summary of the RMP

The MAH shall perform the required pharmacovigilance activities and interventions detailed in

the agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed

subsequent updates of the RMP.

An updated RMP should be submitted:

- At the request of the RMS;

- Whenever the risk management system is modified, especially as the result of new

information being received that may lead to a significant change to the benefit/risk profile or

as the result of an important (pharmacovigilance or risk minimisation) milestone being

reached.

If the dates for submission of a PSUR and the update of a RMP coincide, they can be submitted at the

same time, but via different procedures.

Periodic Safety Update Report (PSUR)

With regard to PSUR submission, the MAH should take the following into account:

• PSURs shall be submitted in accordance with the requirements set out in the list of Union

reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and

published on the European medicines web-portal. Marketing authorisation holders shall

continuously check the European medicines web-portal for the DLP and frequency of

submission of the next PSUR.

• For medicinal products authorized under the legal basis of Article 10(1) or Article 10a of

Directive 2001/83/EC, no routine PSURs need to be submitted, unless otherwise specified in

the EURD list.

• In case the active substance will be removed in the future from the EURD list because the

MAs have been withdrawn in all but one MS, the MAH shall contact that MS and propose

DLP and frequency for further PSUR submissions together with a justification.

IV BENEFIT RISK ASSESSMENT The application contains an adequate review of published clinical data and the bioequivalence has

been shown. The application is approvable from a clinical and pharmaceutical (quality) point of

view.

The application is approved. For intermediate amendments see current product information.

decentralised procedure

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