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Gilenya 0.5mg hard capsules

Last Updated on eMC 30-Jun-2017 View document  | Novartis Pharmaceuticals UK Ltd Contact details

When a pharmaceutical company changes an SPC or PIL, a new version is published on the eMC.  For each version, we show the dates it was published on the eMC and the reasons for change.

Updated on 30-Jun-2017 and displayed until Current

Reasons for adding or updating:

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.6 - Fertility, pregnancy and lactation
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 5.3 - Preclinical safety data
  • Change to section 10 - Date of revision of the text

Date of revision of text on the SPC: 18-May-2017

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Section 4.4 - minor editorial change

Experience with Gilenya is limited in patients receiving concurrent therapy with beta blockers, heart-rate-lowering calcium channel blockers (such as verapamil, or diltiazem or ivabradine), or other substances which may decrease heart rate (e.g. ivabradine, digoxin, anticholinesteratic agents or pilocarpine).

Section 4.5 - minor editorial change,
Within Bradycardia-inducing substances move the word ivabradine.

Section 4.6

Women of childbearing potential / Contraception in females

Before initiation of Gilenya treatment, in women of childbearing potential, a negative pregnancy test result needs to be available and should be counselling should be provided regarding the potential for serious risk to the foetus and the need for effective contraception during treatment with Gilenya.

Pregnancy

Before initiation of treatment in women of childbearing potential a negative pregnancy test result needs to be available. While on treatment, women should not become pregnant and active contraception is recommended. If a woman becomes pregnant while taking Gilenya, discontinuation of Gilenya is recommended.

Breast-feeding

Fingolimod is excreted in milk of treated animals during lactation at concentrations 2-3-fold higher than that found in maternal plasma (see section 5.3). Due to the potential for serious adverse reactions to fingolimod in nursing infants, women receiving Gilenya should not breastfeed. 

Section 5.2

Within Absorption, change increased by 34% to decreased by 34%.

Section 5.3

Fingolimod was teratogenic in the rat when given at doses of 0.1 mg/kg or higher. Drug exposure in rats at this dose was similar to that in patients at the therapeutic dose (0.5 mg). The most common foetal visceral malformations included persistent truncus arteriosus and ventricular septum defect. The teratogenic potential in rabbits could not be fully assessed, however an increased embryo-foetal mortality was seen at doses of 1.5 mg/kg and higher, and a decrease in viable foetuses as well as foetal growth retardation was seen at 5 mg/kg. Drug exposure in rabbits at these doses was similar to that in patients.

 

 Fingolimod was excreted in milk of treated animals during lactation at concentrations 2‑fold to 3-fold higher than that found in maternal plasma. Fingolimod and its metabolites crossed the placental barrier in pregnant rabbits.

 

 

 

 

 

 

 

 

 

Updated on 09-Mar-2017 and displayed until 30-Jun-2017

Reasons for adding or updating:

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
  • Change to section 10 - Date of revision of the text

Date of revision of text on the SPC: 26-Jan-2017

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Black Triangle (CHM): YES

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Update Sections 4.4 and 4.8 to add an approximate time of onset for PML and Cryptococcal meningitis.

Updated on 15-Dec-2016 and displayed until 09-Mar-2017

Reasons for adding or updating:

  • Change to section 4.8 - Undesirable effects
  • Change to section 10 - Date of revision of the text

Date of revision of text on the SPC: 08-Dec-2016

Legal Category:POM

Black Triangle (CHM): YES

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Section 4.8 - Add Kaposi's sarcoma as a Not known adverse reaction and Thrombocytopenia as an Uncommon side effect.

Updated on 11-Feb-2016 and displayed until 15-Dec-2016

Reasons for adding or updating:

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
  • Change to section 9 - Date of first authorisation/renewal of the authorisation
  • Change to section 10 - Date of revision of the text

Date of revision of text on the SPC: 25-Jan-2016

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Update Section 4.4 and 4.8 to include 'Progressive multifocal leukoencephalopathy (PML).

Section 9 - Update Renewal date.

Updated on 02-Dec-2015 and displayed until 11-Feb-2016

Reasons for adding or updating:

  • Change to section 4.3 - Contraindications
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
  • Change to section 9 - Date of first authorisation/renewal of the authorisation
  • Change to section 10 - Date of revision of the text

Date of revision of text on the SPC: 23-Nov-2015

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Section 4.3 - To delete reference to basel cell carcinoma

Section 4.4 - To add paragraph on T-wave inversion and Basel cell carcinoma

Section 4.8 - To add Neoplasms benign, malignant and unspecified (incl cysts and polyps) into the AE table. To add peripheral oedema, T-wave inversion and nausea as AE's. To add further AE's to immune system disorders and delete rash.

Section 9 - Include Renewal date.

Updated on 16-Nov-2015 and displayed until 02-Dec-2015

Reasons for adding or updating:

  • Change to section 4.1 - Therapeutic indications
  • Change to section 10 - Date of revision of the text

Date of revision of text on the SPC: 28-Oct-2015

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Update to section 4.1 with regard to the indication for use in patients with active disease.

Updated on 30-Jun-2015 and displayed until 16-Nov-2015

Reasons for adding or updating:

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.8 - Undesirable effects
  • Change to section 10 - Date of revision of the text

Date of revision of text on the SPC: 21-May-2015

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Update to sections 4.4, 4.5 and 4.8 with information relating to isolated cases of cryptococcal meningitis.

Updated on 27-Mar-2015 and displayed until 30-Jun-2015

Reasons for adding or updating:

  • Change to section 7 - Marketing authorisation holder
  • Change to section 10 - Date of revision of the text

Date of revision of text on the SPC: 13-Feb-2015

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Section 7 - To change the name of the MA holder from Horsham to Frimley.

Updated on 08-Sep-2014 and displayed until 27-Mar-2015

Reasons for adding or updating:

  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 10 - Date of revision of the text

Date of revision of text on the SPC: 24-Jul-2014

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Section 5.1

Paragraphs as below:

Mechanism of action

Fingolimod is a sphingosine 1-phosphate receptor modulator. Fingolimod is metabolised by sphingosine kinase to the active metabolite fingolimod phosphate. Fingolimod phosphate binds at low nanomolar concentrations to sphingosine 1-phosphate (S1P) receptor 1 located on lymphocytes, and readily crosses the blood-brain barrier to bind to S1P receptor 1 located on neural cells in the central nervous system (CNS). By acting as a functional antagonist of S1P receptors on lymphocytes, fingolimod phosphate blocks the capacity of lymphocytes to egress from lymph nodes, causing a redistribution, rather than depletion, of lymphocytes. Animal studies have shown that tThis redistribution reduces the infiltration of pathogenic lymphocytes, including pro-inflammatory Th17 cells, into the CNScentral nervous system, where they would be involved in nerve inflammation and nervous tissue damage. Animal studies and in vitro experiments indicate that fingolimod may also act via interaction with S1P receptors on neural cells.

Section 5.2

Fingolimod is extensively distributed to body tissues with a volume of distribution of about 1,200±260 litres. A study in four healthy subjects who received a single intravenous dose of a radioiodolabelled analogue of fingolimod demonstrated that fingolimod penetrates into the brain. In a study in 13 male multiple sclerosis patients who received Gilenya 0.5 mg/day, the mean amount of fingolimod (and fingolimod phosphate) in seminal ejaculate, at steady-state, was approximately 10,000 times lower than the oral dose administered (0.5 mg).

Updated on 09-Jul-2014 and displayed until 08-Sep-2014

Reasons for adding or updating:

  • Change to section 10 - Date of revision of the text
  • Change to section 4.8 - Undesirable effects

Date of revision of text on the SPC: 19-Jun-2014

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In Section 4.8 (undesirable effects), hypersensitivity and rash have been added as 'not known' adverse reactions under immune system disorders.

Updated on 16-Jun-2014 and displayed until 09-Jul-2014

Reasons for adding or updating:

  • Change to section 1 - Name of the medicinal product
  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 10 - Date of revision of the text

Date of revision of text on the SPC: 23-May-2014

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Section 1

To add the reigstered trademark after the product name.

Section 4.1

-              Patients with high disease activity despite treatment with at least one disease modifying therapy (for exceptions and information about washout periods see sections 4.4 and 5.1)beta-interferon.

These patients may be defined as those who have failed to respond to a full and adequate course (normally at least one year of treatment) of at least one disease modifying therapybeta-interferon. Patients should have had at least 1 relapse in the previous year while on therapy, and have at least 9 T2-hyperintense lesions in cranial MRI or at least 1 Gadolinium-enhancing lesion. A “non-responder” could also be defined as a patient with an unchanged or increased relapse rate or ongoing severe relapses, as compared to the previous year.


Section 4.2

To delete the paragraph above special populations, regarding patients can switch directly from beta-interferon to Gilenya.....

Section 4.4

Paragraphs as shown:

Before initiating treatment with Gilenya, a recent complete blood count (CBC) (i.e. within 6 months or after discontinuation of prior therapy) should be available. Assessments of CBC are also recommended periodically during treatment, at month 3 and at least yearly thereafter, and in case of signs of infection. Absolute lymphocyte count <0.2x109/l, if confirmed, should lead to treatment interruption until recovery, because in clinical studies, fingolimod treatment was interrupted in patients with absolute lymphocyte count <0.2x109/l.


Prior treatment with immunosuppressive or immunomodulatory therapies

There have been no studies performed to evaluate the efficacy and safety of Gilenya when switching patients from teriflunomide, dimethyl fumarate or alemtuzumab treatment to Gilenya. When switching patients from another disease modifying therapy to Gilenya, the half-life and mode of action of the other therapy must be considered in order to avoid an additive immune effect whilst at the same time minimising the risk of disease reactivation. A CBC is recommended prior to initiating Gilenya to ensure that immune effects of the previous therapy (i.e. cytopenia) have resolved.

 

Gilenya can generally be started immediately after discontinuation of interferon or glatiramer acetate to Gilenya, a washout is not necessary, assuming any immune effects (i.e. cytopenia) of such therapies have resolved.

 

For dimethyl fumarate, the washout period should be sufficient for CBC to recover before treatment with Gilenya is started.

 

Due to the long half-life of natalizumab, elimination usually takesconcomitant exposure, and thus concomitant immune effects, could occur for up to 2‑3 months following discontinuation of natalizumab if Gilenya was immediately started. Therefore caution is required when switching patients from natalizumab to Gilenya. Teriflunomide is also eliminated slowly from the plasma. Without an accelerated elimination procedure, clearance of teriflunomide from plasma can take from several months up to 2 years. An accelerated elimination procedure as defined in the teriflunomide summary of product characteristics is recommended or alternatively washout period should not be shorter than 3.5 months. Caution regarding potential concomitant immune effects is required when switching patients from natalizumab or teriflunomide to Gilenya.

 

Alemtuzumab has profound and prolonged immunosuppressive effects. As the actual duration of these effects is unknown, initiating treatment with Gilenya after alemtuzumab is not recommended unless the benefits of such treatment clearly outweigh the risks for the individual patient.

 

When switching from other immunosuppressive medications, the duration and mode of action of such substances must be considered when initiating Gilenya to avoid additive immune suppressive effects.

Updated on 09-May-2014 and displayed until 16-Jun-2014

Reasons for adding or updating:

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 10 - Date of revision of the text

Date of revision of text on the SPC: 28-Mar-2014

Legal Category:POM

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Section 4.2 Posology and Method of Administration

- Neutropenia and cytopenia (Switching therapy to Gilenya)


Section 4.4 Special warnings and precautions for use

- Infections: VZV and concommittant use of corticosteroids, upgrade of PRES from ADR to warnings and precautions

- Changes in frequencies of ADR in line with update of section 4.8


Section 4.5 Interaction with other medicinal products and other forms of interaction

- concomitant use with corticosteriods (connected to VZV)

Section 4.5 is also updated to relocate the information related to potent inhibitors of transporter proteins under the related subheading.


Section 4.8 Undesirable effects

- Revised ADR profile (table and related text) based on pooled analysis from D2301/D2309

 

Section 5.2 to amend the information related to the enzymes involved in the metabolic pathway of fingolimod.  


Section 6.5 - To include a new pack size of 98 capsules.

Updated on 16-Jan-2014 and displayed until 09-May-2014

Reasons for adding or updating:

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.8 - Undesirable effects
  • Change to section 4.9 - Overdose
  • Change to section 10 - Date of revision of the text

Date of revision of text on the SPC: 18-Dec-2013

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Section 4.4

New paragraph added at the end of section above stopping therapy.

Co-administration with potent CYP450 inducers

The combination of fingolimod with potent CYP450 inducers should be used with caution. Concomitant administration with St John’s wort is not recommended (see section 4.5).


Section 4.5

As below, last paragraph has been deleted from section.

Pharmacokinetic interactions of other substances on fingolimod

Fingolimod is metabolised mainly by CYP4F2. Other enzymes like CYP3A4 may also contribute to its metabolism, notably in the case of strong induction of CYP3A4. Co-administration of fingolimod with ketoconazole resulted in a 1.7-fold increase in fingolimod and fingolimod phosphate exposure (AUC) by inhibition of CYP4F2. Caution should be exercised with substances that may inhibit CYP3A4 (protease inhibitors, azole antifungals, some macrolides such as clarithromycin or telithromycin).

 

Co-administration of carbamazepine 600 mg twice daily at steady-state and a single dose of fingolimod 2 mg reduced the AUC of fingolimod and its metabolite by approximately 40%. Other strong CYP3A4 enzyme inducers, for example rifampicin, phenobarbital, phenytoin, efavirenz and St. John’s Wort, may reduce the AUC of fingolimod and its metabolite at least to this extent. As this could potentially impair the efficacy, their co-administration should be used with caution. Concomitant administration with St. John’s Wort is however not recommended (see section 4.4).


Section 4.8

As shown:

Some cases of disseminated herpes infection, including fatal cases, have been reported even at the 0.5 mg dose.Two fatal cases of herpes infection occurred at the higher 1.25 mg dose: A case of herpes simplex encephalitis in a patient in whom initiation of acyclovir therapy was delayed by one week, and a case of primary disseminated varicella zoster infection in a patient not previously exposed to varicella receiving concomitant high-dose steroid therapy for a multiple sclerosis relapse.

Section 4.9

No cases of overdose have been reported. However, sSingle doses up to 80 times the recommended dose (0.5 mg) were well tolerated in healthy volunteers. At 40 mg, 5 of 6 subjects reported mild chest tightness or discomfort which was clinically consistent with small airway reactivity.

Updated on 23-Dec-2013 and displayed until 16-Jan-2014

Reasons for adding or updating:

  • Change to section 4.8 - Undesirable effects
  • Change to section 10 - Date of revision of the text

Date of revision of text on the SPC: 25-Nov-2013

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Section 4.8

The following paragraph on HPS has been added above the paragraph on reporting of suspected adverse reactions.

Haemophagocytic syndrome

Very rare cases of haemophagocytic syndrome (HPS) with fatal outcome have been reported in patients treated with fingolimod in the context of an infection. HPS is a rare condition that has been described in association with infections, immunosuppression and a variety of autoimmune diseases.

Updated on 06-Dec-2013 and displayed until 23-Dec-2013

Reasons for adding or updating:

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects - how to report a side effect
  • Change to section 10 - Date of revision of the text

Date of revision of text on the SPC: 19-Nov-2013

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Section 4.4

To include a recommendation fo Complete Blood Cell Count (CBC) 3 months after initiation of treatment and yearly thereafter.

Section 4.8

To include paragraph at the end of section on reporting of suspected adverse reactions.


Updated on 02-May-2013 and displayed until 06-Dec-2013

Reasons for adding or updating:

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 10 - Date of revision of the text

Date of revision of text on the SPC: 25-Apr-2013

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Update of the existing warning on bradycardia in section 4.4.
Update of lymphoma in section 4.8.
Adding hypotension as an associated symptom of bradyarrhythmia in section 4.8.
Deletion of a foootnote in section 5.1 (editorial change).

Updated on 10-Apr-2013 and displayed until 02-May-2013

Reasons for adding or updating:

  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 10 - Date of revision of the text

Date of revision of text on the SPC: 21-Feb-2013

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Section 5.1

After table 1

Patients who completed the 24-month core FREEDOMS study could enter a dose-blinded extension study (D2301E1) and receive fingolimod. In total, 920 patients entered (n=331 continued on 0.5 mg, 289 continued on 1.25 mg, 155 switched from placebo to 0.5 mg and 145 switched from placebo to 1.25 mg). After 12 months (month 36), 856 patients (93%) were still enrolled. Between months 24 and 36, the annualised relapse rate (ARR) for patients on fingolimod 0.5 mg in the core study who remained on 0.5 mg was 0.17 (0.21 in the core study). The ARR for patients who switched from placebo to fingolimod 0.5 mg was 0.22 (0.42 in the core study).

 

Comparable results were shown in a replicate 2-year randomised, double-blind, placebo-controlled Phase III study on fingolimod in 1,083 patients (n=358 on 0.5 mg, 370 on 1.25 mg, 355 on placebo) with RRMS (D2309; FREEDOMS 2). Median values for baseline characteristics were: age 41 years, disease duration 8.9 years, EDSS score 2.5.

 

Table 2: Study D2309 (FREEDOMS 2): Main results

 

 

Fingolimod

0.5 mg

Placebo

Clinical endpoints

 

 

Annualised relapse rate (primary endpoint)

0.21**

0.40

Percentage of patients remaining relapse-free at 24 months

71.5%**

52.7%

Proportion with 3-month Confirmed Disability Progression†

25%

29%

Hazard ratio (95% CI)

0.83 (0.61,1.12)

 

MRI endpoints

 

 

Median (mean) number of new or enlarging T2 lesions over 24 months

0.0 (2.3)**

4.0 (8.9)

Median (mean) number of Gd-enhancing lesions at Month 24

0.0 (0.4)**

0.0 (1.2)

Median (mean) % change in brain volume over 24 months

-0.71 (-0.86)**

-1.02 (-1.28)

        Disability progression defined as 1-point increase in EDSS confirmed 3 months later

**     p<0.001, *p<0.05 compared to placebo

All analyses of clinical endpoints were intent-to-treat. MRI analyses used evaluable dataset.

 

Study D2302 (TRANSFORMS) was a 1-year randomised, double-blind, double-dummy, active (interferon beta-1a)-controlled Phase III study of 1,280 patients (n=429 on 0.5 mg, 420 on 1.25 mg, 431 on interferon beta-1a, 30 µg by intramuscular injection once weekly). Median values for baseline characteristics were: age 36 years, disease duration 5.9 years, and EDSS score 2.0. Outcome results are shown in Table 23. There were no significant differences between the 0.5 mg and the 1.25 mg doses as regards study endpoints.

 

Table 23: Study D2302 (TRANSFORMS): Main results

 

 

Fingolimod

0.5 mg

Interferon beta-1a, 30 μg

Clinical endpoints

 

 

Annualised relapse rate (primary endpoint)

0.16**

0.33

Percentage of patients remaining relapse-free at 12 months

83%**

71%

Proportion with 3-month Confirmed Disability Progression†

6%

8%

Hazard ratio (95% CI)

0.71 (0.42, 1.21)

 

MRI endpoints

 

 

Median (mean) number of new or enlarging T2 lesions over 12 months

0.0 (1.7)*

1.0 (2.6)

Median (mean) number of Gd-enhancing lesions at 12 months

0.0 (0.2)**

0.0 (0.5)

Median (mean) % change in brain volume over 12 months

‑0.2 (‑0.3)**

‑0.4 (‑0.5)

        Disability progression defined as 1-point increase in EDSS confirmed 3 months later.

*          p<0.01,** p<0.001, compared to interferon beta-1a

All analyses of clinical endpoints were intent-to-treat. MRI analyses used evaluable dataset.

 

Patients who completed the 12-month core TRANSFORMS study could enter a dose-blinded extension (D2302E1) and receive fingolimod. In total, 1,030 patients entered, however, 3 of these patients did not receive treatment (n=356 continued on 0.5 mg, 330 continued on 1.25 mg, 167 switched from interferon beta-1a to 0.5 mg and 174 from interferon beta-1a to 1.25 mg). After 12 months (month 24), 882 patients (86%) were still enrolled. Between months 12 and 24, the ARR for patients on fingolimod 0.5 mg in the core study who remained on 0.5 mg was 0.20 (0.19 in the core study). The ARR for patients who switched from interferon beta-1a to fingolimod 0.5 mg was 0.33 (0.48 in the core study).

 

Updated on 14-Feb-2013 and displayed until 10-Apr-2013

Reasons for adding or updating:

  • Change to section 2 - Qualitative and quantitative composition
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.3 - Contraindications
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
  • Change to section 10 - Date of revision of the text

Date of revision of text on the SPC: 13-Jan-2013

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Section 2

For thea full list of excipients, see section 6.1.


Section 4.2

Paragraph as shown:

Posology

The recommended dose of Gilenya is one 0.5 mg capsule taken orally once daily. Gilenya can be taken with or without food.

 

If a dose is missed treatment should be continued with the next dose as planned.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 (see section 4.4).


Section 4.3

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.


Section 4.4

Paragraphs as shown:

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 Gilenya.



If therapy is discontinued for more than 2 weeks, tThe effects on heart rate and atrioventricular conduction may recur on re-introduction of Gilenya treatment depending on duration of the interruption and time since start of Gilenya 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 and the same precautions as for treatment initiation should apply.

 

Section 4.8

Minor deleting of spaces in 2nd paragraph.

At the end of the SPC:

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu


Updated on 18-Dec-2012 and displayed until 14-Feb-2013

Reasons for adding or updating:

  • Change to section 4.8 - Undesirable effects
  • Change to section 6.4 - Special precautions for storage

Date of revision of text on the SPC: 22-Nov-2012

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The storage condition has been updated in Section 6.4 as following:

6.4     Special precautions for storage

 

Do not store above 2530°C.

Store in the original package in order to protect from moisture.

 

The paragraph entitled "Nervous system disorders" in Section 4.8 has been amended as shown below:

Nervous system disorders

In clinical studies, rRare events involving the nervous system which occurred in patients treated with fingolimod at higher doses (1.25 or 5.0 mg) include including ischaemic and haemorrhagic strokes, and posterior reversible encephalopathy syndrome.  and neurological atypical disorders, such as acute disseminated encephalomyelitis (ADEM)-like events. Rare cases of posterior reversible encephalopathy syndrome have also been reported at doses of 0.5 mg in both the clinical studies and the post-marketing setting.Neurological atypical disorders have also been reported, such as acute disseminated encephalomyelitis (ADEM)-like events.

Updated on 02-Jul-2012 and displayed until 18-Dec-2012

Reasons for adding or updating:

  • Change to section 4.9 - Overdose
  • Change to section 5.1 - Pharmacodynamic Properties
  • Change to section 4.4 - Special warnings and precautions for Use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.8 - Undesirable Effects

Date of revision of text on the SPC: 18-Jun-2012

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Changes to Section 4.4 and 4.5 as shown below:

4.4     Special warnings and precautions for use

 

Bradyarrhythmia

Initiation of Gilenya treatment results in a transient 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 steepest within 6 hours. The negative chronotropic effect of Gilenya persists beyond 6 hours and progressively attenuates over subsequent days of treatment. With continued administration, heart rate returns to baseline within one 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 Gilenya. Therefore, all All patients should be observed 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 bradyarrhythmia-related symptoms occur, appropriate clinical management should be initiated and observation 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.

 

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, 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).

After the first dose, the decline in heart rate starts within one hour and is maximal at approximately 4‑5 hours. With continued administration, heart rate returns to baseline within one month. Conduction abnormalities were typically transient and asymptomatic. They usually did not require treatment and resolved within the first 24 hours on treatment.

 

Due to the risk of serious rhythm disturbances, Gilenya should not be used in patients with second degree Mobitz type II or higher AV block, sick-sinus syndrome, or sino-atrial heart block, a history of symptomatic bradycardia or recurrent syncope, or in patients with significant QT prolongation (QTc>470msec (female) or >450msec (male)). Since significant bradycardia may be poorly tolerated in patients with known ischaemic heart disease (including angina pectoris), cerebrovascular disease, history of myocardial infarction, congestive heart failure, history of cardiac arrest, uncontrolled hypertension or severe sleep apnoea, Gilenya should not be used in these patients. Gilenya has not been studied in patients with sitting heart rate less than 55 beats per minute, patients receiving concurrent therapy with beta blockers or in those with a history of syncope.

 

Gilenya has also not been studied in patients with second degree or higher AV block, sick-sinus syndrome, ischaemic cardiac disease, congestive heart failure or significant cardiovascular disease. Use of Gilenya in such patients should be based on overall benefit-risk assessment and careful observation during initiation of therapy is recommended due to the potential for serious rhythm disturbances. Before initiation of treatment in these patients, advice from a cardiologist is recommended.

 

In such patients, treatment with Gilenya should be considered only if the anticipated benefits outweigh the potential risks. If treatment is considered, advice from a cardiologist should be sought prior to initiation of treatment in order to determine the most appropriate monitoring, at least overnight extended monitoring is recommended for treatment initiation (see also section 4.5).

 

Gilenya has not been studied in patients with arrhythmias requiring treatment with class Ia (e.g. quinidine, disopyramide) or class III (e.g. amiodarone, sotalol) antiarrhythmic medicinal products. Cclass Ia and class III antiarrhythmic medicinal products have been associated with cases of torsades de pointes in patients with bradycardia. Since initiation of Gilenya treatment results in decreased heart rate, Gilenya should not be co-administered used concomitantly with these medicinal products.

 

Experience with Gilenya is limited in patients receiving concurrent therapy with beta blockers, heart-rate-lowering calcium channel blockers (such as verapamil, diltiazem or ivabradine), or other substances which may decrease heart rate (e.g. digoxin, anticholinesteratic agents or pilocarpine). Since the initiation of Gilenya treatment is also associated with slowing of the heart rate (see also section 4.8, Bradyarrhythmia), concomitant use of these substances during Gilenya initiation may be associated with severe bradycardia and heart block. Because of the potential additive effect on heart rate treatment with Gilenya should not be initiated in patients who are concurrently treated with these substances (see also section 4.5). In such patients, treatment with Gilenya should be considered only if the anticipated benefits outweigh the potential risks. If treatment with Gilenya 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 appropriate first dose monitoring, at least overnight extended monitoring is recommendedAt treatment initiation in patients receiving beta blockers, or other substances which may decrease heart rate (e.g. verapamil, digoxin, anticholinesteratic agents or pilocarpine), caution should be exercised because of the additive effects on heart rate (see also section 4.5).

 

If therapy is discontinued for more than 2 weeks, the effects on heart rate and atrioventricular conduction may recur on re-introduction of Gilenya treatment and the same precautions as for treatment initiation should apply.

 

QT interval

In a thorough QT interval study of doses of 1.25 or 2.5 mg fingolimod at steady-state, when a negative chronotropic effect of fingolimod was still present, fingolimod treatment resulted in a prolongation of QTcI, with the upper limit of the 90% CI ≤13.0 ms. There is no dose- or exposure-response relationship of fingolimod and QTcI prolongation. There is no consistent signal of increased incidence of QTcI outliers, either absolute or change from baseline, associated with fingolimod treatment.

 

The clinical relevance of this finding is unknown. In the multiple sclerosis studies, clinically relevant effects on prolongation of the QTc-interval have not been observed but patients at risk for QT prolongation were not included in clinical studies.

 

Medicinal products that may prolong QTc interval are best avoided in patients with relevant risk factors, for example, hypokalaemia or congenital QT prolongation., congestive heart failure, concomitant administration of antiarrhythmic medicinal products in class Ia (e.g. quinidine, disopyramide), or class III (e.g. amiodarone, sotalol).

 

Infections

A core pharmacodynamic effect of Gilenya is a dose-dependent reduction of the peripheral lymphocyte count to 20‑30% of baseline values. This is due to the reversible sequestration of lymphocytes in lymphoid tissues (see section 5.1).

 

Before initiating treatment with Gilenya, a recent complete blood count (CBC) (i.e. within 6 months) should be available. Assessments of CBC are also recommended periodically during treatment, and in case of signs of infection. Absolute lymphocyte count <0.2x109/l, if confirmed, should lead to treatment interruption until recovery, because in clinical studies, fingolimod treatment was interrupted in patients with absolute lymphocyte count <0.2x109/l.

 

Initiation of treatment with Gilenya should be delayed in patients with severe active infection until resolution.

 

Before initiating Gilenya therapy, patients without a history of chickenpox or without vaccination against varicella zoster virus (VZV) should be tested for antibodies to VZV. VZV vaccination of antibody negative patients should be considered prior to commencing treatment with Gilenya, following which initiation of treatment with Gilenya should be postponed for 1 month to allow full effect of vaccination to occur.

 

The immune system effects of Gilenya may increase the risk of infections (see section 4.8). Effective diagnostic and therapeutic strategies should be employed in patients with symptoms of infection while on therapy. During treatment, patients receiving Gilenya should be instructed to report symptoms of infection to their physician.

 

Suspension of Gilenya should be considered if a patient develops a serious infection and consideration of benefit-risk should be undertaken prior to re-initiation of therapy.

 

Elimination of fingolimod following discontinuation of therapy may take up to two months and vigilance for infection should therefore be continued throughout this period. Patients should be instructed to report symptoms of infection up to 2 months after discontinuation of fingolimod.

 

Macular oedema

Macular oedema with or without visual symptoms has been reported in 0.4% of patients treated with fingolimod 0.5 mg, occurring predominantly in the first 3‑4 months of therapy (see section 4.8). An ophthalmological evaluation is therefore recommended at 3‑4 months after treatment initiation. If patients report visual disturbances at any time while on therapy, evaluation of the fundus, including the macula, should be carried out.

 

Patients with history of uveitis and patients with diabetes mellitus are at increased risk of macular oedema (see section 4.8). Gilenya has not been studied in multiple sclerosis patients with concomitant diabetes mellitus. It is recommended that multiple sclerosis patients with diabetes mellitus or a history of uveitis undergo an ophthalmological evaluation prior to initiating therapy and have follow-up evaluations while receiving therapy.

 

Continuation of Gilenya in patients with macular oedema has not been evaluated. It is recommended that Gilenya be discontinued if a patient develops macular oedema. A decision on whether or not Gilenya therapy should be re-initiated after resolution of macular oedema needs to take into account the potential benefits and risks for the individual patient.

 

Liver function

During clinical trials, elevations 3-fold the upper limit of normal (ULN) or greater in liver transaminases occurred in 8% of patients treated with fingolimod 0.5 mg compared to 2% of placebo patients. Elevations 5-fold the ULN occurred in 2% of patients on fingolimod and 1% of patients on placebo. In clinical trials, fingolimod was discontinued if the elevation exceeded 5 times the ULN. Recurrence of liver transaminase elevations occurred with rechallenge in some patients, supporting a relationship to fingolimod. In clinical studies, transaminase elevations occurred at any time during treatment although the majority occurred within the first 12 months. Serum transaminase levels returned to normal within approximately 2 months after discontinuation of fingolimod.

 

Gilenya has not been studied in patients with severe pre-existing hepatic injury (Child-Pugh class C) and should not be used in these patients (see section 4.3).

 

Due to the immunosuppressive properties of fingolimod, initiation of treatment should be delayed in patients with active viral hepatitis until resolution.

 

Recent (i.e. within last 6 months) transaminase and bilirubin levels should be available before initiation of treatment with Gilenya. In the absence of clinical symptoms, liver transaminases should be monitored at Months 1, 3, 6, 9 and 12 on therapy and periodically thereafter. If liver transaminases rise above 5 times the ULN, more frequent monitoring should be instituted, including serum bilirubin and alkaline phosphatase (ALP) measurement. With repeated confirmation of liver transaminases above 5 times the ULN, treatment with Gilenya should be interrupted and only re-commenced once liver transaminase values have normalised.

 

Patients who develop symptoms suggestive of hepatic dysfunction, such as unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine, should have liver enzymes checked and Gilenya should be discontinued if significant liver injury is confirmed (for example liver transaminase levels greater than 5-fold the ULN and/or serum bilirubin elevations). Resumption of therapy will be dependent on whether or not another cause of liver injury is determined and on the benefits to patient of resuming therapy versus the risks of recurrence of liver dysfunction.

 

Although there are no data to establish that patients with pre-existing liver disease are at increased risk of developing elevated liver function tests when taking Gilenya, caution in the use of Gilenya should be exercised in patients with a history of significant liver disease.

 

Interference with serological testing

Since fingolimod reduces blood lymphocyte counts via re-distribution in secondary lymphoid organs, peripheral blood lymphocyte counts cannot be utilised to evaluate the lymphocyte subset status of a patient treated with Gilenya. Laboratory tests involving the use of circulating mononuclear cells require larger blood volumes due to reduction in the number of circulating lymphocytes.

 

Blood pressure effects

Patients with hypertension uncontrolled by medication were excluded from participation in premarketing clinical trials and special care is indicated if patients with uncontrolled hypertension are treated with Gilenya.

 

In MS clinical trials, patients treated with fingolimod 0.5 mg had an average increase of approximately mmHg in systolic pressure, and approximately 1 mmHg in diastolic pressure, first detected approximately 2 months 1 month after treatment initiation, and persisting with continued treatment. In the two-year placebo-controlled study, hypertension was reported as an adverse event in 6.1% of patients on fingolimod 0.5 mg and in 3.8% of patients on placebo. Therefore, blood pressure should be regularly monitored during treatment with Gilenya.

 

Respiratory effects

Minor dose-dependent reductions in values for forced expiratory volume (FEV1) and diffusion capacity for carbon monoxide (DLCO) were observed with Gilenya treatment starting at Month 1 and remaining stable thereafter. Gilenya should be used with caution in patients with severe respiratory disease, pulmonary fibrosis and chronic obstructive pulmonary disease (see also section 4.8).

 

Prior treatment with immunosuppressants

When switching patients from interferon or glatiramer acetate to Gilenya, a washout is not necessary, assuming any immune effects (i.e. cytopenia) of such therapies have resolved.

 

Due to the long half-life of natalizumab, concomitant exposure, and thus concomitant immune effects, could occur for up to 2‑3 months following discontinuation of natalizumab if Gilenya was immediately started. Therefore caution is required when switching patients from natalizumab to Gilenya.

 

When switching from other immunosuppressive medications, the duration and mode of action of such substances must be considered when initiating Gilenya to avoid additive immune suppressive effects.

 

Stopping therapy

If a decision is made to stop treatment with Gilenya a 6 week interval without therapy is needed, based on half-life, to clear fingolimod from the circulation (see section 5.2). Lymphocyte counts progressively return to normal range within 1‑2 months of stopping therapy (see section 5.1). Starting other therapies during this interval will result in concomitant exposure to fingolimod. Use of immunosuppressants soon after the discontinuation of Gilenya may lead to an additive effect on the immune system and caution is therefore indicated.

 

4.5     Interaction with other medicinal products and other forms of interaction

 

Anti-neoplastic, immunosuppressive or immune-modulating therapies

Anti-neoplastic, immunosuppressive or immune-modulating therapies should not be co-administered due to the risk of additive immune system effects (see sections 4.3 and 4.4). Caution is also indicated when switching patients from long-acting therapies with immune effects, such as natalizumab 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 Gilenya vaccination may be less effective. The use of live attenuated vaccines may carry a risk of infections and should therefore be avoided.

 

Bradycardia-inducing substances

Fingolimod has been studied in combination with atenolol and diltiazem. When fingolimod was used with atenolol in an interaction study in healthy volunteers, there was an additional 15% reduction of heart rate at fingolimod treatment initiation, an effect not seen with diltiazem. At treatment initiation Treatment with Gilenya should not be initiated in patients receiving beta blockers, or other substances which may decrease heart rate, such as class Ia and III antiarrhythmics, calcium channel blockers (such aslike ivabradine, verapamil or diltiazem), digoxin, anticholinesteratic agents or pilocarpine, caution should be exercised because of the potential additive effects on heart rate (see sections 4.4 and 4.8). The potential risks and benefits of initiating fingolimod treatment in patients already on a substance which lowers the heart rate should be considered If treatment with Gilenya is considered in such patients, advice from a cardiologist should be sought regarding the switch to non heart-rate lowering medicinal products or appropriate monitoring for treatment initiation, at least overnight monitoring is recommended, if the heart-rate-lowering medication cannot be stopped.

 

Pharmacokinetic interactions of other substances on fingolimod

Fingolimod is metabolised mainly by CYP4F2. Other enzymes like CYP3A4 may also contribute to its metabolism. Co-administration of fingolimod with ketoconazole resulted in a 1.7-fold increase in fingolimod and fingolimod phosphate exposure (AUC). Caution should be exercised with substances that may inhibit CYP3A4 (protease inhibitors, azole antifungals, some macrolides such as clarithromycin or telithromycin).

 

Pharmacokinetic interactions of fingolimod on other substances

Fingolimod is unlikely to interact with substances mainly cleared by the CYP450 enzymes or by substrates of the main transporter proteins.

 

Co-administration of fingolimod with ciclosporin did not elicit any change in the ciclosporin or fingolimod exposure. Therefore, fingolimod is not expected to alter the pharmacokinetics of medicinal products that are CYP3A4 substrates. Potent inhibitors of transporter proteins are not expected to influence fingolimod disposition.

 

Co-administration of fingolimod with oral contraceptives (ethinylestradiol and levonorgestrel) did not elicit any change in oral contraceptive exposure. No interaction studies have been performed with oral contraceptives containing other progestagens, however an effect of fingolimod on their exposure is not expected.

 

It is not known whether the concomitant administration of strong CYP450 inducers may decrease the exposure to fingolimod and fingolimod P.

 
Changes to Section 4.8 as shown below:

 

Bradyarrhythmia

Initiation of Gilenya treatment results in a transient decrease in heart rate and may also be associated with atrioventricular conduction delays (see sections 4.4 and 5.1). In multiple sclerosis clinical studies the maximal decline in heart rate was seen 4‑5within 6 hours after treatment initiation, with declines in mean heart rate of 1213 beats per minute for Gilenya 0.5 mg. Heart rate below 40 beats per minute was rarely observed in patients on Gilenya 0.5 mg. Heart rate returned to baseline within 1 month of chronic treatment. Bradycardia was generally asymptomatic but some patients experienced mild to moderate symptoms, including dizziness, fatigue and/or palpitations, which resolved within the first 24 hours after treatment initiation.

 

In multiple sclerosis clinical studies first-degree atrioventricular block (prolonged PR interval on electrocardiogramECG) was detected after treatment initiation in 4.7% of patients on fingolimod 0.5 mg, in 2.8% of patients on intramuscular interferon beta-1a, and in 1.5% of patients on placebo. Second-degree atrioventricular block was detected in less than 0.5% patients on Gilenya 0.5 mg. In the post-marketing setting, isolated reports of transient, spontaneously resolving complete AV block have been observed during the six hour monitoring period with Gilenya. One case of transient third-degree atrioventricular block occurred three hours after the first dose of fingolimod 1.25 mg was administered and lasted for 30 seconds. 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 Gilenya 0.5 mg received isoprenaline for asymptomatic second-degree Mobitz I atrioventricular block.

 

In the post-marketing setting, isolated 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 medicinal products and/or pre-existing disease. The relationship of such events to Gilenya is uncertain.

 

Blood pressure

In multiple sclerosis clinical studies Gilenya 0.5 mg was associated with an average increase of approximately 3 mmHg in systolic pressure and approximately 1 mmHg in diastolic pressure, manifesting approximately 2 months1 month after treatment initiation. This increase persisted with continued treatment. Hypertension was reported in 6.1% of patients on fingolimod 0.5 mg and in 3.8% of patients on placebo. In the post-marketing setting, cases of hypertension have been reported within the first month of treatment initiation and on the first day of treatment that may require treatment with antihypertensive agents or discontinuation of Gilenya (see also section 4.4, Blood pressure effects).

 

Section 4.9 changes shown below:

4.9     Overdose

 

No cases of overdose have been reported. However, single doses up to 80 times the recommended dose (0.5 mg) were well tolerated in healthy volunteers. At 40 mg, 5 of 6 subjects reported mild chest tightness or discomfort which was clinically consistent with small airway reactivity.

 

Fingolimod can induce bradycardia upon treatment initiation. The decline in heart rate usually starts within one hour of the first dose, and is steepest within 6 hours. The negative chronotropic effect of Gilenya persists beyond 6 hours and progressively attenuates over subsequent days of treatment (see section 4.4 for details). 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 Gilenya, it is important to monitor patients with a continuous (real time) ECG and hourly measurement of heart rate and blood pressure, at least during the first 6 hours (see section 4.4).

 

Additionally, if after 6 hours the heart rate is <45 bpm or if the ECG at 6 hours after the first dose shows second degree or higher AV block, or if it shows a QTc interval ≥500 msec, monitoring should be extended at least for overnight and until the findings have resolved. The occurrence at any time of third degree AV block should also lead to extended monitoring including overnight monitoring.Fingolimod can induce bradycardia and can slow atrioventricular conduction.

 

Neither dialysis nor plasma exchange results in removal of fingolimod from the body.

 

In Section 5.1 the following paragraph has been amended as shown:

Fingolimod causes a transient reduction in heart rate and decrease in atrioventricular conduction at treatment initiation (see sections 4.4 and 4.8). The maximal decline in heart rate is seen in the first 4-5 within 6 hours post dose, with 70% of the negative chronotropic effect achieved on the first day. With continued administration heart rate returns to baseline within one month. The decrease in heart rate induced by fingolimod can be reversed by parenteral doses of atropine or isoprenaline. Inhaled salmeterol has also been shown to have a modest positive chronotropic effect. With initiation of fingolimod treatment there is an increase in atrial premature contractions, but there is no increased rate of atrial fibrillation/flutter or ventricular arrhythmias or ectopy. Fingolimod treatment is not associated with a decrease in cardiac output. Autonomic responses of the heart, including diurnal variation of heart rate and response to exercise are not affected by fingolimod treatment.

 

 

Updated on 11-Jan-2012 and displayed until 02-Jul-2012

Reasons for adding or updating:

  • Change to section 4.4 - Special warnings and precautions for Use
  • Change to section 4.8 - Undesirable Effects
  • Change to section 10 date of revision of the text

Date of revision of text on the SPC: 14-Dec-2011

Legal Category:POM

Black Triangle (CHM): YES

Free-text change information supplied by the pharmaceutical company:

Update to sections 4.4 and 4.8 of the SmPC with a safety update on liver enzyme level and monitoring affecting

Section 4.4 as follows:

Liver function

During clinical trials, elevations 3-fold the upper limit of normal (ULN) or greater in liver transaminases occurred in 8% of patients treated with fingolimod 0.5 mg compared to 2% of placebo patients. Elevations 5-fold the ULN occurred in 2% of patients on fingolimod and 1% of patients on placebo. In clinical trials, fingolimod was discontinued if the elevation exceeded 5 times the ULN. Recurrence of liver transaminase elevations occurred with rechallenge in some patients, supporting a relationship to fingolimod. The majority of elevations occurred within 36‑49 months. In clinical studies, transaminase elevations occurred at any time during treatment although the majority occurred within the first 12 months. Serum transaminase levels returned to normal within approximately 2 months after discontinuation of fingolimod.

 

Gilenya has not been studied in patients with severe pre-existing hepatic injury (Child-Pugh class C) and should not be used in these patients (see section 4.3).

 

Due to the immunosuppressive properties of fingolimod, initiation of treatment should be delayed in patients with active viral hepatitis until resolution.

 

Recent (i.e. within last 6 months) transaminase and bilirubin levels should be available before initiation of treatment with Gilenya. In the absence of clinical symptoms, liver transaminases should be monitored at Months 1, 3, and 6, 9 and 12 on therapy and periodically thereafter. If liver transaminases rise above 5 times the ULN, more frequent monitoring should be instituted, including serum bilirubin and alkaline phosphatase (ALP) measurement. With repeated confirmation of liver transaminases above 5 times the ULN, treatment with Gilenya should be interrupted and only re-commenced once liver transaminase values have normalised.

Section 4.8 as follows:

 

Liver transaminases

In multiple sclerosis clinical studies 8% and 2% of patients treated with Gilenya 0.5 mg experienced asymptomatic elevation in serum levels of hepatic transaminases ≥3x ULN (upper limit of normal) and ≥5x ULN, respectively. Recurrence of liver transaminase elevations has occurred upon re-challenge in some patients, supporting a relationship to the medicinal product. The majority of elevations occurred within 36‑49 months.In clinical studies, transaminase elevations occurred at any time during treatment although the majority occurred within the first 12 months. Serum transaminase levels returned to normal within approximately 2 months after discontinuation of Gilenya. In a small number of patients (N=10 on 1.25 mg, N=2 on 0.5 mg) who experienced liver transaminase elevations 5x ULN and who continued on Gilenya therapy, the elevations returned to normal within approximately 5 months (see also section 4.4, Liver function).

 

 

 

Updated on 11-Apr-2011 and displayed until 11-Jan-2012

Reasons for adding or updating:

  • New SPC for new product

Legal Category:POM

Black Triangle (CHM): YES

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Novartis Pharmaceuticals UK Ltd

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fingolimod hydrochloride

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