https://mb.cision.com/Public/18595/3710575/b6584cb77fd50818_800x800ar.png
** FINTEPLA^=C2=AE=E2=96=BC (fenfluramine) oral solution approved in the EU=
for adjunctive treatment of seizures associated with Lennox-Gastaut syndro=
me (LGS)
------------------------------------------------------------
Brussels, Belgium =E2=80=93 8 February 2023 =E2=80=93 7:00 AM CET=E2=80=93 =
UCB=E2=80=99s FINTEPLA^=C2=AE=E2=96=BC (fenfluramine) oral solution has bee=
n approved in the European Union (EU) for the treatment of seizures associa=
ted with Lennox-Gastaut syndrome (LGS) as an add-on therapy to other anti-e=
pileptic medicines for patients two years of age and older.^1
The approval by the European Commission (EC) was based on safety and effica=
cy data from a global, randomized, placebo-controlled Phase 3 clinical tria=
l, in 263 patients with LGS (aged 2-35 years), that demonstrated adjunctive=
fenfluramine at a dose of 0.7/mg/kg/day provided a significantly greater r=
eduction in the frequency of drop seizures (p=3D0.001) compared to placebo.=
The most common treatment-emergent adverse events were decreased appetite,=
somnolence, fatigue, and pyrexia (fever). No cases of valvular heart disea=
se or pulmonary arterial hypertension were observed.^2
Professor Rima Nabbout, MD, PhD, Professor of Paediatric Neurology at Unive=
rsity Paris cit=C3=A9, APHP, Necker Enfants Malades, Institut Imagine, Pari=
s, France, said: =E2=80=9CLGS is a developmental and epileptic encephalopat=
hy where seizures are frequent, inducing high level of trauma injuries and =
negatively impacting development and quality of life. Seizures are often re=
sistant to currently available medications, making this approval especially=
important for the individuals affected and their families.=E2=80=9D
Mike Davis, Head of Global Epilepsy & Rare Syndromes, UCB, said: =E2=80=9CW=
ith this approval, fenfluramine is now an important additional treatment op=
tion for those impacted by this difficult to treat condition in Europe. Thi=
s approval underscores our commitment to improving treatment outcomes, whil=
e addressing the high unmet need for new treatments for people living with =
LGS and rare epilepsies.=E2=80=9D
LGS is a severe childhood-onset developmental and epileptic encephalopathy =
(DEE) characterized by multiple types of drug-resistant seizures with high =
morbidity, as well as serious impairment of neurodevelopmental, cognitive, =
and motor functions,^3,4 affecting an estimated 2 in 10,000 people in Europ=
ean Union (EU).^5 Seizures leading to falls ("drop attacks/seizures") are c=
ommon in LGS and tonic seizures are a hallmark feature of this syndrome.^3,=
4 In addition, convulsive seizures (e.g., generalized tonic-clonic [GTC] se=
izures) are also commonly observed and usually occur in later stages of LGS=
, but sometimes may precede core seizure types. In addition to being associ=
ated with bodily injury and hospitalizations, GTC seizures are a primary ri=
sk factor of sudden unexpected death in epilepsy (SUDEP). Patients with GTC=
seizures have an approximately 10-fold greater risk for SUDEP than patient=
s with other seizure types.^2
Additionally, the EC has also adopted the EMA Committee for Orphan Medicina=
l Products (COMP) recommendation that the orphan designation for fenflurami=
ne be maintained.^6
About fenfluramine C-IV in EU^1
Fintepla is indicated for the treatment of seizures associated with Lennox-=
Gastaut and Dravet syndrome as an add-on therapy to other anti-epileptic me=
dicines for patients 2 years of age and older. Fenfluramine is a serotonin =
releasing agent, and thereby stimulates multiple 5-HT receptor sub-types th=
rough the release of serotonin. Fenfluramine may reduce seizures by acting =
as an agonist at specific serotonin receptors in the brain, including the 5=
-HT1D, 5-HT2A, and 5-HT2C receptors, and also by acting on the sigma-1 rece=
ptor. The precise mode of action of fenfluramine in Dravet syndrome and Len=
nox-Gastaut syndrome is not known.
Fenfluramine oral solution is available under a controlled access program t=
o ensure regular cardiac monitoring and to mitigate potential off-label use
Please refer to Fintepla, INN-fenfluramine (europa.eu) (https://ec.europa.e=
u/health/documents/community-register/2023/20230124158297/anx_158297_en.pdf=
) (SmPC) before prescribing.=C2=A0
=E2=96=BCThis medicinal product is subject to additional monitoring. This w=
ill allow quick identification of new safety information. Healthcare profes=
sionals are asked to report any suspected adverse reactions.
FINTEPLA^=C2=AE is a registered trademark of the UCB Group of Companies.
Key Safety Information about FINTEPLA^=C2=AE=E2=96=BC in EU^1
Aortic or mitral valvular heart disease and pulmonary arterial hypertension
Because of reported cases of valvular heart disease that may have been caus=
ed by fenfluramine at higher doses used to treat adult obesity, cardiac mon=
itoring must be performed using echocardiography. In the controlled clinica=
l studies of fenfluramine for the treatment of Dravet syndrome and Lennox-G=
astaut syndrome, no valvular heart disease was observed. Prior to starting =
treatment, patients must undergo an echocardiogram to establish a baseline =
prior to initiating treatment and exclude any pre-existing valvular heart d=
isease or pulmonary hypertension. Echocardiogram monitoring should be condu=
cted every 6 months for the first 2 years and annually thereafter. If an ec=
hocardiogram indicates pathological valvular changes, a follow-up echocardi=
ogram should be considered at an earlier timeframe to evaluate whether the =
abnormality is persistent. If pathological abnormalities on the echocardiog=
ram are observed, it is recommended to evaluate the benefit versus risk of =
continuing fenfluramine treatment with the prescriber, caregiver, and cardi=
ologist. If treatment is stopped because of aortic or mitral valvular heart=
disease, appropriate monitoring and follow-up should be provided in accord=
ance with local guidelines for the treatment of aortic or mitral valvular h=
eart disease. With past use in higher doses to treat adult obesity, fenflur=
amine was reported to be associated with pulmonary arterial hypertension. P=
ulmonary arterial hypertension was not observed in the clinical programme, =
but because of the low incidence of this disease, the clinical trial experi=
ence with fenfluramine is inadequate to determine if fenfluramine increases=
the risk for pulmonary arterial hypertension in patients with Dravet syndr=
ome and Lennox-Gastaut syndrome. If echocardiogram findings are suggestive =
of pulmonary arterial hypertension, a repeat echocardiogram should be perfo=
rmed as soon as possible and within 3 months to confirm these findings. If =
the echocardiogram finding is confirmed suggestive of an increased probabil=
ity of pulmonary arterial hypertension defined as =E2=80=9Cintermediate pro=
bability=E2=80=9D by the 2015 European Society of Cardiology (ESC) and the =
European Respiratory Society (ERS) Guidelines, it should lead to a benefit-=
risk evaluation of continuation of Fintepla by the prescriber, carer, and c=
ardiologist. If the echocardiogram finding, after confirmation, suggests of=
a high probability of pulmonary arterial hypertension, as defined by the 2=
015 ESC and ERS Guidelines, it is recommended fenfluramine treatment should=
be stopped.
Decreased appetite and weight loss=C2=A0
Fenfluramine can cause decreased appetite and weight loss. An additive effe=
ct on decreased appetite can occur when fenfluramine is combined with other=
anti-epileptic medicines, for example stiripentol. The decrease in weight =
appears to be dose related. Most subjects resumed weight gain over time whi=
le continuing treatment. The patient's weight should be monitored. A benefi=
t risk evaluation should be undertaken prior to commencing treatment with f=
enfluramine in patients with a history of anorexia nervosa or bulimia nervo=
sa.
Fintepla controlled access programme
A controlled access programme has been created to 1) prevent off-label use =
in weight management in obese patients and 2) confirm that prescribing phys=
icians have been informed of the need for periodic cardiac monitoring in pa=
tients taking Fintepla.=C2=A0
Somnolence
Fenfluramine can cause somnolence. Other central nervous system depressants=
, including alcohol, could potentiate the somnolence effect of fenfluramine=
.
Suicidal behaviour and ideation=C2=A0
Suicidal behaviour and ideation have been reported in patients treated with=
anti-epileptic medicines in several indications. A meta-analysis of random=
ised placebo-controlled trials with anti-epileptic medicines that did not i=
nclude fenfluramine has shown a small increased risk of suicidal behaviour =
and ideation. The mechanism of this risk is not known, and the available da=
ta do not exclude the possibility of an increased risk for fenfluramine. Pa=
tients and caregivers of patients should be advised to seek medical advice =
should any signs of suicidal behaviour and ideation emerge.
Serotonin syndrome
As with other serotonergic agents, serotonin syndrome, a potentially life-t=
hreatening condition, may occur with fenfluramine treatment, particularly w=
ith concomitant use of other serotonergic agents (including SSRIs, SNRIs, t=
ricyclic antidepressants, or triptans); with agents that impair metabolism =
of serotonin such as MAOIs; or with antipsychotics that may affect the sero=
tonergic neurotransmitter systems. Serotonin syndrome symptoms may include =
mental status changes (eg, agitation, hallucinations, coma), autonomic inst=
ability (eg, tachycardia, labile blood pressure, hyperthermia), neuromuscul=
ar aberrations (eg, hyperreflexia, incoordination), and/or gastrointestinal=
symptoms (eg, nausea, vomiting, diarrhoea). If concomitant treatment with =
fenfluramine and other serotonergic agents that may affect the serotonergic=
systems is clinically warranted, careful observation of the patient is adv=
ised, particularly during treatment initiation and dose increases.
Increased seizure frequency
As with other anti-epileptic medicines, a clinically relevant increase in s=
eizure frequency may occur during treatment with fenfluramine, which may re=
quire adjustment in the dose of fenfluramine and/or concomitant anti-epilep=
tic medicines, or discontinuation of fenfluramine, should the benefit-risk =
be negative.=C2=A0
Cyproheptadine=C2=A0
Cyproheptadine is a potent serotonin receptor antagonist and may therefore =
decrease the efficacy of fenfluramine. If cyproheptadine is added to treatm=
ent with fenfluramine, patients should be monitored for worsening of seizur=
es. If fenfluramine treatment is initiated in a patient taking cyproheptadi=
ne, fenfluramine=E2=80=99s efficacy may be reduced.
Glaucoma
Fenfluramine can cause mydriasis and can precipitate angle closure glaucoma=
. Discontinue therapy in patients with acute decreases in visual acuity. Co=
nsider discontinuation if there is ocular pain and another cause cannot be =
determined.
Effect of CYP1A2 and CYP2B6 inducers
Co-administration with strong CYP1A2 inducers or CYP2B6 inducers will decre=
ase fenfluramine plasma concentrations, which may lower the efficacy of fen=
fluramine. If co-administration of a strong CYP1A2 or CYP2B6 inducer with f=
enfluramine is considered necessary, the patient should be monitored for re=
duced efficacy and a dose increase of fenfluramine could be considered prov=
ided that it does not exceed twice the maximum daily dose (52 mg/day). If a=
strong CYP1A2 or CYP2B6 inducer is discontinued during maintenance treatme=
nt with fenfluramine, consider gradual reduction of the fenfluramine dosage=
to the dose administered prior to initiating the inducer.
Effect of CYP1A2 or CYP2D6 inhibitors
Initiation of concomitant treatment with a strong CYP1A2 or CYP2D6 inhibito=
r may result in higher exposure and, therefore, adverse events should be mo=
nitored, and a dose reduction may be needed in some patients.
Coadministration of a single 0.35 mg/kg dose of fenfluramine with fluvoxami=
ne (a strong CYP1A2 inhibitor) at steady state (50 mg once daily) in health=
y volunteers increased the AUC0-t of fenfluramine by a ratio of 2.1-fold an=
d the Cmax by a ratio of 1.2-fold, and decreased the AUC0-t of norfenfluram=
ine by a ratio of 1.3-fold and the Cmax by a ratio of 1.4-fold, as compared=
to fenfluramine administered alone.=C2=A0
Coadministration of a single 0.35 mg/kg dose of fenfluramine with paroxetin=
e (a strong CYP2D6 inhibitor) at steady state (30 mg once daily) in healthy=
volunteers increased the AUC0-t of fenfluramine by a ratio of 1.8-fold and=
the Cmax by a ratio of 1.1-fold, and decreased the AUC0-t of norfenflurami=
ne by a ratio of 1.2-fold and the Cmax by a ratio of 1.3-fold, as compared =
to fenfluramine administered alone.
Excipients
This medicinal product contains sodium ethyl para-hydroxybenzoate (E 215) a=
nd sodium methyl para hydroxybenzoate (E 219) which may cause allergic reac=
tions (possibly delayed). It also contains sulfur dioxide (E 220) which may=
rarely cause severe hypersensitivity reactions and bronchospasm. Patients =
with rare glucose-galactose malabsorption should not take this medicinal pr=
oduct. This medicinal product contains less than 1 mmol sodium (23 mg) per =
the maximum daily dose of 12 mL, that is to say essentially =E2=80=98sodium=
-free=E2=80=99. This medicinal product contains glucose which may be harmfu=
l to the teeth.
For further safety information and full prescribing information visit: =C2=
=A0Fintepla, INN-fenfluramine (europa.eu) (https://ec.europa.eu/health/docu=
ments/community-register/2023/20230124158297/anx_158297_en.pdf)
For further information, contact UCB:=C2=A0
Investor Relations
Antje Witte
T +32.2.559.94.14=C2=A0
email antje.witte@ucb.com=C2=A0
Corporate Communications
Laurent Schots=C2=A0
T +32.2.559.92.64=C2=A0
email laurent.schots@ucb.com
Global Communications
Nick Francis
T +44 7769 307745
email nick.francis@ucb.com =C2=A0
Forward-looking statements=C2=A0
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About UCB
UCB, Brussels, Belgium (www.ucb.com) is a global biopharmaceutical company =
focused on the discovery and development of innovative medicines and soluti=
ons to transform the lives of people living with severe diseases of the imm=
une system or of the central nervous system. With approximately 8 600 peopl=
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References:
1. Fintepla EMA PI. =C2=A0https://ec.europa.eu/health/documents/community-r=
egister/2023/20230124158297/anx_158297_en.pdf. Accessed February 2023.
2. Knupp K, Scheffer I, Ceulemans B, et al. Efficacy and safety of fenflura=
mine for the treatment of seizures associated with Lennox-Gastaut syndrome.=
A Randomized Clinical Trial. JAMA Neurol. 2022;79(6):554-564.
3. Strzelczyk A, Schubert-Bast S. Expanding the Treatment Landscape for Len=
nox-Gastaut Syndrome: Current and Future Strategies. CNS Drugs. 2021;35(1):=
61-83.
4. Specchio, N, Wirrell, EC, Scheffer, IE, Nabbout, R, Riney, K, Samia, P, =
et al. International League Against Epilepsy classification and definition =
of epilepsy syndromes with onset in childhood: Position paper by the ILAE T=
ask Force on Nosology and Definitions. Epilepsia. 2022;63:1398-1442.
5. EU/3/17/1836: Orphan designation for the treatment of Lennox-Gastaut syn=
drome=C2=A0https://www.ema.europa.eu/en/medicines/human/orphan-designations=
/eu3171836. Accessed February 2023.
6. EMA/COMP/946245/2022: Committee for Orphan Medicinal Products (COMP). Mi=
nutes for the meeting on 06-08 December 2022. https://www.ema.europa.eu/en/=
documents/minutes/minutes-comp-meeting-6-8-december-2022_en.pdf. Accessed F=
ebruary 2023.
GenericFile
UCB Press Release Fintepla LGS EU Approval Feb 8 2023 ENG (https://mb.cisio=
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