FINTEPLA 2.2mg / ml oral solution medication leaflet

Fintepla 2.2 mg/ml oral solution

Each ml contains 2.2 mg of fenfluramine (as 2.5 mg fenfluramine hydrochloride).

Glucose (maize): 0.627 mg/ml

Sodium ethyl para-hydroxybenzoate (E 215): 0.23 mg/ml

Sodium methyl para-hydroxybenzoate (E 219): 2.3 mg/ml

Sulfur dioxide (E 220): 0.000009 mg/ml

For the full list of excipients, see section 6.1.

Oral solution.

Clear, colourless, slightly viscous liquid, with a pH of 5.

Fintepla is indicated for the treatment of seizures associated with Dravet syndrome and Lennox-

Gastaut syndrome as an add-on therapy to other anti-epileptic medicines for patients 2 years of ageand older.

Fintepla should be initiated and supervised by physicians with experience in the treatment of epilepsy.

Fintepla is prescribed and dispensed according to the Fintepla controlled access programme (seesection 4.4).

Paediatric (children aged 2 years and older) and adult populations

Table 1: Dosage recommendations for Dravet syndrome (DS) and Lennox-Gastaut syndrome(LGS)

Without concomitant stiripentol* With concomitant stiripentol (DSpatients only)

Weight based Maximal Maximaldosage++ recommended Weight based++ recommendeddaily dose dosage daily dose

Day 0 (Starting 0.1 mg/kg taken 0.1 mg/kg takendose)+ twice daily 26 mg twice daily 17 mg(13 mg twice (8.6 mg twice

Day 7 0.2 mg/kg twice daily i.e. Maintenance dose daily i.e.daily 6.0 ml twice 0.2 mg/kg twice 4.0 ml twicedaily) daily daily)

Day 14** 0.35 mg/kg twicedaily Not applicable

*For patients not on concomitant stiripentol requiring more rapid titration, the dose may be increasedevery 4 days.+For patients with Dravet syndrome, dosage may be increased based on clinical response to themaximum recommended dose, as needed.

**For patients with Lennox-Gastaut syndrome, dosage should be increased as tolerated to therecommended maintenance dose (i.e., Day 14)++To calculate the dose volume up to the maximal recommended dose, you must use the formula:

Weight (kg) x Weight-based dosage (mg/kg) ÷ 2.2 mg/ml = ml dose to be taken twice daily

The calculated dose should be rounded to the nearest graduated increment.

If the calculated dose is 3.0 ml or less, the green printed 3 ml syringe should be used.

If the calculated dose is more than 3.0 ml, the purple printed 6 ml syringe should be used.

The table below must only be used as a check on the calculated dose volume. Table 2 does notreplace the requirement to calculate the specific dose volume.

Table 2: Range of dose volumes in ml for calculation check

Dosing without concomitant STP* Dosing with concomitant

STP**

Weight Starting dose Day 7-13 Day 14 and Starting Day 7 andcategory further dose further0.1 mg/kg 0.2 mg/kg 0.35 mg/kg 0.1 mg/kg 0.2 mg/kgtwice daily twice daily twice daily twice daily twice daily3-5 kg 0.2-0.3 ml 0.3-0.5 ml 0.5-0.8 ml 0.2-0.3 ml 0.3-0.5 ml5-7 kg 0.3-0.4 ml 0.5-0.7 ml 0.8-1.2 ml 0.3-0.4 ml 0.5-0.7 ml7-10 kg 0.4-0.5 ml 0.7-1 ml 1.2-1.6 ml 0.4-0.5 ml 0.7-1 ml10-15 kg 0.5-0.7 ml 1-1.4 ml 1.6-2.4 ml 0.5-0.7 ml 1-1.4 ml15-20 kg 0.7-1 ml 1.4-1.9 ml 2.4-3.2 ml 0.7-1 ml 1.4-1.9 ml20-30 kg 1-1.4 ml 1.9-2.8 ml 3.2-4.8 ml 1-1.4 ml 1.9-2.8 ml30-38 kg 1.4-1.8 ml 2.8-3.5 ml 4.8-6 ml 1.4-1.8 ml 2.8-3.5 ml(maximumdose)38-43 kg 1.8-2 ml 3.5-4 ml 6 ml (maximum 1.8-2 ml 3.5-4 mldose) (maximumdose)43-55 kg 2-2.5 ml 4-5 ml 6 ml (maximum 2-2.5 ml 4 mldose) (maximumdose)55-65 kg 2.5-3 ml 5-6 ml 6 ml (maximum 2.5-3 ml 4 ml(maximum dose) (maximumdose) dose)65-86 kg 3-4 ml 6 ml (maximum 6 ml (maximum 3-4 ml 4 mldose) dose) (maximum (maximumdose) dose)86-130 kg 4-6 ml 6 ml (maximum 6 ml (maximum 4 ml 4 ml(maximum dose) dose) (maximum (maximumdose) dose) dose)

*Without concomitant STP: The maximum dose 13 mg twice daily corresponds to 6 ml twice daily.

**With concomitant STP: The maximum dose of 8.6 mg twice daily corresponds to 4 ml twicedaily.

When discontinuing treatment, the dose should be decreased gradually. As with all anti-epilepticmedicines, abrupt discontinuation should be avoided when possible to minimize the risk of increasedseizure frequency and status epilepticus. A final echocardiogram should be conducted 3-6 months afterthe last dose of treatment with fenfluramine.

Generally, no dose adjustment is recommended when Fintepla is administered to patients with mild tosevere renal impairment, however, a slower titration may be considered. If adverse reactions arereported, a dose reduction may be needed. (see section 5.2)

Fintepla has not been studied in patients with end-stage renal disease. It is not known if fenfluramineor its active metabolite, norfenfluramine, is dialyzable.

There are no specific clinical data on the use of Fintepla with stiripentol in patients with impairedrenal function. Fintepla is therefore not recommended for use in patients with impaired renal functiontreated with stiripentol.

Generally, no dose adjustment is recommended when Fintepla is administered without concomitantstiripentol to patients with mild and moderate hepatic impairment (Child-Pugh Class A and B).

In patients with severe hepatic impairment (Child-Pugh C) not receiving concomitant stiripentol, themaximum dosage for these patients is 0.2 mg/kg twice daily, and the maximal total daily dose is17 mg.

There are limited clinical data on the use of Fintepla with stiripentol in patients with mild impairedhepatic function (see section 5.2).

A slower titration may be considered in patients with hepatic impairment. If adverse reactions arereported, a dose reduction may be needed. (see section 5.2).

There are no clinical data on the use of Fintepla with stiripentol in patients with moderate and severeimpaired hepatic function. Fintepla is therefore not recommended for use in patients with moderateand severe hepatic impairment treated with stiripentol.

There are no data on the use of Fintepla in elderly patients.

The safety and efficacy of Fintepla in children below 2 years of age has not yet been established. Nodata are available.

Fintepla is to be administered orally.

Fintepla may be taken with or without food.

Fintepla is compatible with commercially available gastric and nasogastric feeding tubes (see section6.6).

Fintepla contains a very limited amount of digestible carbohydrates and is compatible with a ketogenicdiet.

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

Aortic or mitral valvular heart disease.

Within 14 days of the administration of monoamine oxidase inhibitors due to an increased risk ofserotonin syndrome.

Aortic or mitral valvular heart disease and pulmonary arterial hypertension

Because of reported cases of valvular heart disease and pulmonary arterial hypertension that may havebeen caused by fenfluramine at higher doses used to treat adult obesity, cardiac monitoring must beperformed using echocardiography. Patients with valvular heart disease or pulmonary arterialhypertension were excluded from the controlled clinical studies of fenfluramine for the treatment of

Dravet syndrome and Lennox-Gastaut syndrome. Neither pulmonary arterial hypertension nor valvularheart disease were observed during these studies. However, post-marketing data show that they canalso occur with doses used to treat Dravet syndrome and Lennox-Gastaut syndrome (see section 4.8).

Prior to starting treatment, patients must undergo an echocardiogram to establish a baseline prior toinitiating treatment (see section 4.3) and exclude any pre-existing valvular heart disease or pulmonaryhypertension.

Echocardiogram monitoring should be conducted every 6 months for the first 2 years and annuallythereafter. Once treatment is discontinued for any reasons, a final echocardiogram should beconducted 3-6 months after the last dose of treatment with fenfluramine.

If an echocardiogram indicates pathological valvular changes, a follow-up echocardiogram should beconsidered at an earlier timeframe to evaluate whether the abnormality is persistent. If pathologicalabnormalities on the echocardiogram are observed, it is recommended to evaluate the benefit versusrisk of continuing fenfluramine treatment with the prescriber, caregiver, and cardiologist.

If treatment is stopped because of aortic or mitral valvular heart disease, appropriate monitoring andfollow-up should be provided in accordance with local guidelines for the treatment of aortic or mitralvalvular heart disease.

If echocardiogram findings are suggestive of pulmonary arterial hypertension, a repeatechocardiogram should be performed as soon as possible and within 3 months to confirm thesefindings. If the echocardiogram finding is confirmed suggestive of an increased probability ofpulmonary arterial hypertension defined as “intermediate probability” by the 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 cardiologist. If theechocardiogram finding, after confirmation, suggests of a high probability of pulmonary arterialhypertension, as defined by the ESC and ERS guidelines, it is recommended fenfluramine treatmentshould be stopped.

Decreased appetite and weight loss

Fenfluramine can cause decreased appetite and weight loss (see section 4.8). An additive effect ondecreased appetite can occur when fenfluramine is combined with other anti-epileptic medicines, forexample stiripentol. The decrease in weight appears to be dose related. Most subjects resumed weightgain over time while continuing treatment. The patient's weight should be monitored. A benefit riskevaluation should be undertaken prior to commencing treatment with fenfluramine in patients with ahistory of anorexia nervosa or bulimia nervosa.

Fintepla controlled access programme

A controlled access programme has been created to 1) prevent off-label use in weight management inobese patients and 2) confirm that prescribing physicians have been informed of the need for periodiccardiac monitoring in patients taking Fintepla.

Somnolence

Fenfluramine can cause somnolence.

Other central nervous system depressants, including alcohol, could potentiate the somnolence effect offenfluramine (see sections 4.5 and 4.7).

Suicidal behaviour and ideation

Suicidal behaviour and ideation have been reported in patients treated with anti-epileptic medicines inseveral indications. A meta-analysis of randomised placebo-controlled trials with anti-epilepticmedicines that did not include fenfluramine has shown a small increased risk of suicidal behaviour andideation. The mechanism of this risk is not known, and the available data do not exclude thepossibility of an increased risk for fenfluramine. Patients and caregivers of patients should be advisedto seek medical advice should any signs of suicidal behaviour and ideation emerge.

Serotonin syndrome

As with other serotonergic agents, serotonin syndrome, a potentially life-threatening condition, mayoccur with fenfluramine treatment, particularly with concomitant use of other serotonergic agents(including SSRIs, SNRIs, tricyclic antidepressants, or triptans); with agents that impair metabolism ofserotonin such as MAOIs; or with antipsychotics that may affect the serotonergic neurotransmittersystems (see sections 4.3 and 4.5).

Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations,coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscularaberrations (e.g., hyperreflexia, incoordination), and/or gastrointestinal symptoms (e.g., nausea,vomiting, diarrhoea).

If concomitant treatment with fenfluramine and other serotonergic agents that may affect theserotonergic systems is clinically warranted, careful observation of the patient is advised, particularlyduring treatment initiation and dose increases. If serotonin syndrome is suspected, a dose reduction ordiscontinuation of therapy with Fintepla and/or other serotonergic agents should be considered.

Increased seizure frequency

As with other anti-epileptic medicines, a clinically relevant increase in seizure frequency may occurduring treatment with fenfluramine, which may require adjustment in the dose of fenfluramine and/orconcomitant anti-epileptic medicines, or discontinuation of fenfluramine, should the benefit-risk benegative.

Cyproheptadine

Cyproheptadine is a potent serotonin receptor antagonist and may therefore decrease the efficacy offenfluramine. If cyproheptadine is added to treatment with fenfluramine, patients should be monitoredfor worsening of seizures. If fenfluramine treatment is initiated in a patient taking cyproheptadine,fenfluramine’s efficacy may be reduced.

Glaucoma

Fenfluramine can cause mydriasis and can precipitate angle closure glaucoma. Discontinue therapy inpatients with acute decreases in visual acuity. Consider discontinuation if there is ocular pain andanother cause cannot be determined.

Effect of CYP1A2 and CYP2B6 inducers

Co-administration with strong CYP1A2 inducers or CYP2B6 inducers will decrease fenfluramineplasma concentrations, which may lower the efficacy of fenfluramine (see section 4.5). If co-administration of a strong CYP1A2 or CYP2B6 inducer with fenfluramine is considered necessary, thepatient should be monitored for reduced efficacy and a dose increase of fenfluramine could beconsidered provided that it does not exceed twice the maximum daily dose (52 mg/day) (see section4.2). If a strong CYP1A2 or CYP2B6 inducer is discontinued during maintenance treatment withfenfluramine, consider gradual reduction of the fenfluramine dosage to the dose administered prior toinitiating the inducer (see section 4.2).

Effect of CYP1A2 or CYP2D6 inhibitors

Initiation of concomitant treatment with a strong CYP1A2 or CYP2D6 inhibitor may result in higherexposure and, therefore, adverse events should be monitored, and a dose reduction may be needed insome patients.

Coadministration of a single 0.35 mg/kg dose of fenfluramine with fluvoxamine (a strong CYP1A2inhibitor) at steady state (50 mg once daily) in healthy volunteers increased the AUC0-t offenfluramine by a ratio of 2.1-fold and the Cmax by a ratio of 1.2-fold, and decreased the AUC0-t ofnorfenfluramine by a ratio of 1.3-fold and the Cmax by a ratio of 1.4-fold, as compared to fenfluramineadministered alone.

Coadministration of a single 0.35 mg/kg dose of fenfluramine with paroxetine (a strong CYP2D6inhibitor) at steady state (30 mg once daily) in healthy volunteers increased the AUC0-t offenfluramine by a ratio of 1.8-fold and the Cmax by a ratio of 1.1-fold, and decreased the AUC0-t ofnorfenfluramine by a ratio of 1.2-fold and the Cmax by a ratio of 1.3-fold, as compared to fenfluramineadministered alone.

This medicinal product contains sodium ethyl para-hydroxybenzoate (E 215) and sodium methyl para-hydroxybenzoate (E 219) which may cause allergic reactions (possibly delayed).

It also contains sulfur dioxide (E 220) which may rarely cause severe hypersensitivity reactions andbronchospasm.

Patients with rare glucose-galactose malabsorption should not take this medicinal product.

This medicinal product contains less than 1 mmol sodium (23 mg) per the maximum daily dose of12 ml, that is to say essentially ‘sodium-free’.

This medicinal product contains glucose which may be harmful to the teeth.

Pharmacodynamic interactions with other central nervous system depressants increase the risk ofaggravated central nervous system depression. Examples of such depressants are other serotonergicagents (including SSRIs, SNRIs, tricyclic antidepressants, or triptans); agents that impair metabolismof serotonin such as MAOIs; or antipsychotics that may affect the serotonergic neurotransmittersystems (see sections 4.3 and 4.4).

Clinical studies

Effect of steady state stiripentol plus clobazam and/or valproate on fenfluramine

At steady state in the Phase 3 studies, the co-administration of 0.2 mg/kg twice daily (0.4 mg/kg/day),maximum 17 mg/day, fenfluramine with a standard anti-epileptic medicine regimen of stiripentol plusclobazam and/or valproate, resulted in a 130% increase in fenfluramine AUC0-24 and a 60% decreasein norfenfluramine AUC0-24, as compared to 0.35 mg/kg twice daily (0.7 mg/kg/day), maximum26 mg/day, fenfluramine without stiripentol (see section 4.2).

Effect of steady state cannabidiol on fenfluramine

Co-administration of a single 0.35 mg/kg dose of fenfluramine with repeated doses of cannabidiolincreased the AUC0-INF of fenfluramine by 59% and the Cmax by 10%, and decreased the AUC0-INF ofnorfenfluramine by 22% and the Cmax by 33%, as compared to fenfluramine administered alone.

Co-administration of a single 0.35 mg/kg dose of fenfluramine, with repeated doses of cannabidiol,did not affect the pharmacokinetics of cannabidiol, as compared to cannabidiol alone. No doseadjustment is necessary when fenfluramine is co-administered with cannabidiol.

Effect of rifampicin (a strong inducer of CYP3A and 2C19 and a moderate inducer of CYP1A2, 2B6,2C8 and 2C9), or strong CYP1A2 or CYP2B6 inducers

Rifampicin induces multiple CYP enzymes which metabolize fenfluramine and norfenfluramine.

Coadministration of a single 0.35 mg/kg dose of fenfluramine with rifampicin at steady state (600 mgonce daily) in healthy volunteers decreased the AUC0-t of fenfluramine by 58% and the Cmax by 40%,and decreased the AUC0-t of norfenfluramine by 50%, and increased the Cmax of norfenfluramine by13%, as compared to fenfluramine administered alone. An increase in fenfluramine dose may benecessary when coadministered with rifampicin or a strong CYP1A2 or CYP2B6 inducer (see section4.4).

Effect of CYP1A2 or CYP2D6 inhibitors

Coadministration of a single 0.35 mg/kg dose of fenfluramine with fluvoxamine (a strong CYP1A2inhibitor) at steady state (50 mg once daily) in healthy volunteers increased the AUC0-t offenfluramine by a ratio of 2.1-fold and the Cmax by a ratio of 1.2-fold, and decreased the AUC0-t ofnorfenfluramine by a ratio of 1.3-fold and the Cmax by a ratio of 1.4-fold, as compared to fenfluramineadministered alone.

Coadministration of a single 0.35 mg/kg dose of fenfluramine with paroxetine (a strong CYP2D6inhibitor) at steady state (30 mg once daily) in healthy volunteers increased the AUC0-t offenfluramine by a ratio of 1.8-fold and the Cmax by a ratio of 1.1-fold, and decreased the AUC0-t ofnorfenfluramine by a ratio of 1.2-fold and the Cmax by a ratio of 1.3-fold, as compared to fenfluramineadministered alone.

Effect of fenfluramine on other medicinal products

Co-administration of a single 0.7 mg/kg dose of fenfluramine, with a single dose of a stiripentol,clobazam, and valproic acid combination, did not affect the pharmacokinetics of stiripentol, nor thepharmacokinetics of clobazam or its Ndesmethyl-metabolite norclobazam, nor the pharmacokineticsof valproic acid, as compared to the stiripentol, clobazam, and valproic acid combination alone.

Effect of fenfluramine on CYP2D6 substrates

In vitro studies indicate that fenfluramine may inhibit CYP2D6. It has been reported that steady-statedesipramine concentrations increase approximately 2-fold with concomitant administration offenfluramine. Co-administration of fenfluramine with CYP2D6 substrates may increase their plasmaconcentrations.

Effect of fenfluramine on CYP2B6 and CYP3A4 substrates

In vitro studies indicate that fenfluramine may induce CYP2B6 and may induce intestinal CYP3A4.

Co-administration of fenfluramine with CYP2B6 substrates or CYP3A4 substrates may decrease theirplasma concentrations.

Effect of fenfluramine on MATE1 substrates

In vitro studies indicate that norfenfluramine (major and pharmacologically active metabolite) mayinhibit MATE1 at clinically relevant concentrations. Co-administration of fenfluramine with MATE1substrates may increase their plasma concentrations.

There are limited data (less than 300 pregnancy outcomes) from the use of fenfluramine in pregnantwomen.

Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicityin the absence of paternal or maternal toxicity (see section 5.3).

As a precautionary measure, it is preferable to avoid the use of Fintepla during pregnancy.

It is unknown whether fenfluramine/metabolites are excreted in human milk.

Available pharmacokinetic data in animals have shown excretion of fenfluramine/metabolites in milk(see section 5.3).

A risk to the suckling child cannot be excluded.

A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from

Fintepla therapy taking into account the benefit of breast-feeding for the child and the benefit oftherapy for the woman.

No effects of fenfluramine on human fertility up to clinical doses of 104 mg/day were noted. However,animal studies suggest that Fintepla may possibly affect female fertility (see section 5.3).

Fintepla has moderate influence on the ability to drive and use machines because it may causesomnolence and fatigue. Patients should be advised not to drive or operate machinery until they havegained sufficient experience to gauge whether it adversely affects their abilities (see section 4.8).

A total of 414 patients have been treated with fenfluramine in double blind randomized-placebocontrolled studies for Dravet syndrome and Lennox-Gastaut syndrome, the most commonly reportedadverse reactions are decreased appetite (31.9%), fatigue (17.6%), diarrhoea (16.7%), and somnolence(15%).

Adverse reactions reported with fenfluramine in placebo-controlled clinical studies and from post-marketing surveillance are listed in the tables below by System Organ Class and frequency.

Frequencies are defined as very common (≥1/10), common (≥1/100 to <1/10) or not known (cannot beestimated from the available data).

Table 3: Adverse reactions

MedDRA System Organ Class Very common Common Not known

Infections and infestations Bronchitis

Metabolism and nutrition Decreased appetitedisorders

Psychiatric disorders Abnormal behaviour Irritability

Aggression

Agitation

Insomnia

Mood swings

Nervous system disorders Somnolence Ataxia Serotonin syndrome

Hypotonia

Lethargy

Status epilepticus

Tremor

Cardiac disorders Valvular heart disease

Respiratory, thoracic and Pulmonary arterialmediastinal disorders hypertension

Gastrointestinal disorders Diarrhoea Constipation

Salivary Hypersecretion

Skin and subcutaneous tissue Rashdisorders

General disorders and Fatigueadministration site conditions

Investigations Weight decreased

Blood glucose decreased

Blood prolactin increased

Decreased appetite and weight loss

Fenfluramine can cause decreased appetite and weight loss. In the controlled trials of children andyoung adults with Dravet syndrome 34.7% of fenfluramine-treated patients had an adverse reaction ofdecreased appetite, compared to 7.6% of patients on placebo, and approximately 7.4% offenfluramine-treated patients had a decrease in weight, compared to 0.8% of patients on placebo. Inthe controlled clinical trials of children and adults with Lennox-Gastaut syndrome, 28.8% offenfluramine-treated patients had an adverse reaction of decreased appetite, compared to 15.3% ofpatients on placebo, and approximately 8.1% of fenfluramine-treated patients had a decrease inweight, compared to 3.1% of patients on placebo. The decreases in appetite and weight appeared to bedose related. Most subjects resumed weight gain over time while continuing fenfluramine treatment.

Status epilepticus and seizures (Epilepsy, Seizure cluster, Change in seizure)

In the Dravet syndrome phase 3 clinical trials, the observed frequency of status epilepticus was 1.5%in the placebo group and 5.1% in the combined fenfluramine group. In the LGS phase 3 clinical trial,the observed frequency of status epilepticus was 1.0% in the placebo group and 1.5% in thefenfluramine group. There were no discontinuations due to status epilepticus in the Dravet syndromeand the LGS phase 3 clinical trials.

In the controlled trials in patients with Dravet syndrome seizures were reported less frequently in thefenfluramine treated patients (6.9%) than in patients on placebo (10.6%). However, seizures assessedas related to the study drug were more commonly reported in fenfluramine treated patients thanplacebo, 3.7% of fenfluramine-treated patients compared to 1.5% of patients on placebo. In the LGStrial, seizures were reported with a similar frequency in the fenfluramine treated patients (9.1%) andpatients on placebo (9.2%). However, seizures assessed as related to the study drug were morecommonly reported in fenfluramine treated patients than placebo, 6.1% of fenfluramine-treatedpatients compared to 1.0% of patients on placebo.

The mean days to onset of seizure events in the LGS phase 3 trial after starting treatment was44.4 days in the combined fenfluramine groups and 36.6 days in the placebo group.

Echocardiographic safety assessments

Valvular heart disease and pulmonary arterial hypertension were evaluated via echocardiography inthe clinical studies for Dravet syndrome and Lennox-Gastaut syndrome. No patient developed valvularheart disease or pulmonary arterial hypertension in the completed clinical studies for both indications.

The percentage of trace and mild mitral regurgitation and trace aortic regurgitation from pooled doubleblinded DS and LGS clinical studies are shown below. These are defined as non-pathologic findingsby the ESC/EACTS guidelines. Where trace mitral or aortic regurgitation were observed, the resultswere often transient.

* Trace of mitral regurgitation:

- Combined fenfluramine group: 18.6% (77/414)

- Placebo: 13.9% (32/230)

* Mild mitral regurgitation:

- Combined fenfluramine group: 0.7% (3/414)

- Placebo: 0% (0/230)

* Trace aortic regurgitation:

- Combined fenfluramine group: 2.4% (10/414)

- Placebo: 0.9% (2/230)

Pulmonary arterial hypertension in a child associated with fenfluramine for Dravet syndrome has beenreported post-marketing. The patient discontinued fenfluramine and the reaction resolved post-discontinuation. Valvular heart disease in a child associated with fenfluramine for Dravet syndromehas also been reported post-marketing (see section 4.4).

Lethargy, somnolence, and fatigue (grouping of fatigue/asthenia/malaise/decreased activity)

In the controlled trials in subjects with Dravet syndrome, lethargy was commonly reported in 9.7%,and somnolence and fatigue were very commonly reported in 13.9% and 19%, respectively in thefenfluramine treatment groups combined. In the controlled study with Lennox-Gastaut syndrome,lethargy was commonly reported in 4.5% of subjects in the fenfluramine treatment group. Fatigue andsomnolence were very commonly reported in 16.2% and 16.2% of subjects, respectively. The majorityof the adverse reactions of lethargy, somnolence, and fatigue/asthenia were reported in the first 2weeks of treatment with fenfluramine and were mild or moderate in severity. Discontinuation due tolethargy, somnolence, and fatigue/asthenia was rare and, in most cases, these adverse events resolvedor improved with ongoing treatment. In the controlled trials with Dravet syndrome, 0.5% and 1.4% ofsubjects in the fenfluramine treatment groups combined discontinued due to lethargy and somnolence,respectively. In the LGS study 4, 1.5% of subjects in the fenfluramine treatment group discontinueddue to somnolence.

In the Phase 3 LGS controlled trial in children and young adults, diarrhoea (13.1%) and vomiting(10.6%) were observed more frequently in the combined fenfluramine groups than in the placebogroup (4.1% and 6.1%, respectively) during the 14-week titration and maintenance periods. In Study 4the mean time to onset of diarrhoea in the combined fenfluramine groups was 25.4 days versus 46.0days in the placebo group while the mean time to onset of vomiting in the combined fenfluraminegroups was 36.7 days versus 38.2 days in the placebo group.

In the LGS controlled trial through the open-label trial, diarrhoea and constipation were observedmore frequently in the higher dose groups. The mean time to onset of diarrhoea was 215.7 days, 95.2days, and 79.6 days in the >0 - <0.4 mg/kg/day, 0.4 - <0.6 mg/kg/day, and ≥0.6 mg/kg/day mean dailydose groups respectively while the mean time to onset of constipation was 113.0 days, 173.7 days, and140.1 days in the >0 - <0.4 mg/kg/day, 0.4 - <0.6 mg/kg/day, and ≥0.6 mg/kg/day mean daily dosegroups respectively.

All events reported for diarrhoea and constipation were mild or moderate in severity.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Only limited data have been reported concerning clinical effects and management of overdose offenfluramine. Agitation, drowsiness, confusion, flushing, tremor (or shivering), fever, sweating,abdominal pain, hyperventilation, and dilated non-reactive pupils were reported at much higher dosesof fenfluramine than those included in the clinical trial program.

Vital functions should be monitored closely, and supportive treatment administered in case ofconvulsions, arrhythmias, or respiratory difficulties.

Pharmacotherapeutic group: antiepileptics, other antiepileptics; ATC code: N03AX26

Fenfluramine is a serotonin releasing agent, and thereby stimulates multiple 5-HT receptor sub-typesthrough the release of serotonin. Fenfluramine may reduce seizures by acting as an agonist at specificserotonin receptors in the brain, including the 5-HT1D, 5-HT2A, and 5-HT2C receptors, and also byacting on the sigma-1 receptor. The precise mode of action of fenfluramine in Dravet syndrome and

Lennox-Gastaut syndrome is not known.

Dravet syndrome

Children and young adults with Dravet syndrome

The effectiveness of fenfluramine in children and young adults with Dravet syndrome was evaluatedin three randomised, multicentre, placebo-controlled studies (1501, 1502, 1504).

Study 1 (n=119) and Study 3 (n=143) are the prospective, merged analyses of the first 119 patientsenrolled (Study 1) and the remaining subsequent total of 143 enrolled patients (Study 3) from 2identical double-blind, placebo-controlled studies, ZX008-1501 and ZX008-1502. Study 1501 and

Study 1502 were conducted in parallel and the design was identical: 3-arm, multicentre, randomised,double-blind, parallel group, placebo-controlled studies consisting of a 6-week baseline periodfollowed by a 2-week titration period and a 12-week maintenance period for a total of 14-weekstreatment. Patients taking concomitant stiripentol were not enrolled in these studies. Eligible patientswere randomised 1:1:1 to one of two doses of fenfluramine (0.7 mg/kg/day or 0.2 mg/kg/day,maximum 26 mg/day) or placebo. The mean (standard deviation) age of patients enrolled was9.0 (4.7) years in Study 1 and was 9.3 (4.7) years in Study 3, with a range of 2 to 18 years. Themajority of patients were ≥6 years of age (73.9% in Study 1 and 74.6% in Study 3). All enrolledpatients were inadequately controlled on at least one anti-epileptic medicine, with or without vagalnerve stimulation and/or ketogenic diet, the most frequently used concomitant anti-epileptic medicines(≥25% overall) being valproate, clobazam, topiramate and levetiracetam.

Table 5. Dravet syndrome: Study 1 and Study 3 results of primary and selected secondaryefficacy endpoints during maintenance period

Study 1 Study 3

Placebo Fenfluramine Fenfluramine Placebo Fenfluramine Fenfluramine0.2 mg/kg/da 0.7 mg/kg/da 0.2 mg/kg/da 0.7 mg/kg/day y y y

Convulsive Seizure Frequency during Maintenance period

CSF at Baseline, 40 39 40 48 46 48*

N, Median (per 28 days) 31.4 17.5 21.2 12.7 18.0 13.0(min, max) (3.3, (4.8, 623.5) (4.9, 127.0) (4.0, 229.3) (4.0, 1464.0) (2.7, 2700.7)147.3)39 39 40 48 46 48

CSF at end of25.7 17.1 4.9 10.6 7.6 3.2maintenance period.(3.6, (0.0, 194.3) (0, 105.5) (1.0, 139.0) (0.0, 2006.8) (0.0, 3651.7)

N, Median (min, max)204.7)

Reduction in mean - 36.7% 67.3% - 49.3% 65.7%monthly baseline-adjusted p=0.016 p<0.001 p< 0.0001 p< 0.0001

CSF compared to Placebo% Reduction in convulsive seizures during Maintenance period

Number (%) of patients 4 17 (43.6%) 29 (72.5%) 4 (8.3%) 21 (45.7%) 33 (68.8%)with ≥50% reduction in (10.3%) ES1=33.3% ES=62.2% ES=37.3% ES=60.4%

RR: 5.48 RR: 8.25monthly convulsive RR2: 4.25 RR: 7.07seizures - changefrom baseline

Number (%) of patients 2 (5.1%) 10 (25.6%) 21 (52.5%) 2 (4.2%) 9 (19.6%) 23 (47.9%)with ≥75% reduction in ES=20.5% ES=47.4% ES=15.4% ES=43.7%monthly convulsive RR: 5.00 RR: 10.24 RR: 4.70 RR: 11.50seizures - changefrom baseline

Number (%) of patients 0 (0%) 6 (15.4%) 6 (15.0%) 0 (0%) 1 (2.2%) 10 (20.8%)with ≥100% reduction in ES=15.4% ES=15.0%monthly convulsiveseizures - changefrom baseline

Longest seizure-free interval during Titration + Maintenance period

Longest seizure-free 9.5 days 15.0 days 25.0 days 10.0 days 18.5 days 30 daysinterval (median) p=0.035 p<0.001 p=0.0002 p<0.00011 Effect size (ES) (Risk difference) calculated as proportion of Active-Placebo; 2 RR: Relative Risk

*49 patients were enrolled and only 48 were administered with the treatment

Study 2 (previously known as 1504) (N=87) was a 2-arm, multicentre, randomised, double-blind,parallel group, placebo-controlled study consisting of a 6-week baseline period followed by a 3-weektitration period and a 12-week maintenance period for a total of 15 weeks treatment. Eligible patientswere randomised 1:1 to fenfluramine 0.4 mg/kg/day (maximum 17 mg/day) or placebo added to theirstable standard of care regimen of stiripentol (plus clobazam and/or valproate) and possibly otheranti-epileptic medicines. The mean (standard deviation) age of patients enrolled in Study 2 was9.1 (4.80) years, with a range of 2 to 19 years. The majority of patients were ≥6 years of age (72.4%)and the minority <6 years (27.6%), male (57.5%) and, where reported, white (59.8%). All enrolledsubjects were inadequately controlled on at least one anti-epileptic medicine, which includedstiripentol, with or without vagal nerve stimulation and/or ketogenic diet. The median baselineconvulsive seizure frequency per 28 days was 10.7 and 14.0 in the placebo and fenfluramine0.4 mg/kg/day groups, respectively.

Table 6. Dravet syndrome: Study 2 (previously known as Study ZX008-1504) results of primaryand selected secondary efficacy endpoints during maintenance period

Study 2

Placebo + stiripentol Fenfluramine0.4 mg/kg/day + stiripentol

Convulsive Seizure Frequency during Maintenance period

N Baseline. 44 43

Median (min, max) 10.7 14.3(2.7, 162.7) (2.7, 213.3)

N At end of maintenance period. 44 42

Median (min, max) 11.4 3.9(0.7, 169.3) (0.0, 518.0)

Reduction in mean monthly baseline-adjusted - 54.9 %

Convulsive Seizure Frequency compared to p<0.001

Placebo% reduction in convulsive seizures during Maintenance period

Number (%) of patients with ≥50% reduction in 4 (9.1%) 23 (54.8%)monthly convulsive seizures - change ES1=45.7from baseline RR2: 6.02

Number (%) of patients with ≥75% reduction in 2 (4.5%) 17 (40.5%)monthly convulsive seizures - change ES=36.0%from baseline RR: 8.90

Number (%) of patients with ≥100% reduction in 0 (0%) 2 (4.8%)monthly convulsive seizures - change ES=4.8%from baseline

Longest seizure-free interval during Titration + maintenance period

Longest seizure-free interval (median) 13.0 days 22.0 daysp=0.0041 Effect size (ES) (Risk difference) calculated as proportion of Active-Placebo; 2 RR: Relative Risk

The Dravet syndrome population in Study 1, Study 2 and Study 3 was predominantly paediatricpatients, with only 11 adult patients who were 18-19 years old (3.2%), and therefore limited efficacyand safety data were obtained in the adult Dravet syndrome population.

Open-label data

Dravet syndrome patients who participated in Study 1, Study 2 and Study 3 could participate in anopen-label extension study (Study 5). The primary objective of the open-label extension (OLE) studywas long-term safety of fenfluramine at doses of 0.2 to 0.7 mg/kg/day, whereby the dose offenfluramine could be titrated to optimize treatment. Data are reported for 374 patients whoparticipated in the open-label study and received fenfluramine for up to 3 years (median treatmentperiod: 824 days; range: 7-1280). A median percentage change from Baseline in convulsive seizurefrequency (CSF) during the overall OLE Treatment Period of -66.81% (p <0.001) was observed. Of375 study participants, 12.8% discontinued the study due to lack of efficacy, 2.9% due to adverseevents, 5.3% due to physician or family request.

Lennox-Gastaut syndrome

Children and adults with Lennox-Gastaut syndrome

The effectiveness of fenfluramine for the treatment of seizures associated with Lennox-Gastautsyndrome in patients 2 to 35 years of age was evaluated in a randomized, double-blind, placebo-controlled study (Study 4 Part 1). Part 1 includes 2 independently analyzed cohorts, Cohort A and

Cohort B. Cohort A is the primary analysis cohort and includes subjects from North America, Europe,and Australia, and Cohort B includes subjects from Japan.

Study 4 Part 1 Cohort A

Study 4 Part 1 Cohort A compared a 0.7 mg/kg/day (N=87) and a 0.2 mg/kg/day (N=89) dose (up to amaximum dose per day of 26 mg) of fenfluramine with placebo (N=87). Patients had a diagnosis of

Lennox-Gastaut syndrome and were inadequately controlled on at least one anti-epileptic medicine,with or without vagal nerve stimulation and/or ketogenic diet. The study had a 4-week baseline period,during which patients were required to have a minimum of 8 drop seizures while on stable anti-epileptic medicine therapy. Drop seizures included: generalized tonic-clonic, secondarily generalizedtonic-clonic, tonic, atonic, or tonic-atonic seizures that were confirmed to result in drops. The baselineperiod was followed by randomization into a 2-week titration period and a subsequent 12-weekmaintenance period, where the dose of fenfluramine remained stable.

In Study 4 Part 1, 99% of patients were taking between 1 and 4 concomitant anti-epileptic medicines.

The most frequently used concomitant anti-epileptic medicines (in at least 25% of patients) wereclobazam (45.2%), lamotrigine (33.5%), and valproate (55.9%).

The primary efficacy endpoint in Study 4 Part 1 was percent change from baseline in the frequency ofdrop seizures per 28 days during the combined 14-week titration and maintenance periods (i.e.,treatment period) in the fenfluramine 0.7 mg/kg/day group compared to the placebo group. Keysecondary endpoints included the proportion of patients who achieve a ≥50% reduction from baselinein drop seizure frequency per 28 days for the fenfluramine 0.7 mg/kg/day group compared to theplacebo group and proportion of patients who achieve improvement (minimally, much, or very muchimproved) in the Clinical Global Impression − Improvement (CGI-I) as assessed by the Principal

Investigator for the fenfluramine 0.7 mg/kg/day group compared to the placebo group.

In Study 4 Part 1, the median percent change from baseline (reduction) in the frequency of dropseizures per 28 days was significantly greater for the fenfluramine 0.7 mg/kg/day group comparedwith the placebo group (Table 7). A reduction in drop seizures was observed within 2 weeks ofinitiating treatment with fenfluramine, and the effect remained consistent over the 14-week treatmentperiod.

Among subjects with ≥124 drop seizures per 28 days during Baseline, the reduction in DSFwere -19.98%, -7.37%, -11.21% for subjects in the fenfluramine 0.7 mg/kg/day group, 0.2 mg/kg/daygroup, and placebo group respectively.

Table 7. Lennox-Gastaut syndrome: Study 4 Part 1 Cohort A of primary and selected secondaryefficacy endpoints during maintenance period

Study 4 Part 1 Cohort A

Fenfluramine

Placebo 0.7 mg/kg/day(N = 87) (N = 87)

Percentage Change from BL in DSF During M

DSF Summary Statistics a

Median at BL 53.00 82.00

Median during M 47.33 55.73

Median Percentage Change from BL During M -7.28 -27.16

Nonparametric Model bp-value for comparison with placebo — 0.0018

HL Estimate for Median Difference (A-P)

Estimate (Std Err) — -20 (5.795)95% CI — -31.61, -8.89

Percentage of Patients with ≥ 50% Reduction from BL in DSF (50% Responder Rate) During

M≥ 50% reduction in DSF, n (%) 11 (12.6) 27 (31.4)p-value for comparison with placebo c 0.0044

Percentage of Patients with Improvement d on the CGI-I Investigator Rating at End of M

Subjects with score 1, 2, or 3, n (%) 27 (33.8) 39 (48.8)p-value vs placebo e 0.0567

ANCOVA = analysis of covariance; A-P = active group-placebo group; BL = Baseline Period; CGI I = Clinical Global Impression -

Improvement; CI = confidence interval; DSF = drop seizure frequency per 28 days; HL = Hodges-Lehmann; Std Err = standard error;

T+M = Titration and Maintenance Periodsa BL, T+M, and percentage change from BL in M values for seizure frequency per 28 days are presented in original scale.b Results are based on a nonparametric ANCOVA model with treatment group (3 levels) and weight strata (< 37.5 kg, ≥ 37.5 kg) asfactors, rank of BL seizure frequency as a covariate, and rank of percentage change from BL in seizure frequency during treatment (M)as responsec Based on a logistic regression model that included a categorical response variable (achieved percentage point reduction, yes or no),weight group strata (< 37.5 kg, ≥ 37.5 kg), and Baseline DSF as a covariate.

d Minimally, much, or very much improvede Based on a Cochran-Mantel-Haenszel test comparing active treatment with placebo, after adjusting for weight strata

The median percent reduction from baseline in drop seizure frequency per 28 days for the lower doseof fenfluramine (0.2 mg/kg/day) during the Maintenance Period did not reach statistical significancecompared to placebo (Median change between 0.2 group of patients and placebo in % change frombaseline during Maintenance Period -11.48 [95% CI -26.61, 3.31]).

The seizure type with the greatest median percentage change from Baseline in the fenfluramine0.7 mg/kg/day group relative to the placebo group was generalised tonic-clonic seizures (-45.7%fenfluramine 0.7 mg/kg/day [n=38] versus 3.7% placebo [n=38]).

Study 4 Part 1 Cohort B

This study compared a 0.7 mg/kg/day (N=11) and a 0.2 mg/kg/day (N=11) dose (up to a maximumdose per day of 26 mg) of fenfluramine with placebo (N=11).

The primary study endpoint was assessed from Part 1 Cohort A data only, due to the small size of

The results from Cohort B support the clinical benefit of fenfluramine reported for Cohort A for theadjunctive treatment of drop seizures associated with LGS in Japanese subjects.

Table 8: Lennox-Gastaut syndrome: Study 4 Part 1 Cohort B of primary and selected secondaryefficacy endpoints during maintenance period

Study 4 Part 1 Cohort B

Fenfluramine

Placebo 0.7 mg/kg/day(N = 11) (N = 11)

Primary Endpoint: Percentage Change from BL in DSF During M

DSF Summary Statistics a

Median at BL 53.00 58.00

Median during M 51.90 31.86

Median Percentage Change from BL During M -18.18 -45.07

HL Estimate for Median Difference (A-P)

Estimate (Std Err) -25.54 (17.000)95% CI (-57.57, 9.07)

Key Secondary Endpoint: Percentage of Patients with ≥ 50% Reduction from BL in DSF (50%

Responder Rate) During M≥ 50% reduction in DSF, n (%) 1 (9.1%) 4 (36.4%)

ANCOVA = analysis of covariance; A-P = active group-placebo group; BL = Baseline Period; CI = confidenceinterval; DSF = drop seizure frequency per 28 days; HL = Hodges-Lehmann; Std Err = standard error;

M = Maintenance Perioda BL, M, and percentage change from BL in M values for seizure frequency per 28 days are presented inoriginal scale.

Open-label data

Lennox-Gastaut patients who completed Study 4 Part 1 (ZX008-1601) could participate in Part 2, anopen-label, 52-week, flexible-dose extension study. The primary objective of Study 4 Part 2 was toassess the long-term safety and tolerability of fenfluramine at doses of 0.2 mg/kg/day to0.7 mg/kg/day. 279 patients were enrolled in the open label extension study received fenfluramine0.2 mg/kg/day for 1 month, then the dose was titrated to optimize treatment. The safety data fromopen-label phase of Study 4 are consistent with known safety profile of fenfluramine.

Among the 177 LGS subjects treated with fenfluramine for ≥12 months, 24.3% received afenfluramine mean daily dose of >0 to <0.4 mg/kg/day, 45.2% had received a fenfluramine mean dailydose of 0.4 to <0.6 mg/kg/day and 30.5% received a fenfluramine mean daily dose ≥0.6 mg/kg/day.

The most common reason for discontinuation during the open label extension study was lack ofefficacy (58 [20.8%]), adverse event (15 [5.4%]), and withdrawal by subject (17 [6.1%]).

The European Medicines Agency has deferred the obligation to submit the results of studies with

Fintepla in one or more subsets of the paediatric population in Dravet syndrome (see section 4.2 forinformation on paediatric use).

Pharmacokinetics

The pharmacokinetics of fenfluramine and norfenfluramine were studied in healthy subjects, inpaediatric patients with Dravet syndrome, and in paediatric and adult patients with Lennox-Gastautsyndrome.

Fenfluramine has a time to maximum plasma concentration (Tmax) in the range of 3 to 5 hours atsteady state. The absolute bioavailability of fenfluramine is approximately 68%-83%. There was noeffect of food on the pharmacokinetics of fenfluramine or norfenfluramine.

For fenfluramine, the Cmax occurs ~3 h following a single oral dose in healthy volunteers and is28.6 ng/ml following a dose of 0.35 mg/kg and 59.3 ng/ml following a dose of 0.7 mg/kgfenfluramine. The AUCinf is 673 ng × h/ml and 1660 ng × h/ml following 0.35 mg/kg and 0.7 mg/kg,respectively. For norfenfluramine, the Cmax occurs ~12 h following a single oral dose in healthyvolunteers and is 11.7 ng/ml and 16.1 ng/ml following a dose of 0.35 mg/kg or 0.7 mg/kg,respectively. The AUCinf is 798 ng × h/ml and ~800 ng × h/ml following 0.35 mg/kg and 0.7 mg/kg,respectively. Cmax and AUCinf of fenfluramine appear dose proportional over the 0.35 to 0.7 mg/kgdose range in healthy volunteers. The Cmax and AUCinf of norfenfluramine are less than doseproportional over the 0.35 to 0.7 mg/kg dose range in healthy volunteers. The AUCinf increase was0.5-fold for the 0.7 mg/kg dose compared to the 0.35 mg/kg dose. The Cmax increase was 0.7-fold forthe 0.7 mg/kg dose compared to the 0.35 mg/kg dose.

In paediatric Dravet syndrome patients following fenfluramine dosing of 0.2 mg/kg/day, administeredtwice daily, steady state exposure (AUC0-24) is 371 ng*h/ml for fenfluramine and 222 ng*h/ml fornorfenfluramine. In paediatric patients following fenfluramine dosing of 0.7 mg/kg/day, administeredtwice daily with a maximum of 26 mg/day; steady state AUC0-24 is 1400 ng*h/ml for fenfluramine and869 ng*h/ml for norfenfluramine following a dose of 0.7 mg/kg/day, administered twice daily. Cmax,sswas 68.6 ng/ml for fenfluramine and 37.8 ng/ml for norfenfluramine. When stiripentol is givenconcomitantly, the steady state AUC0-24 is 1030 ng*h/ml for fenfluramine and 139 ng*h/ml fornorfenfluramine following a dose of 0.2 mg/kg/day, administered twice daily; the steady state AUC0-24is 3240 ng*h/ml for fenfluramine and 364 ng*h/ml for norfenfluramine following a dose of0.35 mg/kg/day, administered twice daily.

In paediatric and adult patients with Lennox-Gastaut syndrome who receive fenfluramine0.7 mg/kg/day, administered twice daily, up to a total daily dose of 26 mg fenfluramine, steady-statesystemic exposure (Cmax and AUC0-24h) of fenfluramine is slightly lower on average but not consideredto be meaningfully different than in patients with Dravet syndrome.

The plasma half-life of fenfluramine and norfenfluramine indicates that approximately 94% ofsteady-state would be reached in approximately 4 days for fenfluramine and 5 days fornorfenfluramine (4 half-lives). In healthy subjects, the Cmax accumulation ratio is 3.7-fold forfenfluramine and 6.4-fold for norfenfluramine and the AUC0-24 accumulation ratio is 2.6-fold forfenfluramine and 3.7-fold for norfenfluramine.

Fenfluramine is 50% bound to human plasma proteins in vitro and binding is independent offenfluramine concentrations. The geometric mean (CV%) volume of distribution (Vz/F) offenfluramine is 11.9 (16.5%) L/kg following oral administration of fenfluramine in healthy subjects.

Over 75% of fenfluramine is metabolised to norfenfluramine prior to elimination, primarily by

CYP1A2, CYP2B6, and CYP2D6. Norfenfluramine is then deaminated and oxidized to form inactivemetabolites. The extent to which these inactive metabolites are present in plasma and urine isunknown. The involvement of enzymes other than CYPs (e.g. UGTs) in the metabolism ofnorfenfluramine is unknown, but literature data indicate that norfenfluramine may be glucuronidatedto a significant extent.

Fenfluramine and norfenfluramine were not in vitro substrates of P-glycoprotein, BCRP, OATP1B1,

OATP1B3, OATP1A2, OATP2B1, OCT1, OAT1, OAT3, OCT2, MATE1 and MATE2-K.

Most of an orally administered dose of fenfluramine (>90%) is excreted in the urine mainly asmetabolite; less than 5% is found in faeces. The geometric mean (CV%) clearance (CL/F) offenfluramine is 6.9 L/h (29%) and the half-life is 20 hours following oral administration offenfluramine in healthy subjects. The elimination half-life of norfenfluramine is ~30 h.

Genetic polymorphisms

No impact of genotype in CYP1A2, CYP2B6, CYP2C19, CYP2D6, or CYP3A4 on fenfluramine ornorfenfluramine PK was observed.

Renal elimination is the predominant route of elimination of fenfluramine, with more than 90% of theadministered dose eliminated in the urine as parent or metabolites. In a study comparing thepharmacokinetics of a single dose of 0.35 mg/kg fenfluramine in subjects with severe renalimpairment (determined by modification of diet in renal disease estimated glomerular filtration rate<30 ml/min/1.73 m2) and matched healthy volunteers, Cmax and AUC0-t of fenfluramine increased by20% and 87%, respectively, in severe renal impairment. These increases in fenfluramine exposures arenot clinically significant. Small and insignificant changes in AUC0-t and Cmax of norfenfluramine wereobserved in subjects with severe renal impairment. No dose adjustment is recommended when

Fintepla is administered to patients with mild to severe renal impairment, however, a slower titrationmay be considered. If adverse reactions are reported, a dose reduction may be needed.

In a study comparing the pharmacokinetics of a single dose of 0.35 mg/kg fenfluramine in subjectswith mild, moderate or severe hepatic impairment (Child-Pugh Class A, B, or C, respectively), AUC0-tof fenfluramine increased by 95% in subjects with mild hepatic impairment, 113% in subjects withmoderate hepatic impairment, and 185% in subjects with severe hepatic impairment relative tomatched subjects with normal liver function. Increases in Cmax of fenfluramine ranged from 19% to29% in hepatic impairment. Systemic exposures of norfenfluramine either increased slightly by up to18% (AUC0-t) or decreased by up to 45% (Cmax) in subjects with hepatic impairment. In subjects withmild, moderate, and severe hepatic impairment, the mean plasma elimination half-life of fenfluramineincreased to 34.5 hours, 41.1 hours, and 54.6 hours, respectively, compared to 22.8 hours in subjectswith normal hepatic function. The corresponding mean plasma elimination half-life of norfenfluraminewas 54.0 hours, 72.5 hours, and 69.0 hours, respectively, compared to 30.2 hours in subjects withnormal hepatic function. The differences in exposures in mild and moderate hepatic impairment arenot considered to be clinically meaningful. Dosage of fenfluramine should be reduced in patients withsevere hepatic impairment. [see section 4.2, Posology and method of administration for specialpopulations]

The retrospective analysis of steady-state exposures of fenfluramine and norfenfluramine in Study 2,

Cohort 2 (n=12) indicated no clinically meaningful changes in the absence or presence of stable dosesof stiripentol in patients with Dravet syndrome in the Phase 3 trials who were categorized with mildhepatic impairment as compared to those with normal hepatic function (AST/ALT and BILI ≤ ULN).

Fenfluramine is not recommended for use in patients with moderate and severe hepatic impairmenttreated with stiripentol.

Drug clearance and PK exposure of fenfluramine and norfenfluramine are consistent across a broadrange of BMI (12.3 to 35 kg/m2).

The pharmacokinetics of fenfluramine and norfenfluramine were consistent between males andfemales.

The evaluation was limited by the small sample size of non-white subjects that no conclusion on theeffect of race on the pharmacokinetics can be made. The genetic polymorphs of the enzymes thatmetabolize fenfluramine are similar across races, only their frequency differs. Thus, although the meanexposure may differ slightly depending on race, the range of exposure would be expected to besimilar.

Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproductionand development.

In a lactation study, rats were dosed orally with radiolabeled dexfenfluramine at 1.2 mg/kg, andsamples of plasma and milk were collected over 24 hours following the dose. Both dexfenfluramineand nordexfenfluramine were found in milk at 2 hours after dosing and levels declined over 24 hours.

No dexfenfluramine was found in the milk at 24 hours. Nordexfenfluramine was present in smallamounts at 24 hours. The radioactivity milk:plasma ratio was 9 ± 2 at 2 hours and 5 ± 1 at 24 hours.

Based on a bodyweight comparison, the human equivalent dose (0.2 mg/kg dexfenfluramine) is lessthan the maximum recommended human dose of fenfluramine.

Reproduction and development

Fenfluramine and norfenfluramine crossed the placenta in pregnant rats and rabbits. Plasma exposureswere higher in rat foetuses than in the dams, while plasma exposures in rabbits were comparablebetween does and foetuses; however the effects in human foetuses are unknown.

In an embryofoetal development study in rats, decreased foetal body weight and increased incidencesof external and skeletal malformations were observed at the high dose level in association withmaternal toxicity. No foetal abnormalities were noted at exposures at least five-fold the plasma AUCin humans administered the maximum recommended therapeutic dose of fenfluramine.

No fenfluramine-related external, visceral or skeletal malformations or variations were determined inan embryofoetal development study in rabbits but increased post-implantation losses were evident atall doses secondarily to fenfluramine maternal toxicity (body weight loss and decreased foodconsumption). Additional clinical signs of dilated pupils and increased respiration rate and tremorswere observed. Plasma exposures (AUC) in rabbits were below those in humans at the maximumrecommended therapeutic dose of fenfluramine.

In a pre- and post-natal study in rats, maternal toxicity was associated with an increase in stillbirths atthe high dose. No adverse effects on the F0 and F1 generations were confirmed at five-fold higherplasma exposures (AUC) than in humans at the maximum recommended therapeutic dose offenfluramine. In the first generation of offspring, there were no effects on overall reproductivefunction.

Fenfluramine did not affect the reproductive performance of male rats. In female rats, a reduction inthe fertility index (defined by the proportion of matings that resulted in pregnancies) was observed atmaternally toxic doses that correlated with less corpora lutea, significantly fewer implantation sitesand a higher percentage of pre- and post-implantation losses. No effects on the fertility index werenoticed at plasma exposures (AUC) approximately equivalent to those in humans at the maximumrecommended therapeutic dose of fenfluramine.

Sodium ethyl para-hydroxybenzoate (E 215)

Sodium methyl para-hydroxybenzoate (E 219)

Sucralose (E 955)

Hydroxyethylcellulose (E 1525)

Monosodium phosphate (E 339)

Disodium phosphate (E 339)

Cherry flavouring powder:

Acacia (E 414)

Glucose (maize)

Ethyl benzoate

Natural flavouring preparations

Natural flavouring substances

Flavouring substances

Maltodextrin (maize)

Sulfur dioxide (E 220)

Potassium citrate (E 332)

Citric acid monohydrate (E 330)

Water for injections

Not applicable.

4 years.

This medicinal product should be used within 3 months of first opening the bottle.

This medicinal product does not require any special storage conditions. Do not refrigerate or freeze.

Fintepla is presented in a white High Density Polyethylene (HDPE) bottle with a child-resistant,tamper-evident cap packaged in a carton, a Low Density Polyethylene (LDPE) press-in bottle adaptor,and Polypropylene (PP)/HDPE oral syringes. The oral syringe included in the pack should be used toadminister the prescribed dose.

Presentations:

Bottle containing 60 ml oral solution, a bottle adaptor, two 3 ml oral syringes with 0.1 ml graduations,and two 6 ml syringes with 0.2 ml graduations.

Bottle containing 120 ml oral solution, a bottle adaptor, two 3 ml oral syringes with 0.1 mlgraduations, and two 6 ml syringes with 0.2 ml graduations.

Bottle containing 250 ml oral solution, a bottle adaptor, two 3 ml oral syringes with 0.1 mlgraduations, and two 6 ml syringes with 0.2 ml graduations.

Bottle containing 360 ml oral solution, a bottle adaptor, two 3 ml oral syringes with 0.1 mlgraduations, and two 6 ml syringes with 0.2 ml graduations.

Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Inserting the bottle adaptor:

When the bottle is first opened the bottle adaptor must be pushed into the bottle.

Wash and dry hands.

Remove the bottle adaptor packaging.

Place the bottle on a flat, firm surface.

Open the bottle.

Hold the bottle firmly.

Align the bottle adaptor with the open top of the bottle.

Push the bottle adaptor into the bottle using the palm of the hand.

The bottle adaptor should be flush with the top of the bottle.

The bottle adaptor should not be removed after each use.

The bottle cap can be screwed onto the bottle with the bottle adaptor in place.

Cleaning the syringe:

Separate the plunger from the syringe to rinse each part.

Rinse the oral syringe with clean water and allow it to air dry after each use.

Rinse the inside of the syringe and the plunger.

The syringe and plunger can be cleaned in a dishwasher.

Clean water can be pulled into the syringe with the plunger and pushed out several times to clean thesyringe.

The syringe and plunger must be completely dry before the next use.

Feeding tubes

Fintepla oral solution is compatible with most enteral feeding tubes.

To flush the feeding tube, fill the syringe used for dosing with water and flush the tube. Do this 3times.

UCB Pharma S.A.,

Allée de la Recherche 60,

B-1070 Bruxelles,

Belgium

EU/1/20/1491/001

EU/1/20/1491/002

EU/1/20/1491/003

EU/1/20/1491/004

Date of first authorisation: 18 December 2020

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.