4.1. Therapeutic indications

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 age and older.

4.2. Posology and method of administration

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 (see section 4.4).

Posology

Children aged 2 years and older and adults

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

without concomitant stiripentol*

with concomitant stiripentol (DS patients only)

Weight based dosage++

Maximal recommended daily dose

Weight based dosage++

Maximal recommended daily dose

Day 0 (Starting dose)+

0.1 mg/kg taken twice daily

26 mg

(13 mg twice daily i.e. 6.0 ml twice daily)

0.1 mg/kg taken twice daily

17 mg

(8.6 mg twice daily i.e. 4.0 ml twice daily)

Day 7

0.2 mg/kg twice daily

Maintenance dose

0.2 mg/kg twice daily

Day 14**

0.35 mg/kg twice daily

Not applicable

* For patients not on concomitant stiripentol requiring more rapid titration, the dose may be increased every 4 days.

+For patients with Dravet syndrome, dosage may be increased based on clinical response to the maximum recommended dosage, as needed.

**For patients with Lennox-Gastaut syndrome, dosage should be increased as tolerated to the recommended maintenance dosage (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

Always round the calculated dose up or down to the nearest graduation mark, following standard rounding conventions. For example, for a patient that needs a dose of 2.15 ml, the applied volume needs to be rounded up to 2.2 ml as the 3 ml syringe can only deliver 2.1 ml or 2.2 ml. Likewise a volume of 1.13 ml would need to be rounded down to a delivered volume of 1.1 ml. For a patient that needs a dose of 3.15 ml, the applied volume needs to be rounded up to 3.2 ml as the 6 ml syringe can only deliver 3.0 ml or 3.2 ml. Likewise a volume of 4.25 ml would need to be rounded down to a delivered volume of 4.2 ml.

If the calculated dose is 3 ml or less, the green printed 3 ml syringe should be used (with 0.1 ml graduation marks).

If the calculated dose is more than 3 ml, the purple printed 6 ml syringe should be used (with 0.2 ml graduation marks).

The table below must only be used as a check on the calculated dose volume. Table 2 does not replace 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 category

Starting dose

Day 7‑13

Day 14 and further

Starting dose

Day 7 and further

0.1 mg/kg

twice daily

0.2 mg/kg

twice daily

0.35 mg/kg

twice daily

0.1 mg/kg

twice daily

0.2 mg/kg

twice daily

3‑5 kg

0.1‑0.2 ml

0.3‑0.5 ml

0.5‑0.8 ml

0.1‑0.2 ml

0.3‑0.5 ml

5‑7 kg

0.2‑0.3 ml

0.5‑0.6 ml

0.8‑1.1 ml

0.2‑0.3 ml

0.5‑0.6 ml

7‑10 kg

0.3‑0.5 ml

0.6‑0.9 ml

1.1‑1.6 ml

0.3‑0.5 ml

0.6‑0.9 ml

10‑15 kg

0.5‑0.7 ml

0.9‑1.4 ml

1.6‑2.4 ml

0.5‑0.7 ml

0.9‑1.4 ml

15‑20 kg

0.7‑0.9 ml

1.4‑1.8 ml

2.4‑3.2 ml

0.7‑0.9 ml

1.4‑1.8 ml

20‑30 kg

0.9‑1.4 ml

1.8‑2.7 ml

3.2‑4.8 ml

0.9‑1.4 ml

1.8‑2.7 ml

30‑38 kg

1.4‑1.7 ml

2.7‑3.4 ml

4.8‑6 ml (maximum dose)

1.4‑1.7 ml

2.7‑3.4 ml

38‑43 kg

1.7‑2 ml

3.4‑4 ml

6 ml (maximum dose)

1.7‑2 ml

3.4‑4 ml (maximum dose)

43‑55 kg

2‑2.5 ml

4‑5 ml

6 ml (maximum dose)

2‑2.5 ml

4 ml (maximum dose)

55‑65 kg

2.5‑3 ml

5‑6 ml (maximum dose)

6 ml (maximum dose)

2.5‑3 ml

4 ml (maximum dose)

65‑86 kg

3‑4 ml

6 ml (maximum dose)

6 ml (maximum dose)

3‑4 ml (maximum dose)

4 ml (maximum dose)

86‑130 kg

4‑6 ml (maximum dose)

6 ml (maximum dose)

6 ml (maximum dose)

4 ml (maximum dose)

4 ml (maximum 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 twice daily.

Discontinuation of treatment

When discontinuing treatment, the dose should be decreased gradually. Abrupt discontinuation should be avoided when possible to minimize the risk of increased seizure frequency and status epilepticus. A final echocardiogram should be conducted 3-6 months after the last dose of treatment with fenfluramine.

Special populations

Renal impairment

Generally, no dose adjustment is recommended when Fintepla is administered to patients with mild to severe renal impairment, however, a slower titration may be considered. If adverse reactions are reported, 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 fenfluramine or its active metabolite, norfenfluramine, is dialyzable.

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

Hepatic impairment

Generally, no dose adjustment is recommended when Fintepla is administered without concomitant stiripentol 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, the maximum dosage for these patients is 0.2 mg/kg twice daily, and the maximal total daily dose is 17 mg.

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

A slower titration may be considered in patients with hepatic impairment. If adverse reactions are reported, 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 severe impaired hepatic function. Fintepla is therefore not recommended for use in patients with moderate and severe hepatic impairment treated with stiripentol.

Elderly

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

Paediatric population

The safety and efficacy of Fintepla in children below 2 years of age has not yet been established. No data are available.

Method of administration

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 section 6.6).

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

4.3. Contraindications

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

Aortic or mitral valvular heart disease.

Pulmonary arterial hypertension.

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

4.4. Special warnings and precautions for use

Aortic or mitral valvular heart disease and pulmonary arterial hypertension

Fenfluramine can cause valvular heart disease and pulmonary arterial hypertension in patients treated for Dravet syndrome or Lennox-Gastaut syndrome (see section 4.8). Therefore, echocardiographic monitoring must be performed.

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

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

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

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

If echocardiogram findings are suggestive of pulmonary arterial hypertension, a repeat echocardiogram should be performed as soon as possible and within 3 months to confirm these findings. If the echocardiogram finding is confirmed suggestive of an increased probability of pulmonary 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 the echocardiogram finding, after confirmation, suggests of a high probability of pulmonary arterial hypertension, as defined by the ESC and ERS guidelines, it is recommended fenfluramine treatment should be stopped.

Decreased appetite and weight loss

Fenfluramine can cause decreased appetite and weight loss (see section 4.8). An additive effect 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 while continuing treatment. The patient's weight should be monitored. A benefit risk evaluation should be undertaken prior to commencing treatment with fenfluramine in patients with a history 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 in obese patients and 2) confirm that prescribing physicians have been informed of the need for periodic cardiac monitoring in patients taking Fintepla.

Somnolence

Fenfluramine can cause somnolence.

Other central nervous system depressants, including alcohol, could potentiate the somnolence effect of fenfluramine (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 in several indications. A meta-analysis of randomised placebo-controlled trials with anti-epileptic medicines that did not include fenfluramine has shown a small increased risk of suicidal behaviour and ideation. The mechanism of this risk is not known, and the available data do not exclude the possibility of an increased risk for fenfluramine. Patients 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 medicinal products, serotonin syndrome, a potentially life-threatening condition, may occur with fenfluramine treatment, particularly with concomitant use of other serotonergic medicinal products (including SSRIs, SNRIs, tricyclic antidepressants, or triptans); with medicinal products that impair metabolism of serotonin such as MAOIs; or with antipsychotics that may affect the serotonergic neurotransmitter systems (see sections 4.3 and 4.5).

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

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

Increased seizure frequency

A clinically relevant increase in seizure frequency may occur during treatment with fenfluramine, which may require adjustment in the dose of fenfluramine and/or concomitant anti-epileptic medicines, or discontinuation of fenfluramine, should the benefit-risk be negative.

Cyproheptadine

Cyproheptadine is a potent serotonin receptor antagonist and may therefore decrease the efficacy of fenfluramine. If cyproheptadine is added to treatment with fenfluramine, patients should be monitored for 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 in patients with acute decreases in visual acuity. Consider 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 decrease fenfluramine plasma 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, the patient should be monitored for reduced efficacy and a dose increase of fenfluramine could be considered provided that it does not exceed twice the maximum daily dose (52 mg/day) (see section 4.2). If a strong CYP1A2 or CYP2B6 inducer is discontinued during maintenance treatment with fenfluramine, consider gradual reduction of the fenfluramine dosage to the dose administered prior to initiating 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 higher exposure and, therefore, adverse events should be monitored, and a dose reduction may be needed in some patients.

Coadministration of a single 0.35 mg/kg dose of fenfluramine with fluvoxamine (a strong CYP1A2 inhibitor) at steady state (50 mg once daily) in healthy volunteers increased the AUC0-t of fenfluramine by a ratio of 2.1-fold and the Cmax by a ratio of 1.2-fold, and decreased the AUC0-t of norfenfluramine by a ratio of 1.3-fold and the Cmax by a ratio of 1.4-fold, as compared to fenfluramine administered alone.

Coadministration of a single 0.35 mg/kg dose of fenfluramine with paroxetine (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 norfenfluramine 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) 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 and bronchospasm.

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 of 12 ml, that is to say essentially 'sodium-free'.

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

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

Pharmacodynamic interactions

Pharmacodynamic interactions with other central nervous system depressants increase the risk of aggravated central nervous system depression. Examples of such depressants are other serotonergic medicinal products (including SSRIs, SNRIs, tricyclic antidepressants, or triptans); medicinal products that impair metabolism of serotonin such as MAOIs; or antipsychotics that may affect the serotonergic neurotransmitter systems (see sections 4.3 and 4.4).

Pharmacokinetic interactions

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 plus clobazam and/or valproate, resulted in a 130% increase in fenfluramine AUC0‑24 and a 60% decrease in norfenfluramine AUC0‑24, as compared to 0.35 mg/kg twice daily (0.7 mg/kg/day), maximum 26 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 cannabidiol increased the AUC0‑INF of fenfluramine by 59% and the Cmax by 10%, and decreased the AUC0‑INF of norfenfluramine 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 dose adjustment 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 inducer:

Rifampicin induces multiple CYP enzymes which metabolize fenfluramine and norfenfluramine.Coadministration of a single 0.35 mg/kg dose of Fintepla with rifampicin at steady state (600 mg once 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 by 13%, as compared to fenfluramine administered alone. An increase in fenfluramine dose may be necessary when coadministered with rifampicin or a strong CYP1A2 or CYP2B6 inducer (see section 4.4).

Effect of CYP1A2 or CYP2D6 inhibitors

Coadministration of a single 0.35 mg/kg dose of fenfluramine with fluvoxamine (a strong CYP1A2 inhibitor) at steady state (50 mg once daily) in healthy volunteers increased the AUC0-t of fenfluramine by a ratio of 2.1-fold and the Cmax by a ratio of 1.2-fold, and decreased the AUC0-t of norfenfluramine by a ratio of 1.3-fold and the Cmax by a ratio of 1.4-fold, as compared to fenfluramine administered alone.

Coadministration of a single 0.35 mg/kg dose of fenfluramine with paroxetine (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 norfenfluramine by a ratio of 1.2-fold and the Cmax by a ratio of 1.3-fold, as compared to fenfluramine administered alone.

In vitro studies

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 the pharmacokinetics of clobazam or its Ndesmethyl-metabolite norclobazam, nor the pharmacokinetics of 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-state desipramine concentrations increase approximately 2-fold with concomitant administration of fenfluramine. Co-administration of fenfluramine with CYP2D6 substrates may increase their plasma concentrations.

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 their plasma concentrations.

Effect of fenfluramine on MATE1 substrates

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

4.6. Fertility, pregnancy, and lactation

Pregnancy

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

Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity in 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.

Breast-feeding

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 of therapy for the woman.

Fertility

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

4.7. Effects on ability to drive and use machines

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

4.8. Undesirable effects

Summary of the safety profile

The most commonly reported adverse reactions are decreased appetite (31.9%), fatigue (17.6%), diarrhoea (16.7%), and somnolence (15%).

Tabulated list of adverse reactions

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 be estimated from the available data).

Table 3: Adverse reactions

MedDRA System Organ Class

Very common

Common

Not known

Infections and infestations

Bronchitis

Metabolism and nutrition disorders

Decreased appetite

Psychiatric disorders

Abnormal behaviour

Aggression

Agitation

Insomnia

Mood swings

Irritability

Nervous system disorders

Somnolence

Ataxia

Hypotonia

Lethargy

Seizure

Status epilepticus

Tremor

Serotonin syndrome

Cardiac disorders

Valvular heart disease

Respiratory, thoracic and mediastinal disorders

Pulmonary arterial hypertension

Gastrointestinal disorders

Diarrhoea

Constipation

Salivary

Hypersecretion

Vomiting

Skin and subcutaneous tissue disorders

Rash

General disorders and administration site conditions

Fatigue

Investigations

Weight decreased

Blood glucose decreased

Blood prolactin increased

Description of selected adverse reactions

Decreased appetite and weight loss

Fenfluramine can cause decreased appetite and weight loss. In the controlled trials of children and young adults with Dravet syndrome 34.7% of fenfluramine-treated patients had an adverse reaction of decreased appetite, compared to 7.6% of patients on placebo and approximately 7.4% of fenfluramine-treated patients had a decrease in weight, compared to 0.8% of patients on placebo. In the controlled clinical trials of children and adults with Lennox-Gastaut syndrome, 28.8% of fenfluramine-treated patients had an adverse reaction of decreased appetite, compared to 15.3% of patients on placebo, and approximately 8.1% of fenfluramine-treated patients had a decrease in weight, compared to 3.1% of patients on placebo. The decreases in appetite and weight appeared to be dose 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 the fenfluramine group. There were no discontinuations due to status epilepticus in the Dravet syndrome and the LGS phase 3 clinical trials.

In the controlled trials in patients with Dravet syndrome seizures were reported less frequently in the fenfluramine treated patients (6.9%) than in patients on placebo (10.6%). However, seizures assessed as related to the study drug were more commonly reported in fenfluramine treated patients than placebo, 3.7% of fenfluramine-treated patients compared to 1.5% of patients on placebo. In the LGS trial, seizures were reported with a similar frequency in the fenfluramine treated patients (9.1%) and patients on placebo (9.2%). However, seizures assessed as related to the study drug were more commonly reported in fenfluramine treated patients than placebo, 6.1% of fenfluramine-treated patients 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 was 44.4 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 in the clinical studies for Dravet syndrome and Lennox-Gastaut syndrome. No patient developed valvular heart 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 double blinded DS and LGS clinical studies are shown below. These are defined as non-pathologic findings by the ESC/EACTS guidelines. Where trace mitral or aortic regurgitation were observed, the results were 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)

Nevertheless, pulmonary arterial hypertension and valvular heart disease associated with fenfluramine for Dravet syndrome and Lennox-Gastaut syndrome have been reported. Resolution of pulmonary arterial hypertension has been reported following discontinuation in at least one case (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 the fenfluramine 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 and somnolence were very commonly reported in 16.2% and 16.2% of subjects, respectively. The majority of the adverse reactions of lethargy, somnolence, and fatigue/asthenia were reported in the first 2 weeks of treatment with fenfluramine and were mild or moderate in severity. Discontinuation due to lethargy, somnolence, and fatigue/asthenia was rare and, in most cases, these adverse reactions resolved or improved with ongoing treatment. In the controlled trials with Dravet syndrome, 0.5% and 1.4% of subjects 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 discontinued due to somnolence.

Gastrointestinal disorders

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 placebo group (4.1% and 6.1%, respectively) during the 14‑week titration and maintenance periods. In Study 4 the mean time to onset of diarrhoea in the combined fenfluramine groups was 25.4 days versus 46.0 days in the placebo group while the mean time to onset of vomiting in the combined fenfluramine groups 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 observed more frequently in the higher dose groups. The mean time to onset of diarrhoea was 215.7 days, 95.2 days, 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 daily dose groups respectively while the mean time to onset of constipation was 113.0 days, 173.7 days, and 140.1 days in the >0 - <0.4 mg/kg/day, 0.4 - <0.6 mg/kg/day, and ≥0.6 mg/kg/day mean daily dose groups respectively.

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system: Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

4.9. Overdose

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

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