FINTEPLA Oral solution Ref.[27912] Active ingredients: Fenfluramine

Aortic or mitral valvular heart disease and pulmonary arterial hypertension

Because of reported cases of valvular heart disease that may have been caused by fenfluramine at higher doses used to treat adult obesity, cardiac monitoring must be performed using echocardiography. Patients with valvular heart disease or pulmonary arterial hypertension were excluded from the controlled clinical studies of fenfluramine for the treatment of Dravet syndrome and Lennox-Gastaut syndrome. No valvular heart disease was observed during these studies.

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. 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.

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 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.

With past use in higher doses to treat adult obesity, fenfluramine was reported to be associated with pulmonary arterial hypertension. Pulmonary arterial hypertension was not observed in the clinical programme, but post-marketing data show that it can also occur with doses used to treat epilepsy (see section 4.8).

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 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 cardiologist. If the echocardiogram finding, after confirmation, suggests of a high probability of pulmonary arterial hypertension, as defined by the 2015 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 agents, serotonin syndrome, a potentially life-threatening condition, may occur with fenfluramine treatment, particularly with concomitant use of other serotonergic agents (including SSRIs, SNRIs, tricyclic antidepressants, or triptans); with agents 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 (eg, 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 agents that may affect the serotonergic systems is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases.

Increased seizure frequency

As with other anti-epileptic medicines, 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 coadministration 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 AUC_0-t of fenfluramine by a ratio of 2.1-fold and the C_max by a ratio of 1.2-fold, and decreased the AUC_0-t of norfenfluramine by a ratio of 1.3-fold and the C_max 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 AUC_0-t of fenfluramine by a ratio of 1.8-fold and the C_max by a ratio of 1.1-fold, and decreased the AUC_0-t of norfenfluramine by a ratio of 1.2-fold and the C_max 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 parahydroxybenzoate (E219) which may cause allergic reactions (possibly delayed).

It also contains sulfur dioxide (E220) 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.

Pharmacodyamic 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 agents (including SSRIs, SNRIs, tricyclic antidepressants, or triptans); agents 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 AUC_0-24 and a 60% decrease in norfenfluramine AUC_0-24, 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 AUC_0-INF of fenfluramine by 59% and the C_max by 10%, and decreased the AUC_0-INF of norfenfluramine by 22% and the C_max 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 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 mg once daily) in healthy volunteers decreased the AUC_0-t of fenfluramine by 58% and the C_max by 40%, and decreased the AUC_0-t of norfenfluramine by 50%, and increased the C_max 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 AUC_0-t of fenfluramine by a ratio of 2.1-fold and the C_max by a ratio of 1.2-fold, and decreased the AUC_0-t of norfenfluramine by a ratio of 1.3-fold and the C_max 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 AUC_0-t of fenfluramine by a ratio of 1.8-fold and the C_max by a ratio of 1.1-fold, and decreased the AUC_0-t of norfenfluramine by a ratio of 1.2-fold and the C_max 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.

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 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 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).

Summary of the safety profile for Dravet Syndrome

The most commonly reported adverse reactions are decreased appetite (34.7%), diarrhoea (19.9%), upper respiratory tract infection (18.1%), echocardiogram abnormal* (18.1%), fatigue (18.1%), pyrexia (17.6%), blood glucose decreased (14.4%) and somnolence (13.0%).

^* Consisted of trace and mild mitral regurgitation, and trace aortic regurgitation, which are considered physiologic.

Summary of the safety profile for Lennox-Gastaut Syndrome

The most commonly reported adverse reactions are decreased appetite (27.8%), fatigue (18.8%), upper respiratory tract infection (15.9%), somnolence (13.6%), diarrhoea (11.9%) and vomiting (10.8%).

Tabulated list of adverse reactions

Adverse reactions reported with fenfluramine in placebo-controlled clinical studies and from postmarketing surveillance are listed in the tables below by System Organ Class and frequency. Frequencies are defined as very common (≥1/10) or common (≥1/100 to <1/10) or not known (cannot be estimated from the available data).

Table 3. Adverse reactions for Dravet Syndrome:

^* Consisted of trace and mild mitral regurgitation, and trace aortic regurgitation, which are considered physiologic.

Table 4. Adverse reactions for Lennox-Gastaut Syndrome:

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 18.9% of fenfluramine-treated patients had a decrease in weight ≥7% from their baseline weight, compared to 2.4% of patients on placebo. In the controlled clinical trials of children and adults with LennoxGastaut syndrome, 27.8% of fenfluramine-treated patients had an adverse reaction of decreased appetite, compared to 11.5% of patients on placebo, and approximately 4% of fenfluramine-treated patients had a decrease in weight of ≥7% from their baseline weight, compared to 0% 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

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 1.1% in the placebo group and 1.1% 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 (5.1%) than in patients on placebo (9.8%). However, seizures assessed as related to the study drug were more commonly reported in fenfluramine treated patients than placebo, 2.8% 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 (6.8%) and patients on placebo (6.9%). However, seizures assessed as related to the study drug were more commonly reported in fenfluramine treated patients than placebo, 6.3% of fenfluramine-treated patients compared to 1.1% of patients on placebo.

The mean days to onset of seizure events in the LGS phase 3 trial after starting treatment was 26.3 days in the fenfluramine 0.2 mg/kg/day group, 31.3 days in the fenfluramine 0.7 mg/kg/day and 31.3 days in the placebo group.

Echocardiographic safety assessments

Valvular heart disease and pulmonary arterial hypertension were evaluated in the placebo-controlled and open-label extension studies via echocardiography for 341 Dravet syndrome patients and 263 Lennox-Gastaut syndrome patients. No patient developed valvular heart disease or pulmonary arterial hypertension in the placebo-controlled studies or during the open-label extension studies with exposure of up to 3 years. In the Dravet syndrome double-blind studies, trace mitral valve regurgitation was reported in 17.9% of patients in the fenfluramine 0.2 mg/kg/day group (n=7/39), 23.3% in the fenfluramine 0.4 mg/kg/day group (n=10/43), 22.5% in the fenfluramine 0.7 mg/kg/day group (n=9/40), and in 9.5% in the placebo group (n=8/84). Mild mitral valve regurgitation was reported in 2.3% of patients in the fenfluramine 0.4 mg/kg/day group (n=1/43). Trace aortic valve regurgitation was reported in 7.9% of patients in the fenfluramine 0.7 mg/kg/day group (n=3/40). In the Lennox-Gastaut syndrome double-blind study, trace mitral valve regurgitation was reported in 14.8% of patients in the fenfluramine 0.2 mg/kg/day group (n=13/89), 17.6% in the fenfluramine 0.7 mg/kg/day group (n=15/87), (and 22.1% in the placebo group (n=19/87). Mild mitral valve regurgitation was reported in 1.1% of patients in the fenfluramine 0.7 mg/kg/day group (n=1/87).

Trace aortic valve regurgitation was reported in 5.6% of patients in the fenfluramine 0.2 mg/kg/day group (n=5/89) and 2.3% in the placebo group (n=2/87). One 11-year-old patient in the fenfluramine 0.2 mg/kg/day group exhibited mild aortic valve regurgitation. No abnormalities in valve morphology were observed, and upon a diagnostic evaluation via transoesophageal echocardiogram, the finding was downgraded to absent. Trace and mild mitral regurgitation and trace aortic regurgitation are all non-pathologic findings as defined by the 2015 ESC and ERS Guidelines. Where trace mitral or aortic regurgitation were observed, the results were often transient. Pulmonary arterial hypertension in a child associated with fenfluramine (10.12 mg/day) for Dravet syndrome has been reported postmarketing. The patient discontinued fenfluramine and the reaction resolved post-discontinuation (see section 4.4).

Lethargy, somnolence, and fatigue

In the controlled trials in subjects with Dravet syndrome, lethargy was commonly reported in 9.7%, and somnolence and fatigue/asthenia were very commonly reported in 13.0% and 18.1%, respectively in the fenfluramine treatment groups combined. In the controlled study with Lennox-Gastaut syndrome, lethargy was commonly reported in 4% of subjects. Fatigue/asthenia and somnolence were very commonly reported in 18.8% and 13.6% 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 events resolved or improved with ongoing treatment. In the controlled trials with Dravet syndrome, 0.8% and 1.6%nsubjects in the fenfluramine treatment groups combined discontinued due to lethargy and somnolence, respectively. In the LGS study, 1.7% 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 (11.9%) and vomiting (10.8%) were observed more frequently in the combined fenfluramine groups than in the placebo group (4.6% and 5.7%, respectively) during the 14-week titration and maintenance periods. The mean time to onset of diarrhoea in the fenfluramine groups was 25.0 and 26.1 days in the 0.2 mg/kg/day and 0.8 mg/kg/day groups respectively versus 46.0 days in the placebo group while the mean time to onset of vomiting in the fenfluramine groups was 29.8 and 29.1 days in the 0.2 mg/kg/day and 0.8 mg/kg/day groups respectively versus 42.8 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.

Infections and infestations disorders

In the Phase 3 LGS controlled trial in children and young adults, upper respiratory tract infection (7.4%) was observed more frequently in the combined fenfluramine groups than in the placebo group (3.4%) during the 14 week titration and maintenance periods. The mean time to onset of upper respiratory tract infection in the fenfluramine groups was 42.9 days and 40.8 days in the 0.2 mg/kg/day and 0.8 mg/kg/day groups respectively versus 46.7 days in the placebo group.

A higher frequency of infections was reported in the active arm among 2–6-year-old age group in the LGS controlled study. The combined incidences of upper respiratory tract infections (including streptococcal pharyngitis, pharyngotonsillitis, rhinitis, sinusitis and viral upper respiratory tract infection) was most commonly reported in 14.2% of subjects in the fenfluramine treatment group. Bronchitis (2.3%), influenza (2.3%), otitis media (1.1%), and pneumonia (2.3%) were commonly reported. Most of these infections were reported for 2 or more subjects in the fenfluramine treatment group and were not reported in the placebo group. In the LGS controlled trial through the open-label trial, nasopharyngitis, upper respiratory tract infection, gastroenteritis viral, and pneumonia were observed more frequently in the higher dose groups. The mean time to onset of these events was 6.0 – 155.1 days, 107.1 – 212.5 days, and 155.7 – 320.7 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 nasopharyngitis, upper respiratory tract infection, gastroenteritis viral, were mild or moderate in severity. Two cases of severe pneumonia were reported in the 0.4 - <0.6 mg/kg/day mean daily dose group during the open-label part of the trial.

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 listed in Appendix V.

Not applicable.