Source: European Medicines Agency (EU) Revision Year: 2024 Publisher: UCB Pharma S.A., Allée de la Recherche 60, B-1070 Bruxelles, Belgium
Pharmacotherapeutic group: antiepileptics, other antiepileptics
ATC code: N03AX26
Fenfluramine is a serotonin releasing agent, and thereby stimulates multiple 5-HT receptor sub-types through the release of serotonin. Fenfluramine may reduce seizures by acting as an agonist at specific serotonin receptors in the brain, including the 5-HT1D, 5-HT2A, and 5-HT2C receptors, and also by acting on the sigma-1 receptor. The precise mode of action of fenfluramine in Dravet syndrome and Lennox-Gastaut syndrome is not known.
The effectiveness of fenfluramine in children and young adults with Dravet syndrome was evaluated in 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 patients enrolled (Study 1) and the remaining subsequent total of 143 enrolled patients (Study 3) from 2 identical 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 period followed by a 2-week titration period and a 12-week maintenance period for a total of 14-weeks treatment. Patients taking concomitant stiripentol were not enrolled in these studies. Eligible patients were 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 was 9.0 (4.7) years in Study 1 and was 9.3 (4.7) years in Study 3, with a range of 2 to 18 years. The majority of patients were ≥6 years of age (73.9% in Study 1 and 74.6% in Study 3). All enrolled patients were inadequately controlled on at least one anti-epileptic medicine, with or without vagal nerve stimulation and/or ketogenic diet, the most frequently used concomitant anti-epileptic medicines (≥25% overall) being valproate, clobazam, topiramate and levetiracetam.
In Study 1, the median baseline convulsive seizure frequency per 28 days was 4.0, 17.5, and 21.2 in the placebo, fenfluramine 0.2 mg/kg/day, and fenfluramine 0.7 mg/kg/day groups, respectively. In Study 3, the median baseline convulsive seizure frequency per 28 days was 12.7, 18.0, and 13.0 in the placebo, fenfluramine 0.2 mg/kg/day, and fenfluramine 0.7 mg/kg/day groups, respectively.
Table 5. Dravet syndrome: Study 1 and Study 3 results of primary and selected secondary efficacy endpointssly known as 1504): results of primary and selected secondary efficacy endpoints:
| Study 1 | Study 3 | ||||||
|---|---|---|---|---|---|---|---|
| Placebo | Fenfluramine 0.2 mg/kg/day | Fenfluramine 0.7 mg/kg/day | Placebo | Fenfluramine 0.2 mg/kg/day | Fenfluramine 0.7 mg/kg/day | ||
| Convulsive Seizure Frequency Maintenance period | N Baseline. Median (min, max) | 40 34.0 (3.3, 147.3) | 39 17.5 (4.8, 623.5) | 40 21.2 (4.9, 127.0) | 48 12.7 (4.0, 229.3) | 46 18.0 (4.0, 1464.0) | 48 13.0 (2.7, 2700.7) |
| N At end of maintenance period. Median (min, max) | 39 25.7 (3.6, 204.7) | 39 17.1 (0.0, 194.3) | 40 4.9 (0, 105.5) | 48 10.6 (1.0, 139.0) | 46 7.6 (0.0, 2006.8) | 48 3.2 (0.0, 3651.7) | |
| Reduction in mean monthly baseline- adjusted Convulsive Seizure Frequency compared to Placebo | - | 36.7% p=0.016 | 67.3% p<0.001 | - | 49.3% p<0.0001 | 65.7% p<0.0001 | |
| % reduction in convulsive seizures Maintenance period | Number (%) of patients with ≥50% reduction in monthly convulsive seizures - change from baseline Effect size1 Relative Risk | 4 (10.3%) | 17 (43.6%) ES=33.3% RR: 4.25 | 29 (72.5%) ES=62.2% RR: 7.07 | 4 (8.3%) | 21 (45.7%) ES=37.3% RR: 5.48 | 33 (68.8%) ES=60.4% RR: 8.25 |
| Number (%) of patients with ≥75% reduction in monthly convulsive seizures - change from baseline Effect size1 Relative Risk | 2 (5.1%) | 10 (25.6%) ES=20.5% RR: 5.00 | 21 (52.5%) ES=47.4% RR: 10.24 | 2 (4.2%) | 9 (19.6%) ES=15.4% RR: 4.70 | 23 (47.9%) ES=43.7% RR: 11.50 | |
| Number (%) of patients with ≥100% reduction in monthly convulsive seizures - change from baseline Effect size1 | 0 (0%) | 6 (15.4%) ES=15.4% | 6 (15.0%) ES=15.0% | 0 (0%) | 1 (2.2%) | 10 (20.8%) | |
| Longest seizure-free interval (median) Titration + maintenance period | 9.5 days | 15.0 days p=0.035 | 25.0 days p<0.001 | 10.0 days | 18.5 days p=0.0002 | 30 days p<0.0001 | |
1 Effect size (ES) (Risk difference) calculated as proportion of Active-Placebo; RR: Relative Risk
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-week titration period and a 12-week maintenance period for a total of 15 weeks treatment. Eligible patients were randomised 1:1 to fenfluramine 0.4 mg/kg/day (maximum 17 mg/day) or placebo added to their stable standard of care regimen of stiripentol (plus clobazam and/or valproate) and possibly other anti-epileptic medicines. The mean (standard deviation) age of patients enrolled in Study 2 was 9.1 (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 enrolled subjects were inadequately controlled on at least one anti-epileptic medicine, which included stiripentol, with or without vagal nerve stimulation and/or ketogenic diet. The median baseline convulsive seizure frequency per 28 days was 10.7 and 14.3 in the placebo and fenfluramine 0.4 mg/kg/day groups, respectively.
Table 6. Dravet syndrome: Study 2 (previously known as Study ZX008-1504) results of primary and selected secondary efficacy endpoints:
| Study 2 | |||
|---|---|---|---|
| Placebo + stiripentol | Fenfluramine 0.4 mg/kg/day + stiripentol | ||
| Convulsive Seizure Frequency Maintenance period | N Baseline. Median (min, max) | 44 10.7 (2.7, 162.7) | 43 14.3 (2.7, 213.3) |
| N At end of maintenance period. Median (min, max) | 44 11.4 (0.7, 169.3) | 42 3.9 (0.0, 518.0) | |
| Reduction in mean monthly baseline- adjusted Convulsive Seizure Frequency compared to Placebo | - | 54.9% p<0.001 | |
| % reduction in convulsive seizures Maintenance period | Number (%) of patients with ≥50% reduction in monthly convulsive seizures – change from baseline Effect size1 Relative Risk | 4 (9.1%) | 23 (54.8%) ES=45.7 RR: 6.02 |
| Number (%) of patients with ≥75% reduction in monthly convulsive seizures – change from baseline Effect size1 Relative Risk | 2 (4.5%) | 17 (40.5%) ES=36.0% RR: 8.90 | |
| Number (%) of patients with ≥100% reduction in monthly convulsive seizures – change from baseline Effect size1 | 0 (0%) | 2 (4.8%) ES=4.8% | |
| Longest seizure-free interval (median) Titration + maintenance period | 13.0 days | 22.0 days p=0.004 | |
1 Effect size (ES) (Risk difference) calculated as proportion of Active-Placebo; RR: Relative Risk
The Dravet syndrome population in Study 1 and Study 2 was predominantly paediatric patients, with only 7 adult patients who were 18-19 years old (3.4%), and therefore limited efficacy and safety data were obtained in the adult Dravet syndrome population.
Dravet syndrome patients who participated in Study 1 and Study 2 could participate in an open-label extension study (Study 5). The primary objective of the open-label study was long-term effectiveness and safety of fenfluramine at doses of 0.2 to 0.7 mg/kg/day, whereby the dose of fenfluramine could be titrated to optimize treatment. Data are reported for 330 patients who participated in the open-label study and received fenfluramine for up to 3 years (median treatment period: 631 days; range: 7-1086).
A total of 23% of patients discontinued study participation during the open-label extension treatment period, including 15% due to lack of efficacy and 1% due to adverse events.
The effectiveness of fenfluramine for the treatment of seizures associated with Lennox-Gastaut syndrome in patients 2 to 35 years of age was evaluated in a randomized, double-blind, placebocontrolled study (Study 4 Part 1).
Study 4 Part 1 compared a 0.7 mg/kg/day (N=87) and a 0.2 mg/kg/day (N=89) dose (up to a maximum dose per day of 26 mg/kg) of fenfluramine with placebo. 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 generalized tonic-clonic, tonic, atonic, or tonic-atonic seizures that were confirmed to result in drops. The baseline period was followed by randomization into a 2-week titration period and a subsequent 12-week maintenance 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) were clobazam (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 of drop 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. Key secondary endpoints included the proportion of patients who achieve a ≥50% reduction from baseline in drop seizure frequency per 28 days for the fenfluramine 0.7 mg/kg/day group compared to the placebo group and proportion of patients who achieve improvement (minimally, much, or very much improved) 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 drop seizures per 28 days was significantly greater for the fenfluramine 0.7 mg/kg/day group compared with the placebo group (Table 6). A reduction in drop seizures was observed within 2 weeks of initiating treatment with fenfluramine, and the effect remained consistent over the 14-week treatment
period.
Among subjects with ≥124 drop seizures per 28 days during Baseline, the reduction in DSF were – 19.98%, -7.37%, -11.21% for subjects in the fenfluramine 0.7 mg/kg/day group, 0.2 mg/kg/day group, and placebo group respectively.
Table 7. Lennox-Gastaut syndrome: results of selected endpoints in Study 4 Part 1 (Maintenance Period):
| Placebo (N=87) | Fenfluramine 0.7 mg/kg/day (N=87) | |
|---|---|---|
| Primary Endpoint: Percentage Change from BL in DSF During M | ||
| DSF Summary Statisticsa | ||
| 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 Modelb | ||
| p-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 |
| Key Secondary Endpoint: 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 placeboc | 0.0044 | |
| Key Secondary Endpoint: 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 Periods
a 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) as factors, rank of BL seizure frequency as a covariate, and rank of percentage change from BL in seizure frequency during treatment (M) as response
c 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 improved.
e 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 dose of fenfluramine (0.2 mg/kg/day) during the Maintenance Period did not reach statistical significance compared to placebo (Median change between 0.2 group of patients and placebo in % change from baseline during Maintenance Period -11.48 [95% CI -26.61, 3.31]).
The seizure type with the greatest median percentage change from Baseline in the fenfluramine 0.7 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]).
Lennox-Gastaut patients who completed Study 4 Part 1 could participate in Part 2, an open-label, 52-week, flexible-dose extension study. The primary objective of Study 4 Part 2 was to assess the longterm safety and tolerability of fenfluramine at doses of 0.2 mg/kg/day to 0.7 mg/kg/day. All patients received fenfluramine 0.2 mg/kg/day for 1 month, then the dose was titrated to optimize treatment.
Among the 172 LGS subjects treated with Fintepla for ≥ 12 months, 46.5% had received a mean daily dose of 0.4 to <0.6 mg/kg/day, 33.7% received a mean daily dose ≥0.6 mg/kg/day, 19.8% received a mean daily dose of >0 to <0.4 mg/kg/day.
Data are reported for 247 patients who enrolled in Study 4 Part 2 and received fenfluramine for a median duration of 364 days (range: 19-542 days). A total of 143 subjects had completed the study, 19 subjects were ongoing, and 85 subjects had withdrawn. The most common reason for discontinuation was lack of efficacy (55 [22.3%]), adverse event (13 [5.3%]), and withdrawal by subject (13 [5.3%]).
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 for information on paediatric use).
The pharmacokinetics of fenfluramine and norfenfluramine were studied in healthy subjects, in paediatric patients with Dravet syndrome, and in paediatric and adult patients with Lennox-Gastaut syndrome.
Fenfluramine has a time to maximum plasma concentration (Tmax) in the range of 3 to 5 hours at steady state. The absolute bioavailability of fenfluramine is approximately 68%-83%. There was no effect 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 is 28.6 ng/ml following a dose of 0.35 mg/kg and 59.3 ng/ml following a dose of 0.7 mg/kg fenfluramine. 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 healthy volunteers 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/kg dose range in healthy volunteers. The Cmax and AUCinf of norfenfluramine are less than dose proportional over the 0.35 to 0.7 mg/kg dose range in healthy volunteers. The AUCinf increase was 0.5-fold for the 0.7 mg/kg dose compared to the 0.35 mg/kg dose. The Cmax increase was 0.7-fold for the 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, administered twice daily, steady state exposure (AUC0-24) is 371 ng*h/ml for fenfluramine and 222 ng*h/ml for norfenfluramine. In paediatric patients following fenfluramine dosing of 0.7 mg/kg/day, administered twice daily with a maximum of 26 mg/day; steady state AUC0-24 is 1400 ng*h/ml for fenfluramine and 869 ng*h/ml for norfenfluramine following a dose of 0.7 mg/kg/day, administered twice daily. Cmax,ss was 68.6 ng/ml for fenfluramine and 37.8 ng/ml for norfenfluramine. When stiripentol is given concomitantly, the steady state AUC0-24 is 1030 ng*h/ml for fenfluramine and 139 ng*h/ml for norfenfluramine following a dose of 0.2 mg/kg/day, administered twice daily; the steady state AUC0-24 is 3240 ng*h/ml for fenfluramine and 364 ng*h/ml for norfenfluramine following a dose of 0.35 mg/kg/day, administered twice daily.
In paediatric and adult patients with Lennox-Gastaut syndrome who receive Fintepla 0.7 mg/kg/day, administered twice daily, up to a total daily dose of 26 mg fenfluramine, steady-state systemic exposure (Cmax and AUC0-24h) of fenfluramine is slightly lower on average but not considered to be meaningfully different than in patients with Dravet syndrome.
The plasma half-life of fenfluramine and norfenfluramine indicates that approximately 94% of steady-state would be reached in approximately 4 days for fenfluramine and 5 days for norfenfluramine (4 half-lives). In healthy subjects, the Cmax accumulation ratio is 3.7-fold for fenfluramine and 6.4-fold for norfenfluramine and the AUC0-24 accumulation ratio is 2.6-fold for fenfluramine and 3.7-fold for norfenfluramine.
Fenfluramine is 50% bound to human plasma proteins in vitro and binding is independent of fenfluramine concentrations. The geometric mean (CV%) volume of distribution (Vz/F) of fenfluramine 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 inactive metabolites. The extent to which these inactive metabolites are present in plasma and urine is unknown. The involvement of enzymes other than CYPs (e.g. UGTs) in the metabolism of norfenfluramine is unknown, but literature data indicate that norfenfluramine may be glucuronidated to 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 as metabolite; less than 5% is found in faeces. The geometric mean (CV%) clearance (CL/F) of fenfluramine is 6.9 L/h (29%) and the half-life is 20 hours following oral administration of fenfluramine in healthy subjects. The elimination half-life of norfenfluramine is ~30 h.
No impact of genotype in CYP1A2, CYP2B6, CYP2C19, CYP2D6, or CYP3A4 on fenfluramine or norfenfluramine PK was observed.
Renal elimination is the predominant route of elimination of fenfluramine, with more than 90% of the administered dose eliminated in the urine as parent or metabolites. In a study comparing the pharmacokinetics of a single dose of 0.35 mg/kg fenfluramine in subjects with severe renal impairment (determined by modification of diet in renal disease estimated glomerular filtration rate <30 ml/min/1.73m²) and matched healthy volunteers, Cmax and AUC0-t of fenfluramine increased by 20% and 87%, respectively, in severe renal impairment. These increases in fenfluramine exposures are not clinically significant. Small and insignificant changes in AUC0-t and Cmax of norfenfluramine were observed 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 titration may 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 subjects with mild, moderate or severe hepatic impairment (Child-Pugh Class A, B, or C, respectively), AUC0-t of fenfluramine increased by 95% in subjects with mild hepatic impairment, 113% in subjects with moderate hepatic impairment, and 185% in subjects with severe hepatic impairment relative to matched subjects with normal liver function. Increases in Cmax of fenfluramine ranged from 19% to 29% in hepatic impairment. Systemic exposures of norfenfluramine either increased slightly by up to 18% (AUC0-t) or decreased by up to 45% (Cmax) in subjects with hepatic impairment. In subjects with mild, moderate, and severe hepatic impairment, the mean plasma elimination half-life of fenfluramine increased to 34.5 hours, 41.1 hours, and 54.6 hours, respectively, compared to 22.8 hours in subjects with normal hepatic function. The corresponding mean plasma elimination half-life of norfenfluramine was 54.0 hours, 72.5 hours, and 69.0 hours, respectively, compared to 30.2 hours in subjects with normal hepatic function. The differences in exposures in mild and moderate hepatic impairment are not considered to be clinically meaningful. Dosage of fenfluramine should be reduced in patients with severe hepatic impairment [see section 4.2, Posology and method of administration for special populations].
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 doses of stiripentol in patients with Dravet syndrome in the Phase 3 trials who were categorized with mild hepatic 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 impairment treated with stiripentol. Body weight Drug clearance and PK exposure of fenfluramine and norfenfluramine are consistent across a broad range of BMI (12.3 to 35 kg/m²).
The pharmacokinetics of fenfluramine and norfenfluramine were consistent between males and females.
The evaluation was limited by the small sample size of non-white subjects that no conclusion on the effect of race on the pharmacokinetics can be made. The genetic polymorphs of the enzymes that metabolize fenfluramine are similar across races, only their frequency differs. Thus, although the mean exposure may differ slightly depending on race, the range of exposure would be expected to be similar.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction and development.
In a lactation study, rats were dosed orally with radiolabeled dexfenfluramine at 1.2 mg/kg, and samples of plasma and milk were collected over 24 hours following the dose. Both dexfenfluramine and 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 small amounts 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 less than the maximum recommended human dose of Fintepla.
Fenfluramine and norfenfluramine crossed the placenta in pregnant rats and rabbits. Plasma exposures were higher in rat foetuses than in the dams, while plasma exposures in rabbits were comparable between does and foetuses; however the effects in human foetuses are unknown.
In an embryofoetal development study in rats, decreased foetal body weight and increased incidences of external and skeletal malformations were observed at the high dose level in association with maternal toxicity. No foetal abnormalities were noted at exposures at least five-fold the plasma AUC in humans administered the maximum recommended therapeutic dose of Fintepla.
No fenfluramine-related external, visceral or skeletal malformations or variations were determined in an embryofoetal development study in rabbits but increased post-implantation losses were evident at all doses secondarily to fenfluramine maternal toxicity (body weight loss and decreased food consumption). Additional clinical signs of dilated pupils and increased respiration rate and tremors were observed. Plasma exposures (AUC) in rabbits were below those in humans at the maximum recommended therapeutic dose of Fintepla.
In a pre- and post-natal study in rats, maternal toxicity was associated with an increase in stillbirths at the high dose. No adverse effects on the F0 and F1 generations were confirmed at five-fold higher plasma exposures (AUC) than in humans at the maximum recommended therapeutic dose of Fintepla. In the first generation of offspring, there were no effects on overall reproductive function.
Fenfluramine did not affect the reproductive performance of male rats. In female rats, a reduction in the fertility index (defined by the proportion of matings that resulted in pregnancies) was observed at maternally toxic doses that correlated with less corpora lutea, significantly fewer implantation sites and a higher percentage of pre- and post-implantation losses. No effects on the fertility index were noticed at plasma exposures (AUC) approximately equivalent to those in humans at the maximum recommended therapeutic dose of Fintepla.
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