Fintepla

1 INDICATIONS AND USAGE FINTEPLA is indicated for the treatment of seizures associated with Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS) in patients 2 years of age and older. FINTEPLA is indicated for the treatment of seizures associated with Dravet syndrome and Lennox-Gastaut syndrome in patients 2 years of age and older. ( 1 )

2 DOSAGE AND ADMINISTRATION FINTEPLA is to be administered orally and may be taken with or without food. ( 2.2 ) Dravet Syndrome The initial starting and maintenance dosage is 0.1 mg/kg twice daily, which can be increased weekly based on efficacy and tolerability. ( 2.2 ) The maximum daily maintenance dosage of FINTEPLA is 0.35 mg/kg twice daily (maximum daily dosage of 26 mg). ( 2.2 ) Lennox-Gastaut Syndrome The initial starting dosage is 0.1 mg/kg twice daily, which should be increased weekly based on tolerability. ( 2.2 ) The recommended maintenance dosage of FINTEPLA is 0.35 mg/kg twice daily (maximum daily dosage of 26 mg). ( 2.2 ) Dravet Syndrome and Lennox-Gastaut Syndrome Dose adjustment is required in patients taking concomitant stiripentol plus clobazam: the maximum daily maintenance dosage of FINTEPLA is 0.2 mg/kg twice daily (maximum daily dosage of 17 mg). ( 2.2 , 2.3 , 2.4 , 7.1 ) Dosage adjustment is recommended in patients: Taking strong CYP1A2 or CYP2D6 inhibitors ( 2.3 , 7.1 ) With severe renal impairment ( 2.4 , 8.6 ) With mild, moderate, and severe hepatic impairment ( 2.5 , 8.7 ) 2.1 Assessments Prior to Initiating FINTEPLA Prior to starting treatment with FINTEPLA, obtain an echocardiogram assessment to evaluate for valvular heart disease and pulmonary arterial hypertension [see Dosage and Administration (2.6) and Warnings and Precautions (5.1) ] . 2.2 Dosing Information FINTEPLA is to be administered orally and may be taken with or without food. Dravet Syndrome The initial starting and maintenance dosage for patients with Dravet syndrome is 0.1 mg/kg twice daily, which can be increased weekly based on efficacy and tolerability. Table 1 provides the recommended titration schedule, if needed. Patients with Dravet syndrome not on concomitant stiripentol who are tolerating FINTEPLA at 0.1 mg/kg twice daily and require further reduction of seizures may benefit from a dosage increase up to a maximum recommended maintenance dosage of 0.35 mg/kg twice daily (maximum daily dosage of 26 mg). Patients with Dravet syndrome taking concomitant stiripentol plus clobazam who are tolerating FINTEPLA at 0.1 mg/kg twice daily and require further reduction of seizures may benefit from a dosage increase up to a maximum recommended maintenance dosage of 0.2 mg/kg twice daily (maximum daily dosage of 17 mg) [see Drug Interactions (7.1) ]. Lennox-Gastaut Syndrome The initial starting dosage for patients with Lennox-Gastaut syndrome is 0.1 mg/kg twice daily, which should be increased weekly based on tolerability. Table 1 provides the recommended titration schedule. Patients with Lennox-Gastaut syndrome not on concomitant stiripentol who are tolerating FINTEPLA should be titrated to the recommended maintenance dosage of 0.35 mg/kg twice daily (maximum daily dosage of 26 mg). Patients with Lennox-Gastaut syndrome taking concomitant stiripentol plus clobazam who are tolerating FINTEPLA should be titrated to the recommended maintenance dosage of 0.2 mg/kg twice daily (maximum daily dosage of 17 mg) [see Drug Interactions (7.1) ]. Table 1: FINTEPLA Recommended Titration Schedule For patients not on concomitant stiripentol in whom a more rapid titration is warranted, the dose may be increased every 4 days. Without concomitant stiripentol With concomitant stiripentol plus clobazam Weight-based Dosage To calculate the dose volume: Weight (kg) × Weight-based dosage (mg/kg) ÷ 2.2 mg/mL = mL dose to be taken twice daily Maximum Total Daily Dosage For maximum dosage with concomitant use of strong CYP1A2 or CYP2D6 inhibitors, in patients with severe renal impairment, or in patients with hepatic impairment see Dosage and Administration 2.3, 2.4, 2.5. Weight-based Dosage Maximum Total Daily Dosage Initial Dosage For patients with Dravet syndrome, dosage may be increased based on clinical response to the maximum recommended dosage, as needed. 0.1 mg/kg twice daily 26 mg 0.1 mg/kg twice daily 17 mg Day 7 0.2 mg/kg twice daily 26 mg 0.15 mg/kg twice daily 17 mg Day 14 For patients with Lennox-Gastaut syndrome, dosage should be increased as tolerated to the recommended maintenance dosage (i.e., Day 14). 0.35 mg/kg twice daily 26 mg 0.2 mg/kg twice daily 17 mg 2.3 Dosage Modifications for Patients with Concomitant Use of Strong CYP1A2 or CYP2D6 Inhibitors (DS and LGS) For patients with concomitant use of FINTEPLA with a strong CYP1A2 or CYP2D6 inhibitor, a maximum total daily dosage of 20 mg without concomitant stiripentol and 17 mg with concomitant stiripentol plus clobazam is recommended [see Drug Interactions (7.1) ] . 2.4 Dosage Modifications for Patients with Severe Renal Impairment (DS and LGS) For patients with severe renal impairment (estimated glomerular filtration rate (eGFR) 15 to 29 mL/min/1.73m 2 ), a maximum total daily dosage of 20 mg without concomitant stiripentol and 17 mg with concomitant stiripentol plus clobazam is recommended [see Use in Specific Populations (8.6) ] . 2.5 Dosage Modifications for Patients with Mild, Moderate, and Severe Hepatic Impairment (DS and LGS) See Table 2 for dosage adjustments and recommendations for patients with hepatic impairment [see Use in Specific Populations (8.7) ] . Table 2: FINTEPLA Dosage Modifications and Recommendations for Patients with Hepatic Impairment Hepatic Impairment Classification Without concomitant stiripentol titrate as recommended [see Dosage and Administration (2.2)] With concomitant stiripentol plus clobazam Maximum total daily dosage Maximum total daily dosage Mild (Child-Pugh A) 20 mg 13 mg Moderate (Child-Pugh B) 20 mg Use not recommended Severe (Child-Pugh C) 17 mg Use not recommended 2.6 Assessments During and After Administration of FINTEPLA To evaluate for valvular heart disease and pulmonary arterial hypertension, obtain an echocardiogram assessment every 6 months during treatment with FINTEPLA, and 3 to 6 months after the final dose of FINTEPLA [see Warnings and Precautions (5.1) ]. 2.7 Administration Instructions A calibrated measuring device (either a 3 mL or 6 mL oral syringe) will be provided by the pharmacy and is recommended to measure and administer the prescribed dose accurately [see How Supplied/Storage and Handling (16.1) ] . A household teaspoon or tablespoon is not an adequate measuring device and should not be used. Discard any unused FINTEPLA oral solution remaining after 3 months of first opening the bottle or the "Discard After" date on the bottle, whichever is sooner. FINTEPLA is compatible with commercially available gastric and nasogastric feeding tubes. 2.8 Discontinuation of FINTEPLA When discontinuing FINTEPLA, the dose should be decreased gradually. As with all antiepileptic drugs, abrupt discontinuation should be avoided when possible, to minimize the risk of increased seizure frequency and status epilepticus [see Warnings and Precautions (5.6) ].

4 CONTRAINDICATIONS FINTEPLA is contraindicated in patients with: Hypersensitivity to fenfluramine or any of the excipients in FINTEPLA [see Description (11) ] Concomitant use, or within 14 days of the administration, of monoamine oxidase inhibitors because of an increased risk of serotonin syndrome [see Warnings and Precautions (5.7) ] Hypersensitivity to fenfluramine or any of the excipients in FINTEPLA ( 4 ) Within 14 days of the administration of monoamine oxidase inhibitors due to an increased risk of serotonin syndrome ( 4 )

5 WARNINGS AND PRECAUTIONS Decreased Appetite and Decreased Weight: Advise patients that FINTEPLA can cause decreased appetite and decreased weight. ( 5.3 ) Somnolence, Sedation, and Lethargy: Monitor for somnolence and sedation. Advise patients not to drive or operate machinery until they have gained sufficient experience on FINTEPLA. ( 5.4 ) Suicidal Behavior and Ideation: Monitor patients for suicidal behavior and thoughts. ( 5.5 ) Withdrawal of Antiepileptic Drugs: FINTEPLA should be gradually withdrawn to minimize the risk of increased seizure frequency and status epilepticus. ( 5.6 ) Serotonin Syndrome: Advise patients that serotonin syndrome is a potentially life-threatening condition and may occur with FINTEPLA, particularly with concomitant administration of FINTEPLA with other serotonergic drugs. ( 5.7 ) Increase in Blood Pressure: Monitor blood pressure during treatment. ( 5.8 ) Glaucoma: Discontinue therapy in patients with acute decrease in visual acuity or ocular pain. ( 5.9 ) 5.1 Valvular Heart Disease and Pulmonary Arterial Hypertension FINTEPLA can cause valvular heart disease (VHD) and pulmonary arterial hypertension (PAH). There is a known association between serotonergic drugs with 5-HT2B receptor agonist activity, including fenfluramine (the active ingredient in FINTEPLA), and valvular heart disease and pulmonary arterial hypertension. Although no patients receiving FINTEPLA developed valvular heart disease or pulmonary arterial hypertension in clinical trials for DS and LGS of up to 3 years in duration, cases of valvular heart disease and pulmonary arterial hypertension have been reported during use of FINTEPLA in the postmarketing setting [see Boxed Warning and Adverse Reactions (6.1) ] . Because of this risk, cardiac monitoring is required prior to starting treatment, during treatment, and after treatment with FINTEPLA concludes . Cardiac monitoring via echocardiogram can identify evidence of valvular heart disease and pulmonary arterial hypertension prior to a patient becoming symptomatic, aiding in early detection of these conditions. Monitoring Prior to starting treatment, patients must undergo an echocardiogram to evaluate for valvular heart disease and pulmonary arterial hypertension. Echocardiograms should be repeated every 6 months, and once 3-6 months post-treatment with FINTEPLA. The prescriber must consider the benefits versus the risks of initiating or continuing treatment with FINTEPLA if any of the following signs are observed via ECHO: Valvular abnormality or new abnormality via echocardiogram. VHD as indicated by mild or greater aortic regurgitation or moderate or greater mitral regurgitation, with additional characteristics of VHD (e.g., valve thickening or restrictive valve motion). PAH as indicated by elevated right heart/pulmonary artery pressure (PASP > 35 mm Hg). FINTEPLA is available only through a restricted program under a REMS [see Warnings and Precautions (5.2) ]. 5.2 FINTEPLA REMS Program FINTEPLA is available only through a restricted distribution program called the FINTEPLA REMS program because of the risk of valvular heart disease and pulmonary arterial hypertension [see Warnings and Precautions (5.1) ]. Notable requirements of the FINTEPLA REMS Program include: Prescribers must be certified by enrolling in the FINTEPLA REMS program. Prescribers must counsel patients receiving FINTEPLA about the risk of valvular heart disease and pulmonary arterial hypertension, how to recognize signs and symptoms of valvular heart disease and pulmonary arterial hypertension, the need for baseline (pretreatment) and periodic cardiac monitoring via echocardiogram during FINTEPLA treatment, and cardiac monitoring after FINTEPLA treatment. Patients must enroll in the REMS program and comply with ongoing monitoring requirements [see Warnings and Precautions (5.1) ]. The pharmacy must be certified by enrolling in the REMS program and must only dispense to patients who are authorized to receive FINTEPLA. Wholesalers and distributors must only distribute to certified pharmacies. Further information is available at www.FinteplaREMS.com or by telephone at 1-877-964-3649. 5.3 Decreased Appetite and Decreased Weight FINTEPLA can cause decreases in appetite and weight. In placebo-controlled studies for DS (Study 1 and Study 2 combined), approximately 37% of patients treated with FINTEPLA reported, as an adverse reaction, decreased appetite and approximately 9% reported decreased weight, as compared to 8% and 1%, respectively, of patients on placebo . In the placebo- controlled study for LGS (Study 3), approximately 28% of patients treated with FINTEPLA reported, as an adverse reaction, decreased appetite and approximately 5% reported decreased weight, as compared to 15% and 2%, respectively, of patients on placebo [see Adverse Reactions (6.1) ] . By the end of the controlled studies, 19% (Studies 1 and 2 combined) of DS patients and 7% (Study 3) of LGS patients treated with FINTEPLA had a measured decrease in weight of 7% or greater from their baseline weight, compared to 2% (Study 1 and 2) and 0% (Study 3) of patients on placebo. This measured decrease in weight appeared to be dose-related. In the controlled studies for DS, 26% of patients on FINTEPLA 0.7 mg/kg/day (Study 1), 19% of patients on FINTEPLA 0.4 mg/kg/day in combination with stiripentol (Study 2), and 13% of patients taking FINTEPLA 0.2 mg/kg/day (Study 1) experienced at least a 7% decrease in weight from baseline. In the controlled study for LGS, 9% of patients on FINTEPLA 0.7 mg/kg/day (Study 3) and 6% of patients on FINTEPLA 0.2 mg/kg/day (Study 3) experienced at least a 7% decrease in weight from baseline. Approximately half of the patients with LGS and most patients with DS resumed the expected measured increases in weight during the open-label extension studies. Given the frequency of these adverse reactions, the growth of pediatric patients treated with FINTEPLA should be carefully monitored. Weight should be monitored regularly during treatment with FINTEPLA, and dose modifications should be considered if a decrease in weight is observed. 5.4 Somnolence, Sedation, and Lethargy FINTEPLA can cause somnolence, sedation, and lethargy. In controlled studies for DS (Study 1 and Study 2 combined), the incidence of somnolence, sedation, and lethargy was 25% in patients treated with FINTEPLA, compared with 11% of patients on placebo. In the controlled study for LGS (Study 3), the incidence of somnolence, sedation, and lethargy was 19% in patients treated with FINTEPLA, compared with 16% of patients on placebo. In general, these effects may diminish with continued treatment [see Adverse Reactions (6.1) ]. Other central nervous system (CNS) depressants, including alcohol, could potentiate these effects of FINTEPLA. Prescribers should monitor patients for somnolence and sedation and should advise patients not to drive or operate machinery until they have gained sufficient experience on FINTEPLA to gauge whether it adversely affects their ability to drive or operate machinery. 5.5 Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including FINTEPLA, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with an AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, or any unusual changes in mood or behavior. Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs that did not include FINTEPLA showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide. The increased risk of suicidal thoughts or behavior with AEDs was observed as early as 1 week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed. The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years) in the clinical trials analyzed. Table 3 shows absolute and relative risk by indication for all evaluated AEDs. Table 3: Risk of Suicidal Thoughts or Behaviors by Indication for Antiepileptic Drugs in the Pooled Analysis Indication Placebo Patients with Events per 1000 Patients Drug Patients with Events per 1000 Patients Relative Risk: Incidence of Events in Drug Patients/ Incidence in Placebo Patients Risk Difference: Additional Drug Patients with Events per 1000 Patients Epilepsy 1.0 3.4 3.5 2.4 Psychiatric 5.7 8.5 1.5 2.9 Other 1.0 1.8 1.9 0.9 Total 2.4 4.3 1.8 1.9 The relative risk for suicidal thoughts or behavior was higher in clinical trials in patients with epilepsy than in clinical trials in patients with psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications. Anyone considering prescribing FINTEPLA or any other AED must balance the risk of suicidal thoughts or behaviors with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, consider whether the emergence of these symptoms in any given patient may be related to the illness being treated. 5.6 Withdrawal of Antiepileptic Drugs As with most AEDs, FINTEPLA should generally be withdrawn gradually because of the risk of increased seizure frequency and status epilepticus. If withdrawal is needed because of a serious adverse reaction, rapid discontinuation can be considered. 5.7 Serotonin Syndrome Serotonin syndrome, a potentially life-threatening condition, may occur with FINTEPLA, particularly with concomitant administration of FINTEPLA with other serotonergic drugs, including, but not limited to, selective serotonin-norepinephrine reuptake inhibitors (SNRIs), selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), bupropion, triptans, dietary supplements (e.g., St. John's Wort, tryptophan), drugs that impair metabolism of serotonin (including monoamine oxidase inhibitors [MAOIs], which are contraindicated with FINTEPLA [see Contraindications (4) ], dextromethorphan, lithium, tramadol, and antipsychotics with serotonergic agonist activity. Patients should be monitored for the emergence of signs and symptoms of serotonin syndrome, which include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular signs (e.g., hyperreflexia, incoordination), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). If serotonin syndrome is suspected, treatment with FINTEPLA should be stopped immediately and symptomatic treatment should be started. 5.8 Increase in Blood Pressure FINTEPLA can cause an increase in blood pressure [see Adverse Reactions (6.1) ]. Rare cases of significant elevation in blood pressure, including hypertensive crisis, has been reported in adult patients treated with fenfluramine, including patients without a history of hypertension. In clinical trials of up to 3 years in duration, no pediatric or adult patient receiving FINTEPLA developed a hypertensive crisis. Monitor blood pressure in patients treated with FINTEPLA. 5.9 Glaucoma Fenfluramine can cause mydriasis and can precipitate angle closure glaucoma. Consider discontinuing treatment with FINTEPLA in patients with acute decreases in visual acuity or ocular pain.

7 DRUG INTERACTIONS Dose adjustment is required for patients taking stiripentol plus clobazam. ( 2.2 , 2.3 , 7.1 ) Strong CYP1A2 or CYP2D6 inhibitors: a dose adjustment is recommended ( 2.3 , 7.1 ) Strong CYP1A2, CYP2B6, or CYP3A4 inducers: it is recommended to avoid coadministration with FINTEPLA. If coadministration is necessary, consider a FINTEPLA dosage increase. ( 7.1 ) 7.1 Effect of Other Drugs on FINTEPLA Stiripentol Plus Clobazam Coadministration of FINTEPLA with stiripentol plus clobazam, with or without valproate, increases fenfluramine plasma concentrations [see Clinical Pharmacology (12.3) ]. If FINTEPLA is coadministered with stiripentol plus clobazam, the maximum daily dosage of FINTEPLA is 0.2 mg/kg twice daily (maximum daily dosage of 17 mg) [see Dosage and Administration (2.2) ] . Strong CYP1A2, CYP2B6, or CYP3A Inducers Coadministration of FINTEPLA with strong CYP1A2, CYP2B6, or CYP3A inducers will decrease fenfluramine plasma concentrations, which may lower the efficacy of FINTEPLA [see Clinical Pharmacology (12.3) ] . It is recommended to avoid coadministration of strong CYP1A2, CYP2B6 or CYP3A inducers. If coadministration of a strong CYP1A2, CYP2B6, or CYP3A inducer with FINTEPLA is necessary, monitor the patient for reduced efficacy and consider increasing the dosage of FINTEPLA as needed; however, do not exceed the maximum daily dosage of FINTEPLA [see Dosage and Administration (2.2) ]. If a strong CYP1A2, CYP2B6, or CYP3A inducer is discontinued during maintenance treatment with FINTEPLA, consider gradual reduction in the FINTEPLA dosage to the dose administered prior to initiating the inducer [see Warnings and Precautions (5.6) ]. Strong CYP1A2 or CYP2D6 Inhibitors Coadministration of FINTEPLA with strong CYP1A2 or CYP2D6 inhibitors will increase fenfluramine plasma concentrations [see Clinical Pharmacology (12.3) ] . If FINTEPLA is coadministered with strong CYP1A2 or CYP2D6 inhibitors, the maximum daily dosage of FINTEPLA is 20 mg [see Dosage and Administration (2.3) ]. If a strong CYP1A2 or CYP2D6 inhibitor is discontinued during maintenance treatment with FINTEPLA, consider gradual increase in the FINTEPLA dosage to the dose recommended without CYP1A2 or CYP2D6 inhibitors; however, do not exceed the maximum daily dosage of FINTEPLA [see Dosage and Administration (2.2) ]. If FINTEPLA is coadministered with stiripentol and a strong CYP1A2 or CYP2D6 inhibitor, do not exceed the maximum daily dosage of FINTEPLA of 17 mg [see Dosage and Administration (2.3) ]. 7.2 Effects of Serotonin Receptor Antagonists Cyproheptadine and potent 5-HT1A, 5-HT1D, 5-HT2A, and 5-HT2C serotonin receptor antagonists may decrease the efficacy of FINTEPLA. If cyproheptadine or potent 5--HT1A, 5--HT1D, 5-HT2A, or 5-HT2C serotonin receptor antagonists are coadministered with FINTEPLA, patients should be monitored appropriately. 7.3 Serotonergic Drugs Concomitant administration of FINTEPLA and drugs (e.g., SSRIs, SNRIs, TCAs, MAO inhibitors, trazodone, etc.), over-the-counter medications (e.g., dextromethorphan), or herbal supplements (e.g., St. John's Wort) that increase serotonin may increase the risk of serotonin syndrome [see Warnings and Precautions (5.7) ]. Concomitant use of FINTEPLA is contraindicated within 14 days of taking MAOIs. Use FINTEPLA with caution in patients taking other medications that increase serotonin.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in labeling: Valvular Heart Disease and Pulmonary Arterial Hypertension [see Warnings and Precautions (5.1) ] Decreased Appetite and Decreased Weight [see Warnings and Precautions (5.3) ] Somnolence, Sedation, and Lethargy [see Warnings and Precautions (5.4) ] Suicidal Behavior and Ideation [see Warnings and Precautions (5.5) ] Withdrawal of Antiepileptic Drugs [see Warnings and Precautions (5.6) ] Serotonin Syndrome [see Warnings and Precautions (5.7) ] Increase in Blood Pressure [see Warnings and Precautions (5.8) ] Glaucoma [see Warnings and Precautions (5.9) ] The most common adverse reactions (incidence at least 10% and greater than placebo) in patients with Dravet syndrome were decreased appetite; somnolence, sedation, lethargy; diarrhea; constipation; abnormal echocardiogram; fatigue, malaise, asthenia; ataxia, balance disorder, gait disturbance; blood pressure increased; drooling, salivary hypersecretion; pyrexia; upper respiratory tract infection; vomiting; decreased weight; fall; status epilepticus. ( 6.1 ) The most common adverse reactions (incidence at least 10% and greater than placebo) in patients with Lennox-Gastaut syndrome were diarrhea; decreased appetite; fatigue; somnolence; vomiting. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact UCB, Inc. at 1-844-599-2273 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In controlled and uncontrolled trials in patients with Dravet syndrome (DS), 341 patients were treated with FINTEPLA, including 312 patients treated for more than 6 months, 284 patients treated for more than 1 year, and 138 patients treated for more than 2 years. In controlled and uncontrolled trials in patients with Lennox-Gastaut syndrome (LGS), 262 patients were treated with FINTEPLA, including 219 patients treated for more than 6 months, 172 patients treated for more than 1 year, and 127 patients treated for more than 2 years. Dravet Syndrome In placebo-controlled trials of patients with DS taking concomitant standard of care AEDs, 122 patients were treated with FINTEPLA and 84 patients received placebo [see Clinical Studies (14.1) ] . The duration of treatment in these trials was 16 weeks (Study 1) or 17 weeks (Study 2). In Study 1 and Study 2, the mean age was 9 years (range 2 to 19 years) and approximately 46% of patients were female and 74% were White. All patients were receiving at least one other AED. In Study 1 and Study 2, the rates of discontinuation as a result of any adverse reaction were 13%, 0%, and 7% for patients treated with FINTEPLA 0.7 mg/kg/day, 0.2 mg/kg/day, and 0.4 mg/kg/day in combination with stiripentol, respectively, compared to 6% for patients on placebo. The most frequent adverse reaction leading to discontinuation in the patients treated with any dose of FINTEPLA was somnolence (3%). The most common adverse reactions that occurred in patients treated with FINTEPLA (incidence at least 10% and greater than placebo) were decreased appetite; somnolence, sedation, lethargy; diarrhea; constipation; abnormal echocardiogram; fatigue, malaise, asthenia; ataxia, balance disorder, gait disturbance; blood pressure increased; drooling, salivary hypersecretion; pyrexia; upper respiratory tract infection; vomiting; decreased weight; fall; status epilepticus. Table 4 lists the adverse reactions that were reported in 5% or more of patients treated with FINTEPLA and at a rate greater than those on placebo during the titration and maintenance phases of Study 1 and Study 2. Table 4: Adverse Reactions in 5% or More of Patients Treated with FINTEPLA and Greater Than Placebo in Placebo-Controlled Trials for Dravet Syndrome (Study 1 and 2) Adverse Reaction FINTEPLA Dose Group Combined Placebo Group Patients in placebo groups from Studies 1 and 2 were pooled. Study 1 Study 2 0.2 mg/kg/day 0.7 mg/kg/day 0.4 mg/kg/day 0.4 mg/kg/day was not an intermediate dose. Patients on the 0.4 mg/kg/day dose were also taking concomitant stiripentol plus clobazam, which increases exposure of FINTEPLA. N=39 % N=40 % N=43 % N=84 % Decreased appetite 23 38 49 8 Somnolence, sedation, lethargy 26 25 23 11 Abnormal echocardiogram Consisted of trace and mild mitral regurgitation, and trace aortic regurgitation, which are considered physiologic. 18 23 9 6 Diarrhea 31 15 23 6 Constipation 3 10 7 0 Fatigue, malaise, asthenia 15 10 30 5 Ataxia, balance disorder, gait disturbance 10 10 7 1 Abnormal behavior 0 8 9 0 Blood pressure increased 13 8 0 5 Drooling, salivary hypersecretion 13 8 2 0 Hypotonia 0 8 0 0 Rash 8 8 5 4 Blood prolactin increased 0 5 0 0 Chills 0 5 2 0 Decreased activity 0 5 0 1 Dehydration 0 5 0 0 Insomnia 0 5 5 2 Pyrexia 15 5 21 14 Stereotypy 0 5 0 0 Upper respiratory tract infection 21 5 7 10 Vomiting 10 5 5 8 Weight decreased 13 5 7 1 Croup 5 3 0 1 Ear infection 8 3 9 5 Gastroenteritis 8 3 2 0 Increased heart rate 5 3 0 2 Irritability 0 3 9 2 Rhinitis 8 3 7 2 Tremor 3 3 9 0 Urinary incontinence 5 3 0 0 Decreased blood glucose 0 0 9 1 Bronchitis 3 0 9 1 Contusion 5 0 0 0 Eczema 0 0 5 0 Enuresis 5 0 0 0 Fall 10 0 0 4 Headache 8 0 0 2 Laryngitis 0 0 5 0 Negativism 5 0 0 0 Status epilepticus 3 0 12 2 Urinary tract infection 5 0 5 0 Viral infection 0 0 5 1 Lennox-Gastaut Syndrome In the placebo-controlled trial of patients with LGS taking concomitant standard of care AEDs (Study 3), 176 patients were treated with FINTEPLA and 87 patients received placebo [see Clinical Studies (14.2) ] . The duration of treatment in this trial was 16 weeks. The mean age was 13.7 years (range 2 to 35 years) and 29% of patients were at least 18 years of age, 45% of patients were female, and 79% were White. All patients were receiving at least one other AED. The rates of discontinuation as a result of any adverse reaction were 6% and 5% for patients treated with FINTEPLA 0.7 mg/kg/day and 0.2 mg/kg/day, respectively, compared to 1% for patients on placebo. The most frequent adverse reactions leading to discontinuation in the patients treated with any dose of FINTEPLA were seizure (2%) and somnolence (2%). The common adverse reactions that occurred in patients treated with FINTEPLA (incidence at least 10% and greater than placebo) were diarrhea; decreased appetite; fatigue; somnolence; vomiting. Table 5 lists the adverse reactions that were reported in 5% or more of patients treated with FINTEPLA and at a rate greater than those on placebo during the titration and maintenance phases of Study 3. Table 5: Adverse Reactions in 5% or More of Patients Treated with FINTEPLA and Greater Than Placebo in the Placebo-Controlled Trial for Lennox Gastaut Syndrome (Study 3) Adverse Reaction FINTEPLA Dose Group Study 3 Placebo Group 0.2 mg/kg/day 0.7mg/kg/day N=89 % N=87 % N=87 % Decreased appetite 20 36 12 Fatigue, malaise, asthenia 14 24 16 Somnolence, sedation, lethargy 12 22 16 Diarrhea 11 13 5 Constipation 6 9 6 Vomiting 14 8 6 Weight decreased 2 8 2 Upper respiratory tract infection 8 7 3 Seizure 9 5 7 Irritability 8 3 6 Echocardiographic Safety Assessments of Valvular Heart Disease and Pulmonary Arterial Hypertension Valvular heart disease and pulmonary arterial hypertension were evaluated in the placebo- controlled and open-label extension studies via echocardiography for up to 3 years in duration for 341 DS patients and 263 LGS patients [see Warnings and Precautions (5.1) ]. Screening for valvular heart disease assessed for mild or greater aortic regurgitation or moderate or greater mitral regurgitation, and assessed for additional characteristics of VHD (e.g., valve thickening or restrictive valve motion). In these clinical studies, two patients with LGS exhibited mild aortic regurgitation (AR) but neither patient had any cardiac signs or symptoms or evidence of valvular structural changes. Neither patient had VHD. The rates of mild AR are consistent with those seen in the screening period prior to treatment (3 patients in LGS and 1 patient in DS clinical trials). 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of FINTEPLA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Psychiatric disorders : aggression

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (AEDs), such as FINTEPLA, during pregnancy. Encourage women who are taking FINTEPLA during pregnancy to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry by calling the toll-free number 1-888-233-2334 or visiting http://www.aedpregnancyregistry.org. Risk Summary There are no data on FINTEPLA use in pregnant women. Available data from epidemiologic studies with fenfluramine or dexfenfluramine are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. FINTEPLA can cause decreased appetite and decreased weight [see Warnings and Precautions (5.3) ]; monitor for adequate weight gain during pregnancy. In animal studies, administration of fenfluramine throughout organogenesis (rat and rabbit) or throughout gestation and lactation (rat) resulted in adverse effects on development (fetal malformations, embryofetal and offspring mortality and growth impairment) in the presence of maternal toxicity at clinically relevant maternal plasma levels of fenfluramine and its major active metabolite (see Data ) . All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-associated Maternal and/or Embryofetal Risk Epilepsy, with or without exposure to antiepileptic drugs, has been associated with several adverse outcomes during pregnancy, including preeclampsia, preterm labor, antepartum and postpartum hemorrhage, placental abruption, poor fetal growth, prematurity, fetal death, and maternal mortality. The risk of maternal or fetal injury may be greatest for patients with untreated or poorly controlled convulsive seizures. Women with epilepsy who become pregnant should not abruptly discontinue antiepileptic drugs, including FINTEPLA, due to the risk of status epilepticus or severe seizures, which may be life-threatening [see Warnings and Precautions (5.6) ]. Data Animal Data Oral administration of fenfluramine (0, 4.5, 8.6, or 34.6 mg/kg/day) to pregnant rats during organogenesis resulted in decreased fetal body weights and marked increases in fetal malformations (external, visceral, and skeletal) at the highest dose tested, which was associated with maternal toxicity. At the no-effect dose (8.6 mg/kg/day) for adverse effects on embryofetal development in rats, maternal plasma exposures (AUC) of fenfluramine and norfenfluramine (the major metabolite) were approximately 2 and 5 times, respectively, those in humans at the maximum recommended human dose (MRHD) of 26 mg/day. Oral administration of fenfluramine (0, 4.3, 8.6, 13.0 mg/kg/day) to pregnant rabbits throughout organogenesis resulted in increased embryofetal mortality at all doses and increases in fetal malformations (external and skeletal) at the highest dose tested, which was associated with maternal toxicity. A no-adverse-effect dose for adverse effects on embryofetal development in rabbits was not identified. At the lowest dose tested in rabbits (4.3 mg/kg/day), maternal plasma exposures of fenfluramine and norfenfluramine were lower than those in humans at the MRHD. Oral administration of fenfluramine (0, 4.3, 8.6, or 34.6 mg/kg/day) to female rats throughout gestation and lactation resulted in marked increases in stillborn pups and neonatal offspring deaths at the highest dose tested and delayed growth and reflex development during the pre- weaning period at all doses. Maternal body weight gain was decreased at all doses during pregnancy and at the two highest doses during lactation. A no-effect dose for adverse effects on pre- and postnatal development in rats was not determined. At the lowest dose tested in rats (4.3 mg/kg/day), maternal plasma exposures of fenfluramine and norfenfluramine were approximately 0.5 and 3 times, respectively, those in humans at the MRHD.