ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following clinically significant adverse reactions are described elsewhere in labeling:Valvular Heart Disease [see Warnings and Precautions (5.1)] Pulmonary Arterial Hypertension [see Warnings and Precautions (5.2)] Decreased Appetite and Decreased Weight [see Warnings and Precautions (5.4)] Somnolence, Sedation, and Lethargy [see Warnings and Precautions (5.5)] Suicidal Behavior and Ideation [see Warnings and Precautions (5.6)] Withdrawal of Antiepileptic Drugs [see Warnings and Precautions (5.7)] Serotonin Syndrome [see Warnings and Precautions (5.8)] Increase in Blood Pressure [see Warnings and Precautions (5.9)] Glaucoma [see Warnings and Precautions (5.10)] Valvular Heart Disease [see Warnings and Precautions (5.1)] Pulmonary Arterial Hypertension [see Warnings and Precautions (5.2)] Decreased Appetite and Decreased Weight [see Warnings and Precautions (5.4)] Somnolence, Sedation, and Lethargy [see Warnings and Precautions (5.5)] Suicidal Behavior and Ideation [see Warnings and Precautions (5.6)] Withdrawal of Antiepileptic Drugs [see Warnings and Precautions (5.7)] Serotonin Syndrome [see Warnings and Precautions (5.8)] Increase in Blood Pressure [see Warnings and Precautions (5.9)] Glaucoma [see Warnings and Precautions (5.10)] The most common adverse reactions (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. (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Zogenix Inc. at 1-866-964-3649 (1-866-Zogenix) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. 6.1Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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, 341 patients were treated with FINTEPLA, including 312 patients treated for more than months, 284 patients treated for more than year, and 138 patients treated for more than years. In placebo-controlled trials of patients with Dravet syndrome, 122 patients were treated with FINTEPLA [see Clinical Studies (14)]. The duration of treatment in these trials was 16 weeks (Study 1) or 17 weeks (Study 2). In Study and Study 2, the mean age was years (range 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 and Study 2, the rates of discontinuation as 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 (n=3, 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 lists the adverse reactions that were reported in 5% or more of patients treated with FINTEPLA and at rate greater than those on placebo during the titration and maintenance phases of Study and Study 2.Table 3: Adverse Reactions in 5% or More of Patients Treated with FINTEPLA and Greater Than Placebo in Placebo-Controlled Trials (1) 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.(2) Patients in placebo groups from Studies and were pooled.(3) Consisted of trace and mild mitral regurgitation, and trace aortic regurgitation, which are considered physiologic.FINTEPLA Dose GroupCombinedPlaceboGroup(2) Study 1Study 20.2 mg/kg/day0.7 mg/kg/day0.4mg/kg/day(1) N=39%N=40%N=43%N=84%Decreased appetite2338498Somnolence, sedation, lethargy26252311Abnormal echocardiogram(3) 182396Diarrhea3115236Constipation31070Fatigue, malaise, asthenia1510305Ataxia, balance disorder, gait disturbance101071Abnormal behavior0890Blood pressure increased13805Drooling, salivary hypersecretion13820Hypotonia0800Rash8854Blood prolactin increased0500Chills0520Decreased activity0501Dehydration0500Insomnia0552Pyrexia1552114Stereotypy0500Upper respiratory tract infection215710Vomiting10558Weight decreased13571Croup 5301Ear infection8395Gastroenteritis8320Increased heart rate5302Irritability0392Rhinitis8372Tremor3390Urinary incontinence5300Decreased blood glucose0091Bronchitis3091Contusion5000Eczema0050Enuresis5000Fall10004Headache8002Laryngitis0050Negativism5000Status epilepticus30122Urinary tract infection5050Viral infection0051Echocardiographic Safety Assessments of Valvular Heart Disease and Pulmonary Arterial HypertensionValvular heart disease and pulmonary arterial hypertension were evaluated in the placebo-controlled and open-label extension studies via echocardiography for up to years in duration [see Warnings and Precautions (5.1, 5.2)]. No patient developed echocardiographic findings consistent with either valvular heart disease or pulmonary arterial hypertension in the placebo-controlled studies or during the open-label extension study of up to years in duration. In Study and Study 2, 16% of patients taking FINTEPLA compared to 6% of patients taking placebo were reported to have trace mitral regurgitation, and 3% of patients taking FINTEPLA and no patients taking placebo were found to have trace aortic regurgitation. During the open-label extension study, trace mitral regurgitation and trace aortic regurgitation were reported in 14% and 0.4%, respectively, of patients taking FINTEPLA. Trace and mild mitral regurgitation, and trace aortic regurgitation are considered physiologic in the absence of structural valve abnormalities.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. The mechanisms by which fenfluramine exerts its therapeutic effects in the treatment of seizures associated with Dravet syndrome are unknown. Fenfluramine and the metabolite, norfenfluramine, increase extracellular levels of serotonin through interaction with serotonin transporter proteins, and exhibit agonist activity at serotonin 5HT-2 receptors.. 12.2 Pharmacodynamics. Cardiac Electrophysiology At dose times the maximum recommended dose, FINTEPLA did not prolong the QT interval when tested in an adult population.. 12.3 Pharmacokinetics. The pharmacokinetics of fenfluramine and norfenfluramine were studied in healthy subjects and in pediatric patients with Dravet syndrome. The steady-state systemic exposure (Cmax and AUC) of fenfluramine was slightly greater than dose proportional over the dose range of 13 to 51.8 mg twice-daily fenfluramine (i.e., to times the maximum recommended dose). In pediatric patients who received FINTEPLA 0.7 mg/kg/day, up to total daily dose of 26 mg fenfluramine, the geometric mean steady-state fenfluramine (coefficient of variation) Cmax was 68.0 (41%) ng/mL and AUC0-24h was 1390 (44%) ngh/mL.AbsorptionFenfluramine has time to maximum plasma concentration (Tmax) of to hours at steady state. The absolute bioavailability of fenfluramine is approximately 68-74%. There was no effect of food on the pharmacokinetics of fenfluramine or norfenfluramine.DistributionThe geometric mean (CV%) apparent volume of distribution (Vz/F) of fenfluramine is 11.9 (16.5%) L/kg following oral administration of FINTEPLA in healthy subjects. Fenfluramine is 50% bound to human plasma proteins in vitro and binding is independent of drug concentrations. EliminationThe elimination half-life of fenfluramine was 20 hours and the geometric mean (CV%) clearance (CL/F) was 24.8 (29%) L/h, following oral administration of FINTEPLA in healthy subjects.MetabolismOver 75% of fenfluramine is metabolized to norfenfluramine prior to elimination, primarily by CYP1A2, CYP2B6, and CYP2D6. Other CYP enzymes involved to minor extent are CYP2C9, CYP2C19, and CYP3A4/5. Norfenfluramine is then deaminated and oxidized to form inactive metabolites.ExcretionMost of an orally administered dose of fenfluramine (greater than 90%) is excreted in the urine as fenfluramine, norfenfluramine, or other metabolites with fenfluramine and norfenfluramine accounting for less than 25% of the total; less than 5% is found in feces. Specific PopulationsThe effect of age (range: to 50 years), sex, and race had no clinically meaningful effect on the pharmacokinetics of fenfluramine.Drug Interaction Studies Clinical StudiesEffect of single dose of stiripentol, clobazam, and valproic acid combination: Coadministration of single 0.7 mg/kg dose of FINTEPLA, with single dose of stiripentol, clobazam, and valproic acid combination in health volunteers, increased the AUC0-INF of fenfluramine by 69% and the Cmax by 18%, and decreased the AUC0-72 hours of norfenfluramine by 41% and the Cmax by 42%, as compared to FINTEPLA administered alone. Effect of steady state stiripentol plus clobazam, with or without valproate: Fenfluramine pharmacokinetic data were collected from patients after receiving multiple fenfluramine administrations in Study as well as Study 2. Population pharmacokinetic modeling and simulation were used to assess the effect of stiripentol plus clobazam with or without valproate on fenfluramine pharmacokinetics. The effect of stiripentol plus clobazam, with or without valproate, on fenfluramine pharmacokinetics is greater when FINTEPLA is at steady-state than for the first dose of FINTEPLA. When initiating FINTEPLA therapy, coadministration of existing stiripentol plus clobazam with or without valproate is expected to increase the AUC0-24 of the first fenfluramine dose by up to 42% in the patient population. At steady state in the patient population, the coadministration of 0.1 mg/kg twice daily (0.2 mg/kg/day), maximum 17 mg/day, of FINTEPLA with stiripentol plus clobazam with or without valproate, is expected to result in 166% increase in fenfluramine AUC0-24 and 38% decrease in norfenfluramine AUC0-24, as compared to 0.2 mg/kg/day, maximum 26 mg/day, FINTEPLA dose administered alone [see Dosage and Administration (2.1, 2.2) and Drug Interactions (7.1)].Effect of steady state cannabidiol: Coadministration of single 0.35 mg/kg dose of FINTEPLA 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 FINTEPLA administered alone. This interaction is not expected to be clinically significant. Effect of FINTEPLA on other drugs: Coadministration of single 0.7 mg/kg dose of FINTEPLA, with single dose of stiripentol, clobazam, and valproic acid combination, did not affect the pharmacokinetics of stiripentol, nor the pharmacokinetics of clobazam or its N-desmethyl-metabolite norclobazam, nor the pharmacokinetics of valproic acid, as compared to the stiripentol, clobazam, and valproic acid combination alone. Coadministration of single 0.35 mg/kg dose of FINTEPLA, with repeated doses of cannabidiol, did not affect the pharmacokinetics of cannabidiol, as compared to cannabidiol alone.In Vitro StudiesFenfluramine is primarily metabolized by CYP1A2, CYP2B6, and CYP2D6 in vitro. Other CYP enzymes involved to minor extent are CYP2C9, CYP2C19, and CYP3A4/5.Effect of fenfluramine and norfenfluramine on CYP Substrates: fenfluramine and norfenfluramine are not inhibitors or inducers of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4 at clinically relevant concentrations.Effect of transporters on fenfluramine and norfenfluramine: fenfluramine and norfenfluramine are not substrates of the P-g, BCRP, OAT1, OAT3, OCT2, MATE1, or MATE2-K transporters.Effect of FINTEPLA on Transporters: fenfluramine and norfenfluramine are not inhibitors of P-gp, BCRP, OAT1B1, OATP1B3, OAT1, OAT3, OCT2, MATE1, or MATE2-K transporters.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. The effectiveness of FINTEPLA for the treatment of seizures associated with Dravet syndrome in patients years of age and older was established in two randomized, double-blind, placebo-controlled trials in patients to 18 years of age.Study (N=117) compared 0.7 mg/kg/day and 0.2 mg/kg/day dose of FINTEPLA with placebo in patients who were not receiving stiripentol (NCT02682927 and NCT02826863). Study (N=85) compared 0.4 mg/kg/day dose of FINTEPLA with placebo in patients who were receiving stiripentol and either clobazam, valproate, or both (NCT02926898). In both studies, patients had clinical diagnosis of Dravet syndrome and were inadequately controlled on at least one AED or other antiseizure treatment including vagal nerve stimulation or ketogenic diet. Both trials had 6-week baseline period, during which patients were required to have minimum of convulsive seizures while on stable AED therapy. Convulsive seizures included tonic, clonic, generalized tonic-clonic, tonic-atonic, secondarily generalized tonic-clonic, hemiclonic, and focal with observable motor signs. The baseline period was followed by randomization into 2-week (Study 1) or 3-week (Study 2) titration period and subsequent 12-week maintenance period, where the dose of FINTEPLA remained stable.In Study 1, 98% of patients were taking between and concomitant AEDs. The most frequently used concomitant AEDs (in at least 25% of patients), were valproate (61%), clobazam (59%), and topiramate (25%). In Study 2, 100% of patients were taking between and concomitant AEDs. The most frequently used concomitant AEDs (in at least 25% of patients), were stiripentol (100%), clobazam (94%), and valproate (89%).The primary efficacy endpoint in both studies was the change from baseline in the frequency of convulsive seizures per 28 days during the combined 14-week (Study 1) or 15-week (Study 2) titration and maintenance periods (i.e., treatment period). The median longest interval between convulsive seizures was also assessed. In Study and Study 2, the reduction in convulsive seizure frequency per 28 days was statistically significantly greater for all dose groups of FINTEPLA compared to placebo (Table 4). reduction in convulsive seizures was observed within to weeks of starting FINTEPLA, and the effect remained generally consistent over the 14- or 15-week treatment period.Table 4:Change in Convulsive Seizure Frequency During the Treatment Period in Patients with Dravet Syndrome (Study and Study 2)Derived from the primary analysis model+-All 0.4 mg/kg/day patients were also taking concomitant stiripentol, which increases the exposure of FINTEPLA. Convulsive Seizure Frequency (per 28 days)Placebo FINTEPLA0.2 mg/kg/day FINTEPLA0.7 mg/kg/day FINTEPLA0.4 mg/kg/day Study 1N=39N=38N=40NA Baseline Period Median29.418.118.7NA Difference Relative to Placebo-31.7%-70.0%NA p-value compared to placebo0.043<0.001 Study 2N=42NANAN=43 Baseline Period Median11.5NANA15.0 Difference Relative to PlaceboNANA-59.5% p-value compared to placebo<0.001Figure and Figure display the percentage of patients by category of seizure response from baseline in convulsive seizure frequency (per 28 days) during the treatment period in Study and Study 2, respectively. Figure 1: Proportion of Patients by Category of Seizure Response for FINTEPLA and Placebo in Patients with Dravet Syndrome (Study 1)Figure 2: Proportion of Patients by Category of Seizure Response for FINTEPLA and Placebo in Patients with Dravet Syndrome (Study 2)In Study 1, of 40 (8%) patients in the FINTEPLA 0.7 mg/kg/day group and of 38 (8%) patients in the FINTEPLA 0.2 mg/kg/day group reported no convulsive seizures during the 14-week treatment period, compared to patients in the placebo group. In Study 2, of 43 (2%) patients in the FINTEPLA 0.4 mg/kg/day group reported no convulsive seizures during the 15-week treatment period, compared to patients in the placebo group.In Study and Study 2, FINTEPLA was associated with statistically significant longer interval between convulsive seizures compared to placebo (Figure 3). Figure 3: Median Longest Interval Between Convulsive Seizures in Patients with Dravet Syndrome (Study and Study 2). Figure 1. Figure 2. Figure 3.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. FINTEPLA is to be administered orally and may be taken with or without food. (2.2)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)Patients not on concomitant stiripentol: The maximum daily maintenance dosage of FINTEPLA is 0.35 mg/kg twice daily (maximum daily dosage of 26 mg). (2.2)Patients taking concomitant stiripentol plus clobazam: The maximum daily maintenance dosage of FINTEPLA for patients taking these medications is 0.2 mg/kg twice daily (maximum daily dosage of 17 mg). (2.2). FINTEPLA is to be administered orally and may be taken with or without food. (2.2). 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). Patients not on concomitant stiripentol: The maximum daily maintenance dosage of FINTEPLA is 0.35 mg/kg twice daily (maximum daily dosage of 26 mg). (2.2). Patients taking concomitant stiripentol plus clobazam: The maximum daily maintenance dosage of FINTEPLA for patients taking these medications is 0.2 mg/kg twice daily (maximum daily dosage of 17 mg). (2.2). 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 (2.4) and Warnings and Precautions (5.1, 5.2)].. 2.2 Dosing Information FINTEPLA is to be administered orally and may be taken with or without food.The initial starting and maintenance dosage is 0.1 mg/kg twice daily, which can be increased weekly based on efficacy and tolerability. Table provides the recommended titration schedule, if needed.Patients not on concomitant stiripentol who are tolerating FINTEPLA at 0.1 mg/kg twice daily and require further reduction of seizures may benefit from dosage increase up to maximum recommended maintenance dosage of 0.35 mg/kg twice daily (maximum daily dosage of 26 mg).Patients taking concomitant stiripentol and clobazam who are tolerating FINTEPLA at 0.1 mg/kg twice daily and require further reduction of seizures may benefit from dosage increase up to maximum 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 more rapid titration is warranted, the dose may be increased every daysWithout concomitant stiripentolWith concomitant stiripentol and clobazamWeight-based DosageMaximum Total Daily DosageWeight-based DosageMaximum Total Daily Dosage Initial Dosage0.1 mg/kg twice daily26 mg0.1 mg/kg twice daily17 mg Day 0.2 mg/kg twice daily26 mg0.15 mg/kg twice daily17 mg Day 140.35 mg/kg twice daily26 mg0.2 mg/kg twice daily17 mg. FINTEPLA is to be administered orally and may be taken with or without food.. The initial starting and maintenance dosage is 0.1 mg/kg twice daily, which can be increased weekly based on efficacy and tolerability. Table provides the recommended titration schedule, if needed.. Patients not on concomitant stiripentol who are tolerating FINTEPLA at 0.1 mg/kg twice daily and require further reduction of seizures may benefit from dosage increase up to maximum recommended maintenance dosage of 0.35 mg/kg twice daily (maximum daily dosage of 26 mg).. Patients taking concomitant stiripentol and clobazam who are tolerating FINTEPLA at 0.1 mg/kg twice daily and require further reduction of seizures may benefit from dosage increase up to maximum recommended maintenance dosage of 0.2 mg/kg twice daily (maximum daily dosage of 17 mg) [see Drug Interactions (7.1)]. 2.3Assessments During and After Administration of FINTEPLA. To evaluate for valvular heart disease and pulmonary arterial hypertension, obtain an echocardiogram assessment every months during treatment with FINTEPLA, and to months after the final dose of FINTEPLA [see Warnings and Precautions (5.1, 5.2)].. 2.4Administration Instructions. calibrated measuring device (either 3 mL or 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)]. household teaspoon or tablespoon is not an adequate measuring device and should not be used. Discard any unused FINTEPLA oral solution remaining after 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.. 2.5Discontinuation 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 (5.7)].

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).Administration InformationAdvise patients who are prescribed FINTEPLA to use the oral dosing syringes provided by the pharmacy [see Dosage and Administration (2.5) and Instructions for Use]. Instruct patients to discard any unused FINTEPLA months after first opening the bottle or if the discard after date on the dispensing bottle has passed, whichever is sooner [see How Supplied/Storage and Handling (16.2)].Valvular Heart Disease and Pulmonary Arterial HypertensionAdvise patients that cardiac monitoring must be performed using echocardiography to monitor for serious heart valve changes or high blood pressure in the arteries of the lungs [see Warnings and Precautions (5.1, 5.2)].FINTEPLA REMS ProgramFINTEPLA is available only through restricted program called the FINTEPLA REMS program [see Warnings and Precautions (5.3)]. Inform the patient of the following notable requirements:Patients must enroll in the program and comply with ongoing echocardiogram monitoring requirements [see Warnings and Precautions (5.1, 5.2)].FINTEPLA is only prescribed by certified health care providers and only dispensed from certified pharmacies participating in the program. Therefore, provide patients with the telephone number and website for information on how to obtain the product [see Warnings and Precautions (5.3)].Decreased Appetite and Decreased WeightAdvise patients that decreased appetite is frequent during treatment with FINTEPLA, which can cause decrease in weight [see Warnings and Precautions (5.4)]. Somnolence, Sedation, and LethargyInform patients that FINTEPLA can cause somnolence, sedation, and lethargy. Caution patients about operating hazardous machinery, including motor vehicles, until they are reasonably certain that FINTEPLA does not affect them adversely (eg, impair judgment, thinking, or motor skills) [see Warnings and Precautions (5.5)].Suicidal Thinking and Behavior Counsel patients, their caregivers, and their families that antiepileptic drugs may increase the risk of suicidal thoughts and behavior and advise them to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts of self-harm. Instruct patients, caregivers, and families to report behaviors of concern immediately to healthcare providers [see Warnings and Precautions (5.6)].Withdrawal of Antiepileptic Drugs (AEDs)Advise patients not to discontinue use of FINTEPLA without consulting with their healthcare provider. FINTEPLA should normally be gradually withdrawn to reduce the potential for increased seizure frequency and status epilepticus [see Dosage and Administration (2.3), Warnings and Precautions (5.7)].Serotonin SyndromeInform patients about the risk of serotonin syndrome, which can be life-threatening. Advise patients on the signs and symptoms of serotonin syndrome and that certain over-the-counter and herbal supplements can increase this risk [see Warnings and Precautions (5.8)].Increase in Blood PressureInform patients that FINTEPLA can cause an increase in blood pressure [see Warnings and Precautions (5.9)].GlaucomaInform patients that FINTEPLA can cause mydriasis and can precipitate angle closure glaucoma. Instruct patients to contact their healthcare provider if they have any acute decreases in visual acuity or ocular pain [see Warnings and Precautions (5.10)].Pregnancy RegistryAdvise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during FINTEPLA therapy. Encourage women who are taking FINTEPLA to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy [see Use in Specific Populations (8.1)].Marketed by: Zogenix, Inc.5959 Horton Street, Suite 500, Emeryville CA, 94608. Patients must enroll in the program and comply with ongoing echocardiogram monitoring requirements [see Warnings and Precautions (5.1, 5.2)].

INSTRUCTIONS FOR USE SECTION.

INSTRUCTIONS FOR USEFINTEPLA (TM) (fin-TEP-la)(fenfluramine)oral solution, C-IV2.2 mg/mLBe sure that you read, understand, and follow these instructions before you start using FINTEPLA oral solution and each time you get refill. There may be new information.This Instructions for Use contains information on how to take FINTEPLA. This information does not take the place of talking to your healthcare provider about your medical condition or treatment.What is included with FINTEPLAThe following texts are included to prepare and give an oral dose of FINTEPLA:1 bottle of FINTEPLA oral solution (2.2 mg/mL) reusable oral syringes Call the pharmacist at 1-844-288-5007 if you did not receive the texts listed above, or if you need help using them.Important information about FINTEPLAFINTEPLA is an oral medicine (taken by mouth) and is given times each day. Follow your healthcare providers instructions for taking or giving doses of FINTEPLA.If you have questions about how to prepare or give FINTEPLA, contact your healthcare provider or call your pharmacist.Always use the oral syringes provided with FINTEPLA to make sure the right dose is given. If you need new syringe contact your pharmacist. Do not use household teaspoon or tablespoon.Oral syringes provided with FINTEPLA by the pharmacy.With FINTEPLA you will receive reusable oral syringes. oral syringes that can measure up to mL OR oral syringes that can measure up to mLCall the pharmacist at 1-844-288-5007 if you have any questions about the syringes provided with FINTEPLAThis Instructions for Use has been approved by the U.S. Food and Drug Administration.Approved: 06/2020Step 1. Make sure you have:The bottle of FINTEPLA oral solution, and clean, dry reusable syringe that was provided with FINTEPLA.Step 2. Check the Discard After date (MM/DD/YYYY).Do not use the medicine if the Discard After (Throw Away) date has passed.If the date is near, contact your pharmacy or healthcare provider to get refill or new prescription.If the date has passed, dispose of any unused FINTEPLA. Step 3. Press down and turn the childproof cap to the left (counterclockwise) and remove it from the bottle..Set the cap aside (do not throw away).Step 4. Make sure the adapter is on the bottle.If the bottle does not have an adapter, contact the pharmacist. Always leave the adapter in place in the bottle of medicine.Step 5. Remove an oral syringe from its packaging, if needed.Only use the oral syringes provided with FINTEPLA.If an oral syringe is damaged, or you cannot read the dose markings:Use the other oral syringe provided, or Contact the pharmacist to get new one.Step 6. Make sure the plunger is pushed all the way into the oral syringe. Step 7. Hold the bottle of medicine firmly on hard, flat surface. Step 8. Push the tip of the oral syringe into the opening of the adapter until it cannot be pushed further. Preparing dose (continued)Step 9. Hold the oral syringe and bottle together and turn upside down.Step 10. Slowly pull the plunger of the oral syringe to withdraw the prescribed dose.Preparing dose (continued)Step 11. Line up the end of the plunger with the mark for the prescribed dose on the oral syringe. Tips to Getting the Correct Dose If you draw out too much medicine:Leave the oral syringe in the adapter. Push the plunger slowly back into the syringe until you reach the prescribed dose. If you see air bubbles in the medicine:Leave the oral syringe in the adapter.Pull the plunger further down.Allow the bubbles to rise to the tip of the syringe.Push the plunger in all the way.Slowly pull the plunger out to the prescribed dose. Note: Very small bubbles in the liquid are normal. Step 12. Step 12. Hold the oral syringe and bottle together and then turn the bottle right side up..Step 13. Step 13. Holding the bottle firmly, gently pull the oral syringe out of the bottle adapter.Step 14. Make sure the dose in the oral syringe still matches the prescribed dose. If the dose does not match: Put the syringe back into adapter.Refer to steps 9-11 to adjust the dose, as needed. Giving FINTEPLAStep 15. Place the tip of the oral syringe against the inside of the cheek. Step 16. Gently push the plunger in until all the medicine in the oral syringe is given. Do not squirt or forcefully push the medicine into the back of the throat. This may cause choking. Step 17. Place the cap back on the bottle tightly by turning the cap right (clockwise) until it stops. Always leave the adapter in place in the bottle The cap will fit over it. Cleaning the syringeRinse the oral syringe with clean tap water and allow it to air dry after each use. Make sure you rinse the inside of the syringe and the plunger.Cleaning Tips:Pull clean tap water into the syringe with the plunger and push it out several times to clean the syringe.Remove the plunger from the barrel of the oral syringe Rinse both parts under tap waterMake sure the syringe and plunger are completely dry before the next use.The syringe is also safe to clean in the dishwasher.How should store FINTEPLAStore FINTEPLA at room temperature between 68 and 77 (20 and 25).Do not refrigerate or freeze.Keep the cap tightly closed and the bottle upright.Store the FINTEPLA bottle and syringe together in clean area.Throw away (discard) any unused FINTEPLA months after first opening the bottle or if the Discard After date on the package or bottle has passed. Whichever one comes first.Keep FINTEPLA and all medicines out of the reach of children.Marketed by: Zogenix Inc. 5959 Horton Street, Suite 500, Emeryville CA, 94608. bottle of FINTEPLA oral solution (2.2 mg/mL) 2 reusable oral syringes FINTEPLA is an oral medicine (taken by mouth) and is given times each day. Follow your healthcare providers instructions for taking or giving doses of FINTEPLA.. If you have questions about how to prepare or give FINTEPLA, contact your healthcare provider or call your pharmacist.. Always use the oral syringes provided with FINTEPLA to make sure the right dose is given. If you need new syringe contact your pharmacist. Do not use household teaspoon or tablespoon.. The bottle of FINTEPLA oral solution, and A clean, dry reusable syringe that was provided with FINTEPLA.. Do not use the medicine if the Discard After (Throw Away) date has passed.. If the date is near, contact your pharmacy or healthcare provider to get refill or new prescription.. If the date has passed, dispose of any unused FINTEPLA. Set the cap aside (do not throw away).. If the bottle does not have an adapter, contact the pharmacist. Always leave the adapter in place in the bottle of medicine.. Use the other oral syringe provided, or Contact the pharmacist to get new one.. If you draw out too much medicine:Leave the oral syringe in the adapter. Push the plunger slowly back into the syringe until you reach the prescribed dose. Leave the oral syringe in the adapter. Push the plunger slowly back into the syringe until you reach the prescribed dose.. If you see air bubbles in the medicine:Leave the oral syringe in the adapter.Pull the plunger further down.Allow the bubbles to rise to the tip of the syringe.Push the plunger in all the way.Slowly pull the plunger out to the prescribed dose. Leave the oral syringe in the adapter.. Pull the plunger further down.. Allow the bubbles to rise to the tip of the syringe.. Push the plunger in all the way.. Slowly pull the plunger out to the prescribed dose.. Put the syringe back into adapter.. Refer to steps 9-11 to adjust the dose, as needed.. Do not squirt or forcefully push the medicine into the back of the throat. This may cause choking.. Always leave the adapter in place in the bottle The cap will fit over it.. Rinse the oral syringe with clean tap water and allow it to air dry after each use. Make sure you rinse the inside of the syringe and the plunger.. Pull clean tap water into the syringe with the plunger and push it out several times to clean the syringe.. Remove the plunger from the barrel of the oral syringe Rinse both parts under tap water. Make sure the syringe and plunger are completely dry before the next use.. The syringe is also safe to clean in the dishwasher.. Store FINTEPLA at room temperature between 68 and 77 (20 and 25).. Do not refrigerate or freeze.. Keep the cap tightly closed and the bottle upright.. Store the FINTEPLA bottle and syringe together in clean area.. Throw away (discard) any unused FINTEPLA months after first opening the bottle or if the Discard After date on the package or bottle has passed. Whichever one comes first.. Keep FINTEPLA and all medicines out of the reach of children.. ifu4. ifu5. ifu6. ifu7. ifu8. ifu9. ifu10. ifu11. ifu12. ifu13. ifu15. ifu16. ifu17. ifu18. ifu19. ifu20. ifu21. ifu22. ifu23.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. The pharmacokinetics of fenfluramine and norfenfluramine were studied in healthy subjects and in pediatric patients with Dravet syndrome. The steady-state systemic exposure (Cmax and AUC) of fenfluramine was slightly greater than dose proportional over the dose range of 13 to 51.8 mg twice-daily fenfluramine (i.e., to times the maximum recommended dose). In pediatric patients who received FINTEPLA 0.7 mg/kg/day, up to total daily dose of 26 mg fenfluramine, the geometric mean steady-state fenfluramine (coefficient of variation) Cmax was 68.0 (41%) ng/mL and AUC0-24h was 1390 (44%) ngh/mL.AbsorptionFenfluramine has time to maximum plasma concentration (Tmax) of to hours at steady state. The absolute bioavailability of fenfluramine is approximately 68-74%. There was no effect of food on the pharmacokinetics of fenfluramine or norfenfluramine.DistributionThe geometric mean (CV%) apparent volume of distribution (Vz/F) of fenfluramine is 11.9 (16.5%) L/kg following oral administration of FINTEPLA in healthy subjects. Fenfluramine is 50% bound to human plasma proteins in vitro and binding is independent of drug concentrations. EliminationThe elimination half-life of fenfluramine was 20 hours and the geometric mean (CV%) clearance (CL/F) was 24.8 (29%) L/h, following oral administration of FINTEPLA in healthy subjects.MetabolismOver 75% of fenfluramine is metabolized to norfenfluramine prior to elimination, primarily by CYP1A2, CYP2B6, and CYP2D6. Other CYP enzymes involved to minor extent are CYP2C9, CYP2C19, and CYP3A4/5. Norfenfluramine is then deaminated and oxidized to form inactive metabolites.ExcretionMost of an orally administered dose of fenfluramine (greater than 90%) is excreted in the urine as fenfluramine, norfenfluramine, or other metabolites with fenfluramine and norfenfluramine accounting for less than 25% of the total; less than 5% is found in feces. Specific PopulationsThe effect of age (range: to 50 years), sex, and race had no clinically meaningful effect on the pharmacokinetics of fenfluramine.Drug Interaction Studies Clinical StudiesEffect of single dose of stiripentol, clobazam, and valproic acid combination: Coadministration of single 0.7 mg/kg dose of FINTEPLA, with single dose of stiripentol, clobazam, and valproic acid combination in health volunteers, increased the AUC0-INF of fenfluramine by 69% and the Cmax by 18%, and decreased the AUC0-72 hours of norfenfluramine by 41% and the Cmax by 42%, as compared to FINTEPLA administered alone. Effect of steady state stiripentol plus clobazam, with or without valproate: Fenfluramine pharmacokinetic data were collected from patients after receiving multiple fenfluramine administrations in Study as well as Study 2. Population pharmacokinetic modeling and simulation were used to assess the effect of stiripentol plus clobazam with or without valproate on fenfluramine pharmacokinetics. The effect of stiripentol plus clobazam, with or without valproate, on fenfluramine pharmacokinetics is greater when FINTEPLA is at steady-state than for the first dose of FINTEPLA. When initiating FINTEPLA therapy, coadministration of existing stiripentol plus clobazam with or without valproate is expected to increase the AUC0-24 of the first fenfluramine dose by up to 42% in the patient population. At steady state in the patient population, the coadministration of 0.1 mg/kg twice daily (0.2 mg/kg/day), maximum 17 mg/day, of FINTEPLA with stiripentol plus clobazam with or without valproate, is expected to result in 166% increase in fenfluramine AUC0-24 and 38% decrease in norfenfluramine AUC0-24, as compared to 0.2 mg/kg/day, maximum 26 mg/day, FINTEPLA dose administered alone [see Dosage and Administration (2.1, 2.2) and Drug Interactions (7.1)].Effect of steady state cannabidiol: Coadministration of single 0.35 mg/kg dose of FINTEPLA 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 FINTEPLA administered alone. This interaction is not expected to be clinically significant. Effect of FINTEPLA on other drugs: Coadministration of single 0.7 mg/kg dose of FINTEPLA, with single dose of stiripentol, clobazam, and valproic acid combination, did not affect the pharmacokinetics of stiripentol, nor the pharmacokinetics of clobazam or its N-desmethyl-metabolite norclobazam, nor the pharmacokinetics of valproic acid, as compared to the stiripentol, clobazam, and valproic acid combination alone. Coadministration of single 0.35 mg/kg dose of FINTEPLA, with repeated doses of cannabidiol, did not affect the pharmacokinetics of cannabidiol, as compared to cannabidiol alone.In Vitro StudiesFenfluramine is primarily metabolized by CYP1A2, CYP2B6, and CYP2D6 in vitro. Other CYP enzymes involved to minor extent are CYP2C9, CYP2C19, and CYP3A4/5.Effect of fenfluramine and norfenfluramine on CYP Substrates: fenfluramine and norfenfluramine are not inhibitors or inducers of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4 at clinically relevant concentrations.Effect of transporters on fenfluramine and norfenfluramine: fenfluramine and norfenfluramine are not substrates of the P-g, BCRP, OAT1, OAT3, OCT2, MATE1, or MATE2-K transporters.Effect of FINTEPLA on Transporters: fenfluramine and norfenfluramine are not inhibitors of P-gp, BCRP, OAT1B1, OATP1B3, OAT1, OAT3, OCT2, MATE1, or MATE2-K transporters.

SPL MEDGUIDE SECTION.

This Medication Guide has been approved by the U.S. Food and Drug Administration.Revised: 06/2020MEDICATION GUIDEFINTEPLA(R) (fin-TEP-la)(fenfluramine)oral solution, for C-IVRead this Medication Guide before you start taking FINTEPLA and each time you get refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment.What is the most important information should know about FINTEPLAFINTEPLA can cause serious side effects, including:Problems with the valves in the heart (valvular heart disease) and high blood pressure in the arteries of the lungs (pulmonary arterial hypertension) have been associated with fenfluramine, the active ingredient in FINTEPLA. Your healthcare provider will do test called an echocardiogram to check your heart and for high blood pressure in the arteries of the lungs before you start taking FINTEPLA, again every months during treatment, and one time to months after you take your last dose of FINTEPLA. Call your healthcare provider right away if you develop any of these signs and symptoms of heart or lung problems during treatment with FINTEPLA: shortness of breathtiredness or weakness, especially with increased activity lightheadedness or faintingswollen ankles or feetchest painsensations of rapid, fluttering heartbeat (palpitations)irregular pulsebluish color to your lips and skin (cyanosis) Because of the risk of heart valve problems and pulmonary arterial hypertension FINTEPLA is only available through restricted program called the FINTEPLA Risk Evaluation and Mitigation (REMS) Program. Before you or your child receives FINTEPLA, your healthcare provider or pharmacist will make sure you understand how to take FINTEPLA safely. If you have any questions about FINTEPLA, ask your healthcare provider, visit www.FinteplaREMS.com, or call 1-877-964-3649. Decreased appetite and decreased weight. Decreased appetite and decreased weight are both serious and common side effects. Your weight should be checked regularly during your treatment with FINTEPLA. Your healthcare provider may need to make changes to your FINTEPLA dose if your weight decreases. In some cases, FINTEPLA may need to be stopped. Sleepiness, sedation, and lack of energy (lethargy). These are both serious and common side effects of FINTEPLA. Taking FINTEPLA with central nervous system (CNS) depressants including alcohol may increase sleepiness. Do not drive, operate heavy machinery, or do other dangerous activities until you know how FINTEPLA affects you.Like all other antiepileptic drugs, FINTEPLA may cause suicidal thoughts or actions in very small number of people (about in 500). Call your healthcare provider right away if you have any of these symptoms, especially if they are new, worse, or worry you: thoughts about suicide or dyingtrouble sleeping (insomnia)attempts to commit suicidenew or worse irritabilitynew or worse depressionacting aggressive, being angry, or violentnew or worse anxietyacting on dangerous impulsesfeeling agitated or restlessan extreme increase in activity and talking (mania)panic attacksother unusual changes in behavior or mood How can watch for early symptoms of suicidal thoughts and actions Pay attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings.Keep all follow-up visits with your healthcare provider as scheduled. Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal thoughts or actions, your healthcare provider may check for other causes. Do not stop taking FINTEPLA without first talking to your healthcare provider. Stopping seizure medicine such as FINTEPLA suddenly can cause you to have seizures more often or seizures that do not stop (status epilepticus).Call your healthcare provider between visits as needed, especially if you are worried about symptoms.What is FINTEPLAFINTEPLA is prescription medicine used to treat the seizures associated with Dravet syndrome in patients years of age and older.FINTEPLA is federally controlled substance (C-IV) because it contains fenfluramine. Keep FINTEPLA in safe place to prevent misuse, abuse, and protect it from theft. Never give your FINTEPLA to anyone else, because it may harm them. Selling or giving away this medicine is against the law. Tell your healthcare provider if you have abused or been dependent on alcohol, prescription medicines, or street drugs.It is not known if FINTEPLA is safe and effective in children less than years of age.Do not take FINTEPLA if you:are allergic to fenfluramine or any of the ingredients in FINTEPLA. See the end of this Medication Guide for complete list of ingredients in FINTEPLA.are taking or have stopped taking medicines called monoamine oxidase inhibitors (MAOI), serotonin agonists or serotonin reuptake inhibitors in the last 14 days. This may cause serious or life-threatening problem called serotonin syndrome. If you are not sure whether or not you are taking one of these medicines, contact your healthcare provider.Before taking FINTEPLA, tell your healthcare provider about all of your medical conditions, including if you:have heart problemshave or have had weight losshave or have had depression, mood problems, or suicidal thoughts or behaviorhave liver problemshave kidney problemsare pregnant or plan to become pregnant. Tell your healthcare provider right away if you become pregnant while taking FINTEPLA. You and your healthcare provider will decide if you should take FINTEPLA while you are pregnant.If you become pregnant while taking FINTEPLA, talk to your healthcare provider about registering with the North American Antiepileptic Drug Pregnancy Registry. You can enroll in this registry by calling 1-888-233-2334 or go to www. aedpregnancyregistry.org. The purpose of this registry is to collect information about the safety of antiepileptic drugs during pregnancy. are breastfeeding or plan to breastfeed. It is not known if FINTEPLA passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby while taking FINTEPLA.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.Know the medicines you take. Keep list of them to show your healthcare provider or pharmacist when you get new medicine.How should take FINTEPLARead the Instructions for Use at the end of this Medication Guide for information on the right way to use FINTEPLA.Take FINTEPLA exactly as your healthcare provider tells you to take it.Your healthcare provider will tell you how much FINTEPLA to take and when to take it.FINTEPLA may be taken with or without food.Measure your dose of FINTEPLA using the dosing syringe that is provided by the pharmacy. Do not use household teaspoon or tablespoon.FINTEPLA can be given through gastric and nasogastric feeding tubesWhat should avoid while taking FINTEPLADo not drive, operate heavy machinery, or do other dangerous activities until you know how FINTEPLA affects you. FINTEPLA may cause you to feel sleepy.What are the possible side effects of FINTEPLAFINTEPLA may cause serious side effects, including:See What is the most important information should know about FINTEPLA serotonin syndrome. Serotonin syndrome is life-threatening problem that can happen in people taking FINTEPLA, especially if FINTEPLA is taken with certain other medicines to include: anti-depressant medicines called SSRIs, SNRIs, TCAs, and MAOIstryptophanlithiumantipsychoticsSt. Johns Wortdextromethorphantramadol Call your healthcare provider right away if you have any of the following symptoms of serotonin syndrome. mental status changes such as seeing things that are not there (hallucinations), agitation, or comachanges in blood pressuretight musclesfast heartbeatnausea, vomiting, diarrheahigh body temperaturetrouble walking high blood pressure (hypertension). Hypertension is both serious and common side effect. FINTEPLA can cause your blood pressure to increase even if you have never had high blood pressure before. Your healthcare provider will check your blood pressure while you are taking FINTEPLA.increased pressure in your eye (glaucoma). Symptoms of glaucoma may include:red eyesseeing halos or bright colors around lightsnausea or vomitingdecreased vision eye pain or discomfortblurred vision If you have any of these symptoms, call your healthcare provider right away. The most common side effects of FINTEPLA include: diarrhealow energyrespiratory infectiontirednessfeverconstipationabnormal echocardiogramproblems with movement, balance, and walkingincreased droolinginfectionvomitingfallsseizures that do not stopweakness These are not all the possible side effects of FINTEPLA. For more information, ask your healthcare provider or pharmacist. Tell your healthcare provider if you have any side effect that bothers you or that does not go away. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should store FINTEPLAStore FINTEPLA at room temperature between 68F to 77F (20C and 25C).Do not refrigerate or freeze.Store the FINTEPLA bottle and syringe together in clean area.Throw away (discard) any unused FINTEPLA months after first opening the bottle or if the Discard After date on the package or bottle has passed. Whichever one comes first.Keep FINTEPLA and all medicines out of the reach of children.General information about the safe and effective use of FINTEPLA.Medicines are sometimes prescribed for purposes other than those listed in Medication Guide. Do not use FINTEPLA for condition for which it was not prescribed. Do not give FINTEPLA to other people, even if they have the same symptoms that you have. It may harm them.You can ask your pharmacist or healthcare provider for information about FINTEPLA that is written for health professionals.What are the ingredients in FINTEPLAActive ingredient: fenfluramine hydrochlorideInactive ingredients: cherry flavor, citric acid, ethylparaben, hydroxyethylcellulose, methylparaben, potassium citrate, sucralose, and water.FINTEPLA contains no ingredient made from gluten-containing grain (wheat, barley, or rye). Marketed by: Zogenix Inc.5959 Horton Street, Suite 500, Emeryville CA, 94608 For more information about FINTEPLA, go to www.fintepla.com or call 1-866-964-3649. Problems with the valves in the heart (valvular heart disease) and high blood pressure in the arteries of the lungs (pulmonary arterial hypertension) have been associated with fenfluramine, the active ingredient in FINTEPLA. Your healthcare provider will do test called an echocardiogram to check your heart and for high blood pressure in the arteries of the lungs before you start taking FINTEPLA, again every months during treatment, and one time to months after you take your last dose of FINTEPLA. Call your healthcare provider right away if you develop any of these signs and symptoms of heart or lung problems during treatment with FINTEPLA: shortness of breathtiredness or weakness, especially with increased activity lightheadedness or faintingswollen ankles or feetchest painsensations of rapid, fluttering heartbeat (palpitations)irregular pulsebluish color to your lips and skin (cyanosis) Because of the risk of heart valve problems and pulmonary arterial hypertension FINTEPLA is only available through restricted program called the FINTEPLA Risk Evaluation and Mitigation (REMS) Program. Before you or your child receives FINTEPLA, your healthcare provider or pharmacist will make sure you understand how to take FINTEPLA safely. If you have any questions about FINTEPLA, ask your healthcare provider, visit www.FinteplaREMS.com, or call 1-877-964-3649. shortness of breath. tiredness or weakness, especially with increased activity lightheadedness or fainting. swollen ankles or feet. chest pain. sensations of rapid, fluttering heartbeat (palpitations). irregular pulse. bluish color to your lips and skin (cyanosis). Decreased appetite and decreased weight. Decreased appetite and decreased weight are both serious and common side effects. Your weight should be checked regularly during your treatment with FINTEPLA. Your healthcare provider may need to make changes to your FINTEPLA dose if your weight decreases. In some cases, FINTEPLA may need to be stopped. Your weight should be checked regularly during your treatment with FINTEPLA. Your healthcare provider may need to make changes to your FINTEPLA dose if your weight decreases. In some cases, FINTEPLA may need to be stopped. Sleepiness, sedation, and lack of energy (lethargy). These are both serious and common side effects of FINTEPLA. Taking FINTEPLA with central nervous system (CNS) depressants including alcohol may increase sleepiness. Do not drive, operate heavy machinery, or do other dangerous activities until you know how FINTEPLA affects you.. Like all other antiepileptic drugs, FINTEPLA may cause suicidal thoughts or actions in very small number of people (about in 500). Call your healthcare provider right away if you have any of these symptoms, especially if they are new, worse, or worry you: thoughts about suicide or dyingtrouble sleeping (insomnia)attempts to commit suicidenew or worse irritabilitynew or worse depressionacting aggressive, being angry, or violentnew or worse anxietyacting on dangerous impulsesfeeling agitated or restlessan extreme increase in activity and talking (mania)panic attacksother unusual changes in behavior or mood How can watch for early symptoms of suicidal thoughts and actions Pay attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings.Keep all follow-up visits with your healthcare provider as scheduled. Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal thoughts or actions, your healthcare provider may check for other causes. thoughts about suicide or dying. trouble sleeping (insomnia). attempts to commit suicide. new or worse irritability. new or worse depression. acting aggressive, being angry, or violent. new or worse anxiety. acting on dangerous impulses. feeling agitated or restless. an extreme increase in activity and talking (mania). panic attacks. other unusual changes in behavior or mood. Pay attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings.. Keep all follow-up visits with your healthcare provider as scheduled.. Do not stop taking FINTEPLA without first talking to your healthcare provider. Stopping seizure medicine such as FINTEPLA suddenly can cause you to have seizures more often or seizures that do not stop (status epilepticus).Call your healthcare provider between visits as needed, especially if you are worried about symptoms.. FINTEPLA is prescription medicine used to treat the seizures associated with Dravet syndrome in patients years of age and older.. FINTEPLA is federally controlled substance (C-IV) because it contains fenfluramine. Keep FINTEPLA in safe place to prevent misuse, abuse, and protect it from theft. Never give your FINTEPLA to anyone else, because it may harm them. Selling or giving away this medicine is against the law. Tell your healthcare provider if you have abused or been dependent on alcohol, prescription medicines, or street drugs.. It is not known if FINTEPLA is safe and effective in children less than years of age.. are allergic to fenfluramine or any of the ingredients in FINTEPLA. See the end of this Medication Guide for complete list of ingredients in FINTEPLA.. are taking or have stopped taking medicines called monoamine oxidase inhibitors (MAOI), serotonin agonists or serotonin reuptake inhibitors in the last 14 days. This may cause serious or life-threatening problem called serotonin syndrome. If you are not sure whether or not you are taking one of these medicines, contact your healthcare provider.. have heart problems. have or have had weight loss. have or have had depression, mood problems, or suicidal thoughts or behavior. have liver problems. have kidney problems. are pregnant or plan to become pregnant. Tell your healthcare provider right away if you become pregnant while taking FINTEPLA. You and your healthcare provider will decide if you should take FINTEPLA while you are pregnant.If you become pregnant while taking FINTEPLA, talk to your healthcare provider about registering with the North American Antiepileptic Drug Pregnancy Registry. You can enroll in this registry by calling 1-888-233-2334 or go to www. aedpregnancyregistry.org. The purpose of this registry is to collect information about the safety of antiepileptic drugs during pregnancy. If you become pregnant while taking FINTEPLA, talk to your healthcare provider about registering with the North American Antiepileptic Drug Pregnancy Registry. You can enroll in this registry by calling 1-888-233-2334 or go to www. aedpregnancyregistry.org. The purpose of this registry is to collect information about the safety of antiepileptic drugs during pregnancy.. are breastfeeding or plan to breastfeed. It is not known if FINTEPLA passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby while taking FINTEPLA.. Read the Instructions for Use at the end of this Medication Guide for information on the right way to use FINTEPLA.. Take FINTEPLA exactly as your healthcare provider tells you to take it.. Your healthcare provider will tell you how much FINTEPLA to take and when to take it.. FINTEPLA may be taken with or without food.. Measure your dose of FINTEPLA using the dosing syringe that is provided by the pharmacy. Do not use household teaspoon or tablespoon.. FINTEPLA can be given through gastric and nasogastric feeding tubes. Do not drive, operate heavy machinery, or do other dangerous activities until you know how FINTEPLA affects you. FINTEPLA may cause you to feel sleepy.. See What is the most important information should know about FINTEPLA serotonin syndrome. Serotonin syndrome is life-threatening problem that can happen in people taking FINTEPLA, especially if FINTEPLA is taken with certain other medicines to include: anti-depressant medicines called SSRIs, SNRIs, TCAs, and MAOIstryptophanlithiumantipsychoticsSt. Johns Wortdextromethorphantramadol Call your healthcare provider right away if you have any of the following symptoms of serotonin syndrome. mental status changes such as seeing things that are not there (hallucinations), agitation, or comachanges in blood pressuretight musclesfast heartbeatnausea, vomiting, diarrheahigh body temperaturetrouble walking high blood pressure (hypertension). Hypertension is both serious and common side effect. FINTEPLA can cause your blood pressure to increase even if you have never had high blood pressure before. Your healthcare provider will check your blood pressure while you are taking FINTEPLA.increased pressure in your eye (glaucoma). Symptoms of glaucoma may include:red eyesseeing halos or bright colors around lightsnausea or vomitingdecreased vision eye pain or discomfortblurred vision If you have any of these symptoms, call your healthcare provider right away. The most common side effects of FINTEPLA include: diarrhealow energyrespiratory infectiontirednessfeverconstipationabnormal echocardiogramproblems with movement, balance, and walkingincreased droolinginfectionvomitingfallsseizures that do not stopweakness These are not all the possible side effects of FINTEPLA. For more information, ask your healthcare provider or pharmacist. Tell your healthcare provider if you have any side effect that bothers you or that does not go away. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. anti-depressant medicines called SSRIs, SNRIs, TCAs, and MAOIs. tryptophan. lithium. antipsychotics. St. Johns Wort. dextromethorphan. tramadol. mental status changes such as seeing things that are not there (hallucinations), agitation, or coma. changes in blood pressure. tight muscles. fast heartbeat. nausea, vomiting, diarrhea. high body temperature. trouble walking. high blood pressure (hypertension). Hypertension is both serious and common side effect. FINTEPLA can cause your blood pressure to increase even if you have never had high blood pressure before. Your healthcare provider will check your blood pressure while you are taking FINTEPLA.. increased pressure in your eye (glaucoma). Symptoms of glaucoma may include:red eyesseeing halos or bright colors around lightsnausea or vomitingdecreased vision eye pain or discomfortblurred vision red eyes. seeing halos or bright colors around lights. nausea or vomiting. decreased vision eye pain or discomfort. blurred vision. diarrhea. low energy. respiratory infection. tiredness. fever. constipation. abnormal echocardiogram. problems with movement, balance, and walking. increased drooling. infection. vomiting. falls. seizures that do not stop. weakness. Store FINTEPLA at room temperature between 68F to 77F (20C and 25C).. Do not refrigerate or freeze.. Store the FINTEPLA bottle and syringe together in clean area.. Throw away (discard) any unused FINTEPLA months after first opening the bottle or if the Discard After date on the package or bottle has passed. Whichever one comes first.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Decreased Appetite and Decreased Weight: Advise patients that FINTEPLA can cause decreased appetite and decreased weight. (5.4)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. (5.5)Suicidal Behavior and Ideation: Monitor patients for suicidal behavior and thoughts. (5.6)Withdrawal of Antiepileptic Drugs: FINTEPLA should be gradually withdrawn to minimize the risk of increased seizure frequency and status epilepticus. (5.7)Serotonin Syndrome: Advise patients that serotonin syndrome is potentially life-threatening condition and may occur with FINTEPLA, particularly with concomitant administration of FINTEPLA with other serotonergic drugs. (5.8)Increase in Blood Pressure: Monitor blood pressure during treatment. (5.9)Glaucoma: Discontinue therapy in patients with acute decrease in visual acuity or ocular pain. (5.10). Decreased Appetite and Decreased Weight: Advise patients that FINTEPLA can cause decreased appetite and decreased weight. (5.4). 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. (5.5). Suicidal Behavior and Ideation: Monitor patients for suicidal behavior and thoughts. (5.6). Withdrawal of Antiepileptic Drugs: FINTEPLA should be gradually withdrawn to minimize the risk of increased seizure frequency and status epilepticus. (5.7). Serotonin Syndrome: Advise patients that serotonin syndrome is potentially life-threatening condition and may occur with FINTEPLA, particularly with concomitant administration of FINTEPLA with other serotonergic drugs. (5.8). Increase in Blood Pressure: Monitor blood pressure during treatment. (5.9). Glaucoma: Discontinue therapy in patients with acute decrease in visual acuity or ocular pain. (5.10). 5.1 Valvular Heart Disease. Because of the association between serotonergic drugs with 5-HT2B receptor agonist activity, including fenfluramine (the active ingredient in FINTEPLA), and valvular heart disease, 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 prior to patient becoming symptomatic, aiding in early detection of this condition. In clinical trials of up to years in duration, no patient receiving FINTEPLA developed valvular heart disease [see Boxed Warning and Adverse Reactions (6.1)].MonitoringPrior to starting treatment, patients must undergo an echocardiogram to evaluate for valvular heart disease.Echocardiograms should be repeated every months, and once 3-6 months post-treatment with FINTEPLA.If valvular heart disease is observed on an echocardiogram, the prescriber must consider the benefits versus the risks of initiating or continuing treatment with FINTEPLA.FINTEPLA is available only through restricted program under REMS [see Warnings and Precautions (5.3)].. 5.2 Pulmonary Arterial Hypertension. Because of the association between serotonergic drugs with 5-HT2B receptor agonist activity, including fenfluramine (the active ingredient in FINTEPLA), and pulmonary arterial hypertension, cardiac monitoring is required prior to starting treatment, during treatment, and after treatment with FINTEPLA concludes. Cardiac monitoring via echocardiogram can identify evidence of pulmonary arterial hypertension prior to patient becoming symptomatic, aiding in early detection of this condition. In clinical trials of up to years in duration, no patient receiving FINTEPLA developed pulmonary arterial hypertension [see Boxed Warning and Adverse Reactions (6.1)].MonitoringPrior to starting treatment, patients must undergo an echocardiogram to evaluate for pulmonary arterial hypertension.Echocardiograms should be repeated every months, and once 3-6 months post-treatment with FINTEPLA.If pulmonary arterial hypertension is observed on an echocardiogram, the prescriber must consider the benefits versus the risks of initiating or continuing treatment with FINTEPLA.FINTEPLA is available only through restricted program under REMS [see Warnings and Precautions (5.3)].. 5.3 FINTEPLA REMS Program. FINTEPLA is available only through 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, 5.2)].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, 5.2)]. 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 distributers must only distribute to certified pharmacies.Further information is available at www.FinteplaREMS.com or by telephone at 1-877-964-3649.. 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, 5.2)].. 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 distributers must only distribute to certified pharmacies.. 5.4 Decreased Appetite and Decreased Weight FINTEPLA can cause decreases in appetite and weight. In Study and Study 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 [see Adverse Reactions (6.1)]. By the end of the controlled studies, 19% of patients treated with FINTEPLA had measured decrease in weight of 7% or greater from their baseline weight, compared to 2% of patients on placebo. This measured decrease in weight appeared to be dose-related, with 26% of patients on FINTEPLA 0.7 mg/kg/day, 19% of patients on FINTEPLA 0.4 mg/kg/day in combination with stiripentol, and 13% of patients taking FINTEPLA 0.2 mg/kg/day experiencing at least 7% decrease in weight from baseline. Most patients resumed the expected measured increases in weight by the end of the open-label extension study. 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 decrease in weight is observed. 5.5 Somnolence, Sedation, and Lethargy. FINTEPLA can cause somnolence, sedation, and lethargy. In Study and Study combined, the incidence of somnolence, sedation, and lethargy was 25% in patients treated with FINTEPLA, compared with 11% 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.. 5.6 Suicidal Behavior and Ideation. Antiepileptic drugs (AEDs) 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 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 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 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 shows absolute and relative risk by indication for all evaluated AEDs.Table 2:Risk of Suicidal Thoughts or Behaviors by Indication for Antiepileptic Drugs in the Pooled Analysis IndicationPlacebo Patients with Events Per 1000 PatientsDrug Patients with Events Per 1000 PatientsRelative Risk: Incidence of Events in Drug Patients/ Incidence in in Placebo PatientsRisk Difference: Additional Drug Patients with Events per 1000 Patients Epilepsy1.03.43.52.4 Psychiatric5.78.51.52.9 Other1.01.81.90.9 Total2.44.31.81.9The 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.. 5.7 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 serious adverse reaction, rapid discontinuation can be considered.. 5.8 Serotonin Syndrome. Serotonin syndrome, 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. Johns 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. 5.9 Increase in Blood Pressure. FINTEPLA can cause an increase in blood pressure [see Adverse Reactions (6.1)]. Significant elevation in blood pressure, including hypertensive crisis, has been reported rarely in adult patients treated with fenfluramine, including patients without history of hypertension. Monitor blood pressure in patients treated with FINTEPLA. In clinical trials of up to years in duration, no patient receiving FINTEPLA developed hypertensive crisis. 5.10 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.

CLINICAL TRIALS EXPERIENCE SECTION.

6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 months, 284 patients treated for more than year, and 138 patients treated for more than 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 months, 172 patients treated for more than year, and 127 patients treated for more than years.. Dravet SyndromeIn 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 and Study 2, the mean age was years (range 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 and Study 2, the rates of discontinuation as 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 lists the adverse reactions that were reported in 5% or more of patients treated with FINTEPLA and at rate greater than those on placebo during the titration and maintenance phases of Study 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 and 2)Adverse ReactionFINTEPLA Dose GroupCombined Placebo GroupPatients in placebo groups from Studies and were pooled. Study 1Study 20.2 mg/kg/day0.7 mg/kg/day0.4 mg/kg/day0.4 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 appetite2338498Somnolence, sedation, lethargy26252311Abnormal echocardiogramConsisted of trace and mild mitral regurgitation, and trace aortic regurgitation, which are considered physiologic. 182396Diarrhea3115236Constipation31070Fatigue, malaise, asthenia1510305Ataxia, balance disorder, gait disturbance101071Abnormal behavior0890Blood pressure increased13805Drooling, salivary hypersecretion13820Hypotonia0800Rash8854Blood prolactin increased0500Chills0520Decreased activity0501Dehydration0500Insomnia0552Pyrexia1552114Stereotypy0500Upper respiratory tract infection215710Vomiting10558Weight decreased13571Croup5301Ear infection8395Gastroenteritis8320Increased heart rate5302Irritability0392Rhinitis8372Tremor3390Urinary incontinence5300Decreased blood glucose0091Bronchitis3091Contusion5000Eczema0050Enuresis5000Fall10004Headache8002Laryngitis0050Negativism5000Status epilepticus30122Urinary tract infection5050Viral infection0051. Lennox-Gastaut SyndromeIn 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 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 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 lists the adverse reactions that were reported in 5% or more of patients treated with FINTEPLA and at 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 ReactionFINTEPLA Dose GroupStudy 3Placebo Group0.2 mg/kg/day0.7mg/kg/dayN=89%N=87%N=87%Decreased appetite203612Fatigue, malaise, asthenia142416Somnolence, sedation, lethargy122216Diarrhea11135Constipation696Vomiting1486Weight decreased282Upper respiratory tract infection873Seizure957Irritability836. Echocardiographic Safety Assessments of Valvular Heart Disease and Pulmonary Arterial HypertensionValvular heart disease and pulmonary arterial hypertension were evaluated in the placebo- controlled and open-label extension studies via echocardiography for up to 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 patient in DS clinical trials).