ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. Most common adverse reactions (incidence >=5% and greater than placebo) are abdominal pain, dysphagia, upper respiratory tract infections, and vomiting. (6)To report SUSPECTED ADVERSE REACTIONS, contact IntraBio Inc. at 1-833-306-9677 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 drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.The safety of AQNEURSA was evaluated in Trial 1, which included total of 60 patients with Niemann-Pick disease Type (NPC), in placebo-controlled, randomized, crossover trial [see Clinical Studies (14)]. The mean (SD) treatment duration of AQNEURSA was 86.2 (4.7) days (69 min, 97 max); the mean (SD) treatment duration on placebo was 87.3 (4.8) days (78 min, 113 max).Table summarizes adverse reactions that occurred in patients who were treated with AQNEURSA in Treatment Period of Trial 1.Table Adverse Reactions that Occurred in Adult and Pediatric Patients with NPC at an Incidence of >=5% in Treatment Period of Trial 1Adverse ReactionAQNEURSAN=30n (%)PlaceboN=30n (%)Upper respiratory tract infection5 (17)1 (3)Abdominal pain2 (7)0 (0)Dysphagia2 (7)0 (0)Vomiting2 (7)0 (0)RosaceaOne patient experienced an exacerbation of rosacea during Trial that responded to treatment. AQNEURSA was not discontinued.Laboratory FindingsThrombocytopenia with platelets 100 103 cells/uL was observed in four patients during Treatment Period 1, all of whom were receiving miglustat for 42 days or longer at the time of enrollment. In two of these patients, the thrombocytopenia was present at baseline. In the other two patients, the thrombocytopenia developed during the trial.

INSTRUCTIONS FOR USE SECTION.

INSTRUCTIONS FOR USE AQNEURSA [ak nur sah](levacetylleucine) for oral suspensionThis Instructions for Use contains information on how to prepare and take or give AQNEURSA oral suspension. Read this Instructions for Use before you prepare and take or give the first dose of AQNEURSA oral suspension and each time you get refill. There may be new information. This Instructions for Use does not take the place of talking to you or your childs healthcare provider about your or your childs medical condition or treatment.Important Information You Need to Know Before Taking or Giving AQNEURSA Oral SuspensionoTake or give AQNEURSA oral suspension exactly as instructed by your healthcare provider.oTake or give AQNEURSA oral suspension with or without food.oAQNEURSA oral suspension can be taken or given by mouth or through gastrostomy tube (G-tube) feeding tube (French size 18 or larger).oDo not use hot liquid with AQNEURSA oral suspension.oFor instructions on disposing of expired AQNEURSA packets or unused AQNEURSA oral suspension, see the end of this Instructions for Use.Supplies Needed to Prepare and Take or Give AQNEURSA Oral Suspension Gather the following supplies on clean flat surface:othe number of AQNEURSA packets needed for your prescribed doseoa clean spoonoa containeroa measuring cup from your pharmacisto40 mL of water, orange juice, or almond milkocatheter tip syringe (if giving AQNEURSA oral suspension through G-tube)Preparing AQNEURSA Oral SuspensionStep 1: Wash and dry your hands.Step 2: Open and empty the entire contents of AQNEURSA packet into container with 40 mL of: owater, orange juice or almond milk (when taken by mouth), orowater only when given through G-tube. Do not use hot liquid.Step 3: Stir to form the suspension.Note: oGo to Step for taking AQNEURSA oral suspension by mouth, oroGo to Step for giving AQNEURSA oral suspension through gastrostomy tube (G-tube).Taking AQNEURSA Oral Suspension by MouthStep 4: Swallow AQNEURSA oral suspension right away (within 30 minutes).Throw away (dispose of) unused AQNEURSA oral suspension if not taken within 30 minutes.Step 5: If your prescribed dose requires AQNEURSA packets, repeat Steps through 4.Giving AQNEURSA Oral Suspension Through Gastrostomy Tube (G-tube)oGive AQNEURSA oral suspension through G-tube that is French size of 18 or larger.oFollow Steps through to prepare AQNEURSA oral suspension.Note: Only use 40 mL of water for preparing AQNEURSA oral suspension when given through G-tube.Step 6: Draw up the prepared AQNEURSA oral suspension into catheter tip syringe.Step 7: Inject the AQNEURSA oral suspension through the G-tube right away. Throw away (dispose of) unused AQNEURSA oral suspension if not given right away.Step 8: Refill the syringe with an additional 20 mL water.Step 9: Flush the G-tube with water, until no remaining AQNEURSA oral suspension is seen in the syringe or G-tube.Step 10: If your prescribed dose requires AQNEURSA packets, follow Steps through to prepare the AQNEURSA oral suspension, then repeat Steps through 9.Storing AQNEURSAoStore AQNEURSA at room temperature between 68F to 77F (20C to 25C).oKeep AQNEURSA oral suspension and all medicines out of reach of children.Disposing of Expired AQNEURSA Packets or Unused AQNEURSA Oral SuspensionThrow away (dispose of) expired AQNEURSA packets or unused AQNEURSA oral suspension following the steps below:oMix medicine with substance such as dirt, cat litter, or used coffee grounds.oPlace the mixture in container such as sealed plastic bag.oThrow away (dispose of) the container in your household trash.Distributed by: IntraBio Inc., Austin, TX 78701This Instructions for Use has been approved by the U.S. Food and Drug Administration.Issued: 9/2024. oTake or give AQNEURSA oral suspension exactly as instructed by your healthcare provider.. oTake or give AQNEURSA oral suspension with or without food.. oAQNEURSA oral suspension can be taken or given by mouth or through gastrostomy tube (G-tube) feeding tube (French size 18 or larger).. oDo not use hot liquid with AQNEURSA oral suspension.. oFor instructions on disposing of expired AQNEURSA packets or unused AQNEURSA oral suspension, see the end of this Instructions for Use.. othe number of AQNEURSA packets needed for your prescribed dose. oa clean spoon. oa container. oa measuring cup from your pharmacist. o40 mL of water, orange juice, or almond milk. ocatheter tip syringe (if giving AQNEURSA oral suspension through G-tube). owater, orange juice or almond milk (when taken by mouth), or. owater only when given through G-tube.. oGo to Step for taking AQNEURSA oral suspension by mouth, or. oGo to Step for giving AQNEURSA oral suspension through gastrostomy tube (G-tube).. oGive AQNEURSA oral suspension through G-tube that is French size of 18 or larger.. oFollow Steps through to prepare AQNEURSA oral suspension.. oStore AQNEURSA at room temperature between 68F to 77F (20C to 25C).. oKeep AQNEURSA oral suspension and all medicines out of reach of children.. oMix medicine with substance such as dirt, cat litter, or used coffee grounds.. oPlace the mixture in container such as sealed plastic bag.. oThrow away (dispose of) the container in your household trash.. Empty the entire contents of AQNEURSA packet into container with 40 mL water. Stir to form the suspension. Swallow AQNEURSA oral suspension right away. Draw up the prepared AQNEURSA oral suspension into catheter tip syringe. Inject the AQNEURSA oral suspension through the G-tube right away. Refill the syringe with an additional 20 mL water. Flush the G-tube with water.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. The distinct molecular target for levacetylleucine in the treatment of NPC is unknown.. 12.2 Pharmacodynamics. Clinical pharmacodynamic studies have not been conducted for levacetylleucine.A relationship was not observed between increasing levacetylleucine exposure and clinical efficacy. The time course of pharmacodynamic response is unknown.. 12.3 Pharmacokinetics. Levacetylleucine pharmacokinetic parameters at steady state are presented as mean (SD) unless otherwise specified. Levacetylleucine maximum concentration (Cmax) and area under the curve from time to 24 hours (AUC0-24hrs) were 8.3 (3.3) ug/mL and 33.2 (12.5) hug/mL. No levacetylleucine accumulation occurs after repeated administration.AbsorptionLevacetylleucine time to Cmax (Tmax) is hour (ranging from 0.5 to 2.5 hours). DistributionLevacetylleucine apparent (oral) volume of distribution (VSS/F) is 253 (125) L.EliminationLevacetylleucine estimated half-life is around hour and the apparent (oral) clearance is 139 (59) L/h. MetabolismLevacetylleucine is metabolized into acetate and L-leucine by ubiquitously expressed enzymes, which are used endogenously in catabolic and metabolic pathways. Cytochrome P450 enzymes are not involved in the metabolism of levacetylleucine.Specific PopulationsNo clinically significant differences in pharmacokinetics of levacetylleucine were observed based on age (range to 67 years), gender (female 45.5%, male 54.5%), or race/ethnicity (White 91%, Asian 4%, Other or not specified 5%). The effect of renal impairment, hepatic impairment, or pregnancy on levacetylleucine pharmacokinetics is unknown. Body WeightThe volume of distribution and clearance of levacetylleucine increases with increasing body weight (20.5 kg to 98.4 kg), but these effects on pharmacokinetics are minimized by the recommended weight-based dosing.Drug Interaction StudiesIn Vitro StudiesCytochrome P450 (CYP450) enzymes: Levacetylleucine does not inhibit CYP 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4 and does not induce CYP 1A2, 2B6, and or 3A4.Transporter SystemsLevacetylleucine is substrate of organic anion transporter (OAT)1 and OAT3, but not organic cation transporter (OCT)2, breast cancer resistance protein (BCRP), or P-glycoprotein (P-gp). Levacetylleucine inhibits P-gp, BCRP, bile salt export pump (BSEP), OAT1 and OAT3, but does not inhibit organic anion transporting polypeptide (OATP)1B1 and OATP1B3.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. The safety and efficacy of AQNEURSA for the treatment of NPC were evaluated in randomized, double-blind, placebo-controlled, two-period crossover study (NCT05163288) that evaluated the efficacy of AQNEURSA in 60 patients. To be eligible for the study, patients had to be aged years or older with confirmed diagnosis of NPC. Patients were required to have at least mild disease-related neurological symptoms. Patients were assessed over 2-week baseline period. Patients were then randomized in 1:1 ratio to one of the two treatment sequences: oTreatment Sequence (N=30): AQNEURSA in Treatment Period I, followed by immediate crossover to placebo in Treatment Period IIoTreatment Sequence (N=30): placebo in Treatment Period I, followed by immediate crossover to AQNEURSA in Treatment Period II. AQNEURSA and placebo were administered orally with or without food for 12 weeks in each period. Patients aged >=13 years received gram per day (as gram morning dose, gram afternoon dose, and gram evening dose). The AQNEURSA dosage in pediatric patients under 13 years was based on patients body weight [see Dosage and Administration 2.2 )].The approved dosage regimen is based on body weight and not age. Fifty-nine patients (98%) completed the study and received both placebo and AQNEURSA. One patient withdrew based on healthcare provider decision during AQNEURSA treatment. Of the 60 randomized patients (37 adults and 23 pediatric patients), 27 were female and 33 were male. The median age at treatment initiation was 25 years (range: to 67 years). 90% of the patients were White, 3% Asian, and 7% Other. The majority of the patients (n=51, 85%) received miglustat treatment prior to randomization and during the trial.The primary efficacy outcome was assessed using modified version of the Scale for Assessment and Rating of Ataxia (SARA), referred to as the functional SARA (fSARA). The SARA is clinical assessment tool that assesses gait, stability, speech, and upper and lower limb coordination across individual domains. The fSARA consists only of gait, sitting, stance, and speech disturbance domains of the original SARA with modifications to the scoring responses. Each domain was rescored from to 4, where is the best neurological status and the worst, with total score ranging from to 16. The fSARA score was assessed at baseline, weeks, 12 weeks (the end of Period I), 18 weeks, and 24 weeks (the end of Period II). The estimated mean fSARA total score was 5.1 when patients were treated with AQNEURSA and 5.6 when patients were treated with placebo. The estimated treatment difference for the fSARA total score was -0.4 (95% CI: -0.7, -0.2) (Table 3).Table Summary of fSARA Efficacy ResultsCI confidence interval; SD standard deviation; SE standard error.VariablefSARA Total ScoreTreatment Sequence 1:AQNEURSA PlaceboTreatment Sequence 2:Placebo AQNEURSABaseline N=30N=30 Mean (SD)5.2 (3.0)6.3 (3.3)Period N=29N=30 Mean (SD)4.5 (2.6)6.0 (3.4)Period IIN=28Two patients did not have an assessment at the end of Period II (week 24). N=30 Mean (SD)5.1 (2.8)5.6 (3.1)Estimated Mean fSARA Score (SE) by TreatmentAQNEURSA5.1 (0.1)Placebo5.6 (0.1)Treatment Difference (95% CI)-0.4 (-0.7, -0.2)Two-sided p-value <0.001 Patients who received AQNEURSA in Period followed by placebo in Period II (Treatment Sequence 1) showed greater improvement in the fSARA score in Period with mean change from baseline of -0.5 (SD 1.2), compared to Period II with mean change from baseline of (1.5). Similarly, patients who received placebo in Period followed by AQNEURSA in Period II (Treatment Sequence 2) experienced greater improvement in the fSARA score while receiving AQNEURSA in Period II with mean change of -0.7 (0.9), compared to mean change of -0.3 (0.9) in Period I.Figure 1Mean (+/- standard error) plot of the fSARA total score by time and treatment sequenceResults on the fSARA were supported by consistent results demonstrated on the original SARA.. oTreatment Sequence (N=30): AQNEURSA in Treatment Period I, followed by immediate crossover to placebo in Treatment Period II. oTreatment Sequence (N=30): placebo in Treatment Period I, followed by immediate crossover to AQNEURSA in Treatment Period II. Mean (SD). Mean (SD). Mean (SD). Mean (+/- standard error) plot of the fSARA total score by time and treatment sequence.

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.The safety of AQNEURSA was evaluated in Trial 1, which included total of 60 patients with Niemann-Pick disease Type (NPC), in placebo-controlled, randomized, crossover trial [see Clinical Studies (14)]. The mean (SD) treatment duration of AQNEURSA was 86.2 (4.7) days (69 min, 97 max); the mean (SD) treatment duration on placebo was 87.3 (4.8) days (78 min, 113 max).Table summarizes adverse reactions that occurred in patients who were treated with AQNEURSA in Treatment Period of Trial 1.Table Adverse Reactions that Occurred in Adult and Pediatric Patients with NPC at an Incidence of >=5% in Treatment Period of Trial 1Adverse ReactionAQNEURSAN=30n (%)PlaceboN=30n (%)Upper respiratory tract infection5 (17)1 (3)Abdominal pain2 (7)0 (0)Dysphagia2 (7)0 (0)Vomiting2 (7)0 (0)RosaceaOne patient experienced an exacerbation of rosacea during Trial that responded to treatment. AQNEURSA was not discontinued.Laboratory FindingsThrombocytopenia with platelets 100 103 cells/uL was observed in four patients during Treatment Period 1, all of whom were receiving miglustat for 42 days or longer at the time of enrollment. In two of these patients, the thrombocytopenia was present at baseline. In the other two patients, the thrombocytopenia developed during the trial.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. oFor females of reproductive potential, verify that the patient is not pregnant prior to initiating treatment. (2.1)oRecommended dosage (2.2)Patient Body WeightMorning DoseAfternoon DoseEvening Dose15 to <25 kg1 gNo Dose1 g25 to <35 kg1 g1 g1 g35 kg or more2 g1 g1 goSee the full prescribing information for administration instructions. (2.3). oFor females of reproductive potential, verify that the patient is not pregnant prior to initiating treatment. (2.1). oRecommended dosage (2.2). oSee the full prescribing information for administration instructions. (2.3). 2.1 Important Recommendation Prior to AQNEURSA Treatment Initiation. For females of reproductive potential, verify that the patient is not pregnant [see Use in Specific Populations (8.1, 8.3)]. 2.2 Recommended Dosage. The recommended dosage of AQNEURSA is based on the patients actual body weight (kg) to be administered orally up to three times daily. See Table 1.AQNEURSA can be taken with or without food [see Clinical Studies 14)].For gram levacetylleucine doses, prepare two AQNEURSA packets individually [see Dosage and Administration (2.3)].Table Recommended Dosage of Levacetylleucine Based on Body Weight (kg)Patients Body WeightMorning DoseAfternoon DoseEvening Dose15 kg to less than 25 kg1 gramNo Dose1 gram25 kg to less than 35 kg1 gram1 gram1 gram35 kg or more2 gram1 gram1 gramOne AQNEURSA packet contains gram levacetylleucine. Missed DoseIf dose of AQNEURSA is missed, skip the missed dose and take the next dose at the scheduled time. Do not take doses at the same time to make up for missed dose.. 2.3 Preparation and Administration Instructions. Oral AdministrationFor oral administration, administer AQNEURSA as follows: 1.Obtain the required number of AQNEURSA packets for the prescribed dose (one or two packets). 2.Open and empty the entire contents of one AQNEURSA packet into container with 40 mL of water, orange juice, or almond milk. Do not use hot liquid. 3.Stir to form suspension. 4.Swallow the suspension immediately (within 30 minutes). 5.For doses requiring two AQNEURSA packets, repeat steps to 4. 6.Discard unused AQNEURSA suspension if not administered within 30 minutes.Use of Gastrostomy Tube (G-Tube) for Feeding Tube AdministrationFor patients who have G-tube (French size 18 or larger) in place, administer AQNEURSA as follows: 1.Prepare AQNEURSA suspension immediately before administration via gastrostomy tube. 2.Obtain the required number of AQNEURSA packets for the prescribed dose (one or two packets). 3.Open and empty the entire contents of one AQNEURSA packet into container with 40 mL of water ONLY. Do not use hot liquid. 4.Stir to form suspension. 5.Draw up the suspension into catheter tip syringe. 6.Administer the suspension immediately through the G-tube. 7.Flush any residual suspension in the catheter tip syringe with an additional 20 mL of water. 8.Flush the G-tube again, as needed, until no residual suspension is left in the syringe or feeding tube. 9.For doses requiring two AQNEURSA packets, repeat steps to 8. 10.Discard unused AQNEURSA suspension if not administered immediately.. 1.Obtain the required number of AQNEURSA packets for the prescribed dose (one or two packets).. 2.Open and empty the entire contents of one AQNEURSA packet into container with 40 mL of water, orange juice, or almond milk. Do not use hot liquid.. 3.Stir to form suspension. 4.Swallow the suspension immediately (within 30 minutes).. 5.For doses requiring two AQNEURSA packets, repeat steps to 4.. 6.Discard unused AQNEURSA suspension if not administered within 30 minutes.. 1.Prepare AQNEURSA suspension immediately before administration via gastrostomy tube. 2.Obtain the required number of AQNEURSA packets for the prescribed dose (one or two packets).. 3.Open and empty the entire contents of one AQNEURSA packet into container with 40 mL of water ONLY. Do not use hot liquid.. 4.Stir to form suspension. 5.Draw up the suspension into catheter tip syringe. 6.Administer the suspension immediately through the G-tube. 7.Flush any residual suspension in the catheter tip syringe with an additional 20 mL of water. 8.Flush the G-tube again, as needed, until no residual suspension is left in the syringe or feeding tube. 9.For doses requiring two AQNEURSA packets, repeat steps to 8.. 10.Discard unused AQNEURSA suspension if not administered immediately.

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. oN-acetyl-DL-leucine or N-acetyl-D-leucine: Avoid concomitant use with AQNEURSA. (7.1)oP-glycoprotein (P-gp) Transporter Substrates: Monitor for adverse reactions if used with AQNEURSA. (7.2). oN-acetyl-DL-leucine or N-acetyl-D-leucine: Avoid concomitant use with AQNEURSA. (7.1). oP-glycoprotein (P-gp) Transporter Substrates: Monitor for adverse reactions if used with AQNEURSA. (7.2). 7.1 Effect of Other Drugs on AQNEURSA. N-acetyl-DL-leucine and N-acetyl-D-leucineAvoid concomitant use of AQNEURSA with N-acetyl-DL-leucine and N-acetyl-D-leucine. The D-enantiomer, N-acetyl-D-leucine, competes with levacetylleucine for monocarboxylate transporter uptake, which may reduce the levacetylleucine efficacy.. 7.2 Effect of AQNEURSA on Other Drugs. P-glycoprotein (P-gp) Transporter SubstratesMonitor more frequently for P-gp substrate related adverse reactions when used concomitantly with AQNEURSA. Levacetylleucine inhibits P-gp [see Clinical Pharmacology (12.3)]. However, the clinical significance of this finding has not been fully characterized.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Levacetylleucine pharmacokinetic parameters at steady state are presented as mean (SD) unless otherwise specified. Levacetylleucine maximum concentration (Cmax) and area under the curve from time to 24 hours (AUC0-24hrs) were 8.3 (3.3) ug/mL and 33.2 (12.5) hug/mL. No levacetylleucine accumulation occurs after repeated administration.AbsorptionLevacetylleucine time to Cmax (Tmax) is hour (ranging from 0.5 to 2.5 hours). DistributionLevacetylleucine apparent (oral) volume of distribution (VSS/F) is 253 (125) L.EliminationLevacetylleucine estimated half-life is around hour and the apparent (oral) clearance is 139 (59) L/h. MetabolismLevacetylleucine is metabolized into acetate and L-leucine by ubiquitously expressed enzymes, which are used endogenously in catabolic and metabolic pathways. Cytochrome P450 enzymes are not involved in the metabolism of levacetylleucine.Specific PopulationsNo clinically significant differences in pharmacokinetics of levacetylleucine were observed based on age (range to 67 years), gender (female 45.5%, male 54.5%), or race/ethnicity (White 91%, Asian 4%, Other or not specified 5%). The effect of renal impairment, hepatic impairment, or pregnancy on levacetylleucine pharmacokinetics is unknown. Body WeightThe volume of distribution and clearance of levacetylleucine increases with increasing body weight (20.5 kg to 98.4 kg), but these effects on pharmacokinetics are minimized by the recommended weight-based dosing.Drug Interaction StudiesIn Vitro StudiesCytochrome P450 (CYP450) enzymes: Levacetylleucine does not inhibit CYP 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4 and does not induce CYP 1A2, 2B6, and or 3A4.Transporter SystemsLevacetylleucine is substrate of organic anion transporter (OAT)1 and OAT3, but not organic cation transporter (OCT)2, breast cancer resistance protein (BCRP), or P-glycoprotein (P-gp). Levacetylleucine inhibits P-gp, BCRP, bile salt export pump (BSEP), OAT1 and OAT3, but does not inhibit organic anion transporting polypeptide (OATP)1B1 and OATP1B3.

PREGNANCY SECTION.

8.1 Pregnancy. Risk Summary Based on findings from animal reproduction studies, AQNEURSA may cause embryo-fetal harm when administered during pregnancy. In animal reproduction studies, an increase in embryo-fetal death (post implantation loss/resorption), decrease in fetal body weight, and increase in external and skeletal malformations were observed in rats and rabbits when levacetylleucine was administered in pregnant rats and rabbits during the period of organogenesis. These effects were observed in rats and rabbits at the doses that were approximately 1.4-fold and 6-fold, respectively, the maximum recommended human dose (MRHD) in patients taking grams of AQNEURSA per day (see Data ).There are no available data on AQNEURSA use in pregnant females to evaluate drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. Advise pregnant female of the potential risk to the fetus. The decision to continue or discontinue AQNEURSA treatment during pregnancy should consider the females need for AQNEURSA, the potential drug-related risks to the fetus, and the potential adverse outcomes from untreated maternal disease.The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have background risk of birth defect, miscarriage, 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 to 4% and 15 to 20%, respectively. DataAnimal DataIn dose-range finding rat embryo-fetal development study, doses of up to 1000 mg/kg/day oral levacetylleucine were administered daily to pregnant females during organogenesis (Gestation Day [GD] through GD 17). Increases in the mean number of resorptions, mean post-implantation losses and skeletal malformations (thoracic arch of the vertebra-fused thoracic arch, misaligned thoracic arch, hemicentric thoracic centrum, and misaligned thoracic centrum; vertebral column-scoliosis, and ribs-absent costal cartilage and short rib) were observed at dose of 600 mg/kg/day, which is 1.4-fold the g/day MRHD of levacetylleucine based on body surface area. In dose-range finding rabbit embryo-fetal development study, doses of up to 2500 mg/kg/day oral levacetylleucine were administered daily to pregnant females during organogenesis (GD through GD 19). Increased embryo-fetal death (post-implantation loss/resorption), decreased fetal body weight, and increase in external (open or partially open eyes, hyperflexion of limbs) and skeletal malformations (misshapen maxillae and premaxillae, and small interparietal bones) were observed at the dose of 1250 mg/kg/day, which is 6-fold the MRHD of levacetylleucine based on body surface area.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Risk Summary Based on findings from animal reproduction studies, AQNEURSA may cause embryo-fetal harm when administered during pregnancy. In animal reproduction studies, an increase in embryo-fetal death (post implantation loss/resorption), decrease in fetal body weight, and increase in external and skeletal malformations were observed in rats and rabbits when levacetylleucine was administered in pregnant rats and rabbits during the period of organogenesis. These effects were observed in rats and rabbits at the doses that were approximately 1.4-fold and 6-fold, respectively, the maximum recommended human dose (MRHD) in patients taking grams of AQNEURSA per day (see Data ).There are no available data on AQNEURSA use in pregnant females to evaluate drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. Advise pregnant female of the potential risk to the fetus. The decision to continue or discontinue AQNEURSA treatment during pregnancy should consider the females need for AQNEURSA, the potential drug-related risks to the fetus, and the potential adverse outcomes from untreated maternal disease.The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have background risk of birth defect, miscarriage, 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 to 4% and 15 to 20%, respectively. DataAnimal DataIn dose-range finding rat embryo-fetal development study, doses of up to 1000 mg/kg/day oral levacetylleucine were administered daily to pregnant females during organogenesis (Gestation Day [GD] through GD 17). Increases in the mean number of resorptions, mean post-implantation losses and skeletal malformations (thoracic arch of the vertebra-fused thoracic arch, misaligned thoracic arch, hemicentric thoracic centrum, and misaligned thoracic centrum; vertebral column-scoliosis, and ribs-absent costal cartilage and short rib) were observed at dose of 600 mg/kg/day, which is 1.4-fold the g/day MRHD of levacetylleucine based on body surface area. In dose-range finding rabbit embryo-fetal development study, doses of up to 2500 mg/kg/day oral levacetylleucine were administered daily to pregnant females during organogenesis (GD through GD 19). Increased embryo-fetal death (post-implantation loss/resorption), decreased fetal body weight, and increase in external (open or partially open eyes, hyperflexion of limbs) and skeletal malformations (misshapen maxillae and premaxillae, and small interparietal bones) were observed at the dose of 1250 mg/kg/day, which is 6-fold the MRHD of levacetylleucine based on body surface area.. 8.2 Lactation Risk SummaryThere are no data on the presence of levacetylleucine or its metabolites in either human or animal milk, the effects on the breastfed infant or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for AQNEURSA and any potential adverse effects on the breastfed infant from levacetylleucine or from the underlying maternal condition.. 8.3 Females and Males of Reproductive Potential AQNEURSA may cause embryo-fetal harm when administered to pregnant female [see Use in Specific Populations (8.1)].Pregnancy TestingFor female of reproductive potential, verify that the patient is not pregnant prior to initiating treatment with AQNEURSA.ContraceptionFemalesAdvise female of reproductive potential to use effective contraception during treatment and for days after the last dose if AQNEURSA is discontinued.. 8.4 Pediatric Use. The safety and effectiveness of AQNEURSA for the treatment of NPC have been established in 23 pediatric patients weighing >=15 kg in Trial 1. Use of AQNEURSA for this indication is supported by evidence from one adequate and well-controlled study in adults and pediatric patients weighing >=15 kg with additional pharmacokinetic data from 40 adults and 17 pediatric patients who participated in two open-label studies [see Clinical Studies (14) and Clinical Pharmacology (12.3)]. The safety and effectiveness of AQNEURSA have not been established in pediatric patients weighing <15 kg.. 8.5 Geriatric Use. NPC is largely disease of pediatric and young adult patients. Clinical studies of AQNEURSA did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger adult patients.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Embryo-Fetal Toxicity: May cause fetal harm. Advise females of reproductive potential to use effective contraception during treatment and for days after the last dose if AQNEURSA is discontinued. (5.1). 5.1 Embryo-Fetal Toxicity. Based on findings from animal reproduction studies, AQNEURSA may cause embryo-fetal harm when administered during pregnancy. Administration of levacetylleucine to pregnant rats and rabbits during the period of organogenesis caused an increase in embryo-fetal death (post implantation loss/resorption) and skeletal malformations at dose that was approximately 1.4-fold and 6-fold, respectively, the maximum recommended human dose (MRHD) of g/day of levacetylleucine (based on body surface area). The decision to continue or discontinue AQNEURSA treatment during pregnancy should consider the females need for AQNEURSA, the potential drug-related risks to the fetus, and the potential adverse outcomes from untreated maternal disease.For females of reproductive potential, verify that the patient is not pregnant prior to initiating treatment with AQNEURSA. Advise females of reproductive potential to use effective contraception during treatment with AQNEURSA and for days after the last dose if AQNEURSA is discontinued [see Use in Specific Populations (8.1, 8.3)].