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 patient’s 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 2 gram levacetylleucine doses, prepare two AQNEURSA packets individually [see Dosage and Administration (2.3)].

One AQNEURSA packet contains 1 gram levacetylleucine.

Missed Dose

If a dose of AQNEURSA is missed, skip the missed dose and take the next dose at the scheduled time. Do not take 2 doses at the same time to make up for a missed dose.

2.3 Preparation and Administration Instructions

Oral Administration

For 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 a container with 40 mL of water, orange juice, or almond milk. Do not use hot liquid.

 

3. Stir to form a suspension.

 

4. Swallow the suspension immediately (within 30 minutes).

 

5. For doses requiring two AQNEURSA packets, repeat steps 2 to 4.

 

6. Discard unused AQNEURSA suspension if not administered within 30 minutes.

Use of Gastrostomy Tube (G-Tube) for Feeding Tube Administration

For patients who have a 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 a container with 40 mL of water ONLY. Do not use hot liquid.

 

4. Stir to form a suspension.

 

5. Draw up the suspension into a 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 3 to 8.

 

10. Discard unused AQNEURSA suspension if not administered immediately.

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 a dose that was approximately 1.4-fold and 6-fold, respectively, the maximum recommended human dose (MRHD) of 4 g/day of levacetylleucine (based on body surface area).

The decision to continue or discontinue AQNEURSA treatment during pregnancy should consider the female’s 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 7 days after the last dose if AQNEURSA is discontinued [see Use in Specific Populations (8.1, 8.3)].

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of AQNEURSA was evaluated in Trial 1, which included a total of 60 patients with Niemann-Pick disease Type C (NPC), in a 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 2 summarizes adverse reactions that occurred in patients who were treated with AQNEURSA in Treatment Period I of Trial 1.

Rosacea

One patient experienced an exacerbation of rosacea during Trial 1 that responded to treatment. AQNEURSA was not discontinued.

Laboratory Findings

Thrombocytopenia with platelets < 100 10^3 cells/µL 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.

7.1 Effect of Other Drugs on AQNEURSA

N-acetyl-DL-leucine and N-acetyl-D-leucine

Avoid 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 Substrates

Monitor 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.

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 4 grams of AQNEURSA per day (see Data).

There are no available data on AQNEURSA use in pregnant females to evaluate a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. Advise a pregnant female of the potential risk to the fetus. The decision to continue or discontinue AQNEURSA treatment during pregnancy should consider the female’s 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 a 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 2 to 4% and 15 to 20%, respectively.

Data

Animal Data

In a 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] 6 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 a dose of 600 mg/kg/day, which is 1.4-fold the 4 g/day MRHD of levacetylleucine based on body surface area.

In a 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 7 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 Summary

There 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 mother’s 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 a pregnant female [see Use in Specific Populations (8.1)].

Pregnancy Testing

For a female of reproductive potential, verify that the patient is not pregnant prior to initiating treatment with AQNEURSA.

Contraception

Females

Advise a female of reproductive potential to use effective contraception during treatment and for 7 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 a 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.

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 0 to 24 hours (AUC0-24hrs) were 8.3 (3.3) µg/mL and 33.2 (12.5) h*μg/mL.

No levacetylleucine accumulation occurs after repeated administration.

Absorption

Levacetylleucine time to Cmax (Tmax) is 1 hour (ranging from 0.5 to 2.5 hours).

Distribution

Levacetylleucine apparent (oral) volume of distribution (VSS/F) is 253 (125) L.

Elimination

Levacetylleucine estimated half-life is around 1 hour and the apparent (oral) clearance is 139 (59) L/h.

Metabolism

Levacetylleucine 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 Populations

No clinically significant differences in pharmacokinetics of levacetylleucine were observed based on age (range 5 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 Weight

The 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 Studies

In Vitro Studies

Cytochrome 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 Systems

Levacetylleucine is a 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.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Animal studies to evaluate the carcinogenic potential of levacetylleucine have not been conducted.

Mutagenesis

Levacetylleucine was not mutagenic or clastogenic in a battery of in vitro and in vivo assays including bacterial reverse mutation (Ames), chromosomal aberration (in human lymphocytes) and mouse micronucleus assays.

Impairment of Fertility

Animal studies to evaluate effects of levacetylleucine on fertility have not been conducted.