Highlights

See Patient counseling information and medication guide available in the DAILYMED drug label information.

Indications and usage

Levacetylleucine is indicated for the treatment of neurologic manifestations of Niemann-Pick disease type C in adults and pediatric patients weighing 15 kg or more.

Dosage and administration

Important recommendation before levacetylleucine treatment initiation

For females of reproductive potential, verify that the patient is not pregnant.

Recommended dosage

The recommended dosage of levacetylleucine is based on the patient’s actual body weight (kg) to be administered orally up to three times daily. See Table 1.

Levacetylleucine can be taken with or without food.

For 2-gram levacetylleucine doses, prepare two levacetylleucine packets individually.

Table 1. Recommended Dosage of Levacetylleucine Based on Body Weight (kg)

One levacetylleucine packet contains 1 gram levacetylleucine.

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

Preparation and administration instructions

Oral administration. For oral administration, administer levacetylleucine as follows:

Use of a gastrostomy tube (G-Tube) for feeding tube administration. For patients who have a G-tube (French size 18 or larger) in place, administer levacetylleucine as follows:

Dosage forms and strengths

For oral suspension. One gram levacetylleucine as white to off-white strawberry flavored granules in a unit-dose packet.

Contraindications

None.

Warnings and precautions

Embryo-fetal toxicity

Based on findings from animal reproduction studies, levacetylleucine 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 of 4 g/day of levacetylleucine (based on body surface area).

The decision to continue or discontinue levacetylleucine treatment during pregnancy should consider the female’s need for levacetylleucine, 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 before initiating treatment with levacetylleucine. Advise females of reproductive potential to use effective contraception during treatment with levacetylleucine and for 7 days after the last dose if levacetylleucine is discontinued.

Adverse reactions

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 levacetylleucine was evaluated in Trial 1, which included a total of 60 patients with Niemann-Pick disease type C, in a placebo-controlled, randomized, crossover trial. The mean (SD) treatment duration of levacetylleucine 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 levacetylleucine in Treatment Period I of Trial 1.

Table 2. Adverse Reactions that Occurred in Adult and Pediatric Patients with Niemann-Pick Disease Type C at an Incidence of 5% or Greater in Treatment Period I of Trial 1

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

Laboratory findings. Thrombocytopenia with platelets lower than 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.

Drug interactions

Effect of other drugs on levacetylleucine

N-acetyl-DL-leucine and N-acetyl-D-leucine. Avoid concomitant use of levacetylleucine 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 efficacy of levacetylleucine.

Effect of levacetylleucine on other drugs

P-glycoprotein (P-gp) transporter substrates. Monitor more frequently for P-gp substrate-related adverse reactions when used concomitantly with levacetylleucine.

Levacetylleucine inhibits P-gp. However, the clinical significance of this finding has not been fully characterized.

Use in specific populations

Pregnancy

Risk summary. Based on findings from animal reproduction studies, levacetylleucine 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 in patients taking 4 grams of levacetylleucine per day (see Data).

There are no available data on levacetylleucine 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 levacetylleucine treatment during pregnancy should consider the female’s need for levacetylleucine, 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 defects, 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 6 through 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 maximum recommended human dose 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 (gestation day 7 through 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 maximum recommended human dose of levacetylleucine based on body surface area.

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 levacetylleucine and any potential adverse effects on the breastfed infant from levacetylleucine or from the underlying maternal condition.

Females and males of reproductive potential

Levacetylleucine may cause embryo-fetal harm when administered to a pregnant female.

Pregnancy testing. For a female of reproductive potential, verify that the patient is not pregnant before initiating treatment with levacetylleucine.

Contraception.

Females. Advise a female of reproductive potential to use effective contraception during treatment and for 7 days after the last dose if levacetylleucine is discontinued.

Pediatric use

The safety and effectiveness of levacetylleucine for the treatment of Niemann-Pick disease type C have been established in 23 pediatric patients weighing 15 kg or more in Trial 1. Use of levacetylleucine for this indication is supported by evidence from one adequate and well-controlled study in adults and pediatric patients weighing 15 kg or more, with additional pharmacokinetic data from 40 adults and 17 pediatric patients who participated in two open-label studies. The safety and effectiveness of levacetylleucine have not been established in pediatric patients weighing less than 15 kg.

Geriatric use

Niemann-Pick disease type C is largely a disease of pediatric and young adult patients. Clinical studies of levacetylleucine did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger adult patients.

Clinical pharmacology

Mechanism of action

The distinct molecular target for levacetylleucine in the treatment of Niemann-Pick disease type C is unknown.

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.

Pharmacokinetics

Levacetylleucine pharmacokinetic parameters at steady state are presented as mean (SD) unless otherwise specified. Levacetylleucine maximum concentration (C_max) and area under the curve from time 0 to 24 hours (AUC_0-24hrs) 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 C_max (T_max) is 1 hour (ranging from 0.5 to 2.5 hours).

Distribution. Levacetylleucine apparent (oral) volume of distribution (V_SS/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 the 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 increase 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.

Nonclinical toxicology

Carcinogenesis, mutagenesis, and 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 the effects of levacetylleucine on fertility have not been conducted.

Clinical studies

The safety and efficacy of levacetylleucine for the treatment of Niemann-Pick disease type C were evaluated in a randomized, double-blind, placebo-controlled, two-period crossover study (NCT05163288) that evaluated the efficacy of levacetylleucine in 60 patients. To be eligible for the study, patients had to be aged 4 years or older with a confirmed diagnosis of Niemann-Pick disease type C. Patients were required to have at least mild disease-related neurologic symptoms.

Patients were assessed over a 2-week baseline period. Patients were then randomized in a 1:1 ratio to one of the two treatment sequences:

Levacetylleucine and placebo were administered orally with or without food for 12 weeks in each period.

Patients aged 13 years or older received 4 grams per day (as a 2-gram morning dose, 1-gram afternoon dose, and 1-gram evening dose). The levacetylleucine dosage in pediatric patients under 13 years was based on the patient’s body weight. The approved dosage regimen is based on body weight and not age. Fifty-nine patients (98%) completed the study and received both placebo and levacetylleucine. One patient withdrew based on the healthcare provider’s decision during levacetylleucine 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: 5 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 before randomization and during the trial.

The primary efficacy outcome was assessed using a modified version of the Scale for Assessment and Rating of Ataxia (SARA), referred to as the functional SARA (fSARA). The SARA is a clinical assessment tool that assesses gait, stability, speech, and upper and lower limb coordination across eight 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 0 to 4, where 0 is the best neurologic status and 4 the worst, with a total score ranging from 0 to 16.

The fSARA score was assessed at baseline, 6 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 levacetylleucine 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 3. Summary of fSARA Efficacy Results

Patients who received levacetylleucine in Period I followed by placebo in Period II (Treatment Sequence 1) showed a greater improvement in the fSARA score in Period I with a mean change from baseline of -0.5 (SD 1.2), compared to Period II with a mean change from baseline of 0 (1.5). Similarly, patients who received placebo in Period I followed by levacetylleucine in Period II (Treatment Sequence 2) experienced greater improvement in the fSARA score while receiving levacetylleucine in Period II with a mean change of -0.7 (0.9), compared to a mean change of -0.3 (0.9) in Period I.

To see the plot of the fSARA total score by time and treatment sequence, see Figure 1 in the DAILYMED drug label information. Results on the fSARA were supported by consistent results demonstrated on the original SARA.

How supplied/storage and handling

How supplied. Levacetylleucine (levacetylleucine) for oral suspension is supplied as white to off-white granules in a unit-dose multi-layer aluminum/polyethylene packet. Each packet contains 1.7 grams of white to off-white granules, equivalent to 1 gram levacetylleucine.

NDC 83853-101-01: Carton containing 28 unit-dose packets

Storage and handling. Store levacetylleucine at room temperature between 20°C to 25°C (68°F to 77°F); excursion permitted between 15°C to 30°C (59°F to 86°F).

Patient counseling information

Advise the patient and caregiver to read the FDA-approved patient labeling.

Embryo-fetal toxicity. Levacetylleucine may cause embryo-fetal harm. Advise a pregnant female of the potential risk to the fetus. Advise a female of reproductive potential and caregiver to inform their healthcare provider of a known or suspected pregnancy. Advise a female of reproductive potential to use effective contraception during treatment and for 7 days after the last dose if levacetylleucine is discontinued.

Medication guide

See the Medication guide section of the DAILYMED drug label information.

Acknowledgement

This article was excerpted from U.S. FDA Drug Labeling information available on the DailyMed website.