MIPLYFFA

1 INDICATIONS AND USAGE MIPLYFFA is indicated for use in combination with miglustat for the treatment of neurological manifestations of Niemann-Pick disease type C (NPC) in adult and pediatric patients 2 years of age and older. MIPLYFFA is indicated for use in combination with miglustat for the treatment of neurological manifestations of Niemann-Pick disease type C (NPC) in adult and pediatric patients 2 years of age and older. ( 1 )

2 DOSAGE AND ADMINISTRATION Recommended MIPLYFFA oral dosage, in combination with miglustat, for patients with actual body weight of ( 2.1 ): 8 kg to 15 kg, is 47 mg three times a day > 15 kg to 30 kg, is 62 mg three times a day > 30 kg to 55 kg, is 93 mg three times a day > 55 kg, is 124 mg three times a day Administer with or without food. ( 2.1 ) See full prescribing information for recommended dosage in patients with an eGFR ≥ 15 to 15 kg to 30 kg, is 62 mg three times a day > 30 kg to 55 kg, is 93 mg three times a day > 55 kg, is 124 mg three times a day Administer MIPLYFFA with or without food. Missed Dose If a dose of MIPLYFFA is missed, advise the patient to skip the missed dose and to resume taking the prescribed dose at the next scheduled time. 2.2 Recommended Dosage in Patients with Renal Impairment The recommended dosage of MIPLYFFA, in combination with miglustat, in patients with an eGFR ≥ 50 mL/minute is the same as the recommended dosage in patients with normal renal function [see Dosage and Administration ( 2.1 )]. For patients with an eGFR ≥ 15 to 15 kg to 30 kg, is 62 mg two times a day > 30 kg to 55 kg, is 93 mg two times a day > 55 kg, is 124 mg two times a day Administer MIPLYFFA with or without food. 2.3 Preparation and Administration Instructions Swallow MIPLYFFA whole. However, for patients who have difficulty swallowing capsules, administer MIPLYFFA in one of two ways: Oral Administration Carefully open the capsule and sprinkle the entire contents into 15 mL of water or apple juice or 15 mL of soft food (e.g., applesauce, pudding, or yogurt). Stir the mixture for 15 seconds. Consume the entire mixture immediately. Feeding Tube Administration (nasogastric or gastric tube) Carefully open the capsule and sprinkle the entire contents into 20 mL of water. Do not add the capsule contents to other liquids besides water. Stir the mixture for 15 seconds. Administer the entire mixture immediately via feeding tube. Flush the feeding tube with 5 mL of water after administration. Do not save the mixture for later use.

3 DOSAGE FORMS AND STRENGTHS MIPLYFFA (arimoclomol) capsules are available as follows: MIPLYFFA Strength Description of Capsules 47 mg White opaque body with black printing “47”, and green opaque cap with black printing “OZ” 62 mg White opaque body with black printing “62”, and yellow opaque cap with black printing “OZ” 93 mg White opaque body with black printing “93”, and orange opaque cap with black printing “OZ” 124 mg White opaque body with black printing “124”, and red opaque cap with black printing “OZ” Capsules: 47 mg, 62 mg, 93 mg and 124 mg of arimoclomol. ( 3 )

4 CONTRAINDICATIONS None. None. ( 4 )

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described below and elsewhere in the labeling: Hypersensitivity Reactions [see Warning and Precautions ( 5.1 )]. Increased Creatinine without Affecting Glomerular Function [see Warnings and Precautions ( 5.3 )]. Most common adverse reactions (≥15%) are: Upper respiratory tract infection, diarrhea, and decreased weight. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Zevra Therapeutics, Inc. at toll-free phone 1-844-600-2237 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of MIPLYFFA was evaluated in a randomized, double-blind, placebo-controlled, 12-month trial (Trial 1), which included 50 patients 2 to 19 years old with NPC [see Clinical Studies ( 14 )] . Patients received weight-adjusted doses of MIPLYFFA (31 to 124 mg orally three times daily); 28 of the patients were exposed to MIPLYFFA for one year. In Trial 1, 78% of patients received miglustat. Forty-one out of 50 patients that were enrolled in Trial 1 continued into an open-label extension trial, which included 39 patients treated with MIPLYFFA for more than 1 year, 34 patients treated with MIPLYFFA for more than 2 years, and 17 patients treated with MIPLYFFA for more than 5 years. The most common adverse reactions in Trial 1 (≥ 15%) in MIPLYFFA-treated patients who also received miglustat were upper respiratory tract infection, diarrhea, and decreased weight. Three (6%) of the MIPLYFFA-treated patients had the following adverse reactions that led to withdrawal from Trial 1: increased serum creatinine (one patient), and progressive urticaria and angioedema (two patients). Serious adverse reactions reported in MIPLYFFA-treated patients in Trial 1 were hypersensitivity reactions including urticaria and angioedema. Table 1 shows common adverse reactions in Trial 1 that occurred in at least 8% of MIPLYFFA-treated patients who also received miglustat. Table 1: Adverse Reactions in ≥ 8% of Patients with NPC Treated with MIPLYFFA in Trial 1 (Subgroup Who Also Received Miglustat) * Upper Respiratory Tract Infection: Combined incidence of upper respiratory tract infection and rhinitis. ** Urticaria: Includes one patient in which urticaria occurred alone (3%) and two patients who had urticaria with angioedema (6%) Adverse Reaction MIPLYFFA with miglustat N=26 n (%) Placebo with miglustat N=13 n (%) Upper Respiratory Tract Infection* 8 (31) 2 (15) Diarrhea 6 (23) 3 (23) Decreased Weight 4 (15) 0 Decreased appetite 3 (12) 0 Tremor 3 (12) 0 Urticaria** 3 (12) 0 Headache 3 (12) 1 (8) Lower respiratory tract infection 3 (12) 1 (8) Seizure 3 (12) 1 (8) Decreased Weight Adverse reactions of decreased weight were observed in four patients, who were also receiving concomitant miglustat during the trial. The decrease in weight resolved in all but one of the patients. The mean duration of the weight decrease was 33 days and ranged from 22 to 60 days. One patient had two separate instances of weight loss during the trial, lasting 22 and 24 days respectively. The mean weight loss was approximately 6% from baseline in all patients and MIPLYFFA administration was not interrupted in any patient. Laboratory Findings Thrombocytopenia: Thrombocytopenia was observed in three patients during the trial, all of whom were receiving miglustat for six months or longer at the time of enrollment. In two of these patients, the thrombocytopenia was present at baseline and persisted throughout the trial. In the other patient, the thrombocytopenia developed and resolved during the trial. Increased Creatinine: Across clinical trials in patients with NPC, healthy subjects, and patients with other diseases, increases in serum …

7 DRUG INTERACTIONS Substrates of the Organic Cationic Transporter 2 (OCT2 substrates) : Monitor for adverse reactions and reduce the dosage of the OCT2 substrate. ( 7.1 ) 7.1 Effect of MIPLYFFA on Other Drugs Arimoclomol is an inhibitor of the organic cationic transporter 2 (OCT2) transporter and may increase the exposure of drugs that are OCT2 substrates [see Clinical Pharmacology ( 12.3 )] . When MIPLYFFA is used concomitantly with OCT2 substrates, monitor for adverse reactions and reduce the dosage of the OCT2 substrate.

8 USE IN SPECIFIC POPULATIONS Females and Males of Reproductive Potential: Based on animal findings, MIPLYFFA may impair fertility. ( 8.3 ) 8.1 Pregnancy Risk Summary Based on findings from animal reproduction studies, MIPLYFFA may cause embryofetal harm when administered during pregnancy. There are no available data on MIPLYFFA use in pregnant females to evaluate a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Advise pregnant females of the potential risk to the fetus. In animal reproduction studies, oral administration of arimoclomol to pregnant rats and rabbits during organogenesis resulted in post-implantation loss and structural abnormalities in offspring. These occurred at exposures equal to or greater than 10- and 5-fold, in rats and rabbits respectively, the human exposure at the maximum recommended human daily dose of 372 mg ( see Data ). The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data: In an embryofetal development study in pregnant rats, once daily oral doses of arimoclomol were administered throughout organogenesis from gestation day 6 to 17. Increased post-implantation loss was observed at 10-fold the human exposure, based on AUC at the MRHDD, together with increased ossification in the vertebrae and dilated brain ventricles in litters of dams dosed at equal to or greater than 8-fold the human exposure at the MRHDD. In another embryofetal development study in pregnant rats in which arimoclomol was administered three times-daily throughout organogenesis from gestation day 6 to 17, there was an increase in postimplantation loss and reduced maternal, placental, and fetal weights at 14-fold the human exposure, based on AUC at the MRHD. In addition, fetuses of dams treated at this exposure level exhibited domed craniums, partially split sternum, hydrocephaly, dilated brain ventricles, dilated interventricular foramen, misaligned and misshapen hemicentres and misaligned ossification sites in the sternebrae, misaligned costal cartilage, increased ossification, cerebral and cerebellar hemorrhages, bipartite supraoccipital, large interparietal bone, marked enlargement of the anterior and posterior fontanelles, hyoid bone, meningocele and fusion of the jugal and maxilla. In an embryofetal development study in pregnant rabbits, arimoclomol was administered once daily by oral gavage throughout organogenesis from gestation day 7 to 19. Increased incidences of minor skeletal variations (bent hyoid and unossified phalanx) were observed at 5-fold the human AUC at the MRHDD, coinciding with an adverse reduction of maternal body weight. In a pre- and postnatal development study in pregnant rats, oral arimoclomol was administered from gestation day 6 to lactation day 21. Increased embryofetal lethality and reduced pup weight, with a slight reduction in maternal body weight gain, were observed at 10-fold the human AUC at the MRHDD. 8.2 Lactation Risk Summary There are no data on the presence of arimoclomol in 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 MIPLYFFA and any potential adverse effects on the breastfed infant from MIPLYFFA or from the underlying maternal condition. 8.3 Females and Males of Reproductive Potential MIPLYFFA may cause embryofetal harm when administered to a pregnant female [see Use in Specific Populations ( 8.1 )] . Contraception Females: Consider pregnancy planning and prevention for females of reproductive potential. Infertility Based on findings from animal …

12.1 Mechanism of Action The mechanism(s) by which arimoclomol exerts its clinical effects in patients with NPC is unknown.

11 DESCRIPTION MIPLYFFA capsules contain arimoclomol citrate. Arimoclomol citrate is a crystalline powder of white to off-white color that is freely soluble in water. The chemical name is N -[(2R, Z )-2-hydroxy-3-(1piperidyl)propoxy]pyridine-3-carboximidoyl chloride, 1-oxide, citrate. The empirical formula is C 20 H 28 ClN 3 O 10 and the molecular weight is 505.90 g/mol. The chemical structure is: MYPLIFFA contains 47 mg, 62 mg, 93 mg, or 124 mg of arimoclomol (equivalent to 75 mg, 100 mg, 150 mg, or 200 mg of arimoclomol citrate). The inactive ingredients are microcrystalline cellulose (MCC) and magnesium stearate. The inactive ingredients are not water soluble and will remain undissolved if the contents of the capsule are added to beverages or soft food [see Dosage and Administration ( 2.3 )]. The capsule shells contain hypromellose, titanium dioxide, and one or more of the following: Brilliant Blue FCF-FD&C Blue 1, Yellow iron oxide and Red iron oxide. Chemical Structure

16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied MIPLYFFA (arimoclomol) capsules are supplied in high-density polyethylene (HDPE) bottles with child-resistant closure as follows: MIPLYFFA Strength Capsules Description Package Configuration NDC No. 47 mg White opaque body with black printing “47”, and green opaque cap with black printing “OZ” Bottle of 90 capsules 72542-147-01 62 mg White opaque body with black printing “62”, and yellow opaque cap with black printing “OZ”. Bottle of 90 capsules 72542-162-01 93 mg White opaque body with black printing “93”, and orange opaque cap with black printing “OZ” Bottle of 90 capsules 72542-193-01 124 mg White opaque body with black printing “124”, and red opaque cap with black printing “OZ” Bottle of 90 capsules 72542-124-01 Storage and Handling Store MIPLYFFA at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Store in original container. Protect from light.