Arimoclomol Citrate

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 )

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 )

None. None. ( 4 )

Hypersensitivity Reactions : Urticaria and angioedema have been reported. Discontinue MIPLYFFA in patients who develop these adverse reactions. ( 5.1 ) Embryofetal Toxicity : May cause fetal harm. Advise pregnant females of the potential risk to the fetus and consider pregnancy planning and prevention. ( 5.2 ) Increased Creatinine without Affecting Glomerular Function: Mean increases in serum creatinine of 10-20% have been reported. Use alternative measures to assess renal function which are not based on creatinine. ( 5.3 )

5.1 Hypersensitivity Reactions Hypersensitivity reactions such as urticaria and angioedema have been reported in patients treated with MIPLYFFA during Trial 1 [see Clinical Studies ( 14 )] : two patients reported both urticaria and angioedema (6%) and one patient (3%) experienced urticaria alone. The reactions occurred within the first two months of treatment. Discontinue MIPLYFFA in patients who develop severe hypersensitivity reactions. If a mild or moderate hypersensitivity reaction occurs, stop MIPLYFFA and treat promptly. Monitor the patient until signs and symptoms resolve [see Adverse Reactions ( 6.1 )].

5.2 Embryofetal Toxicity Based on findings from animal reproduction studies, MIPLYFFA may cause embryofetal harm when administered during pregnancy. In animal reproduction studies, oral administration of arimoclomol to pregnant rats and rabbits resulted in post-implantation loss and structural abnormalities in offspring. These occurred at exposures equal to or greater than 10- and 5-fold, for rats and rabbits respectively, the human exposure at the maximum recommended human daily dose of 372 mg. Advise pregnant females of the potential risk to the fetus. Consider pregnancy planning and prevention for females of reproductive potential [see Use in Specific Populations ( 8.1 , 8.3 )] .

5.3 Increased Creatinine without Affecting Glomerular Function Across clinical trials of MIPLYFFA consisting of patients with NPC, healthy subjects, and patients with other diseases, there were mean increases in serum creatinine of 10% to 20% compared to baseline. These increases occurred mostly in the first month of MIPLYFFA treatment and were not associated with changes in glomerular function. The increases in serum creatinine may be due to inhibition of renal tubular secretion transporters [see Drug Interactions ( 7 ) and Clinical Pharmacology ( 12.2 , 12.3 )]. During MIPLYFFA treatment, use alternative measures that are not based on creatinine to assess renal function such as BUN, cystatin C, or measured GFR. Increases in creatinine reversed upon MIPLYFFA discontinuation [see Clinical Pharmacology ( 12.2 )] .

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 creatinine (mean increase was 10-20%) occurred mainly within the first month of dosing and were reversible upon treatment discontinuation.

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.

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 studies, MIPLYFFA may impair fertility in females and males of reproductive potential. In a rat fertility study, oral administration of arimoclomol resulted in decreased male and female fertility at 9-fold and increased pre-implantation loss at 5-fold the human exposure, based on AUC at MRHD. It is not known if these effects are reversible [see Nonclinical Toxicology ( 13.1 )] .

8.4 Pediatric Use The safety and effectiveness of MIPLYFFA in combination with miglustat for the treatment of neurological manifestations of NPC have been established in pediatric patients 2 years of age and older. Use of MIPLYFFA in combination with miglustat for this indication is supported by evidence from a randomized, double-blind, placebo-controlled 12-month trial (Trial 1) [see Clinical Studies ( 14 )]. The safety and effectiveness of MIPLYFFA have not been established in pediatric patients younger than 2 years of age. Juvenile Animal Toxicity Data In juvenile toxicity studies in rats, increased incidences of renal pelvic dilatation were observed at all dose levels corresponding to 4-, 7- and 17-fold the human exposure based on AUC at MRHDD after both 2 and 8 weeks of dosing when animals were dosed from postnatal day 7.

8.5 Geriatric Use NPC is largely a disease of pediatric and young adult patients. Clinical trials of MIPLYFFA in combination with miglustat in patients with NPC did not include patients aged 65 years or older.

8.6 Renal Impairment The recommended MIPLYFFA dosage in combination with miglustat in patients with an eGFR 15 mL/minute to < 50 mL/minute is lower than the recommended dosage (less frequent dosing) in patients with normal renal function [see Dosage and Administration ( 2.2 )]. 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. Plasma concentrations of arimoclomol increased in patients with eGFR ≥ 15 mL/minute to < 50 mL/minute [see Clinical Pharmacology ( 12.3 )]. The pharmacokinetics of arimoclomol have not been evaluated in patients with eGFR < 15 mL/minute.

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