Highlights

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

Indications and usage

Arimoclomol is indicated for use in combination with miglustat for the treatment of neurologic manifestations of Niemann-Pick disease type C in adult and pediatric patients 2 years of age and older.

Dosage and administration

Recommended dosage

The recommended oral dosage of arimoclomol, in combination with miglustat, for patients with an actual body weight of:

Administer arimoclomol with or without food.

Missed dose. If a dose of arimoclomol is missed, advise the patient to skip the missed dose and to resume taking the prescribed dose at the next scheduled time.

Recommended dosage in patients with renal impairment

The recommended dosage of arimoclomol, 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.

For patients with an eGFR ≥ 15 to < 50 mL/minute, the recommended oral dosage of arimoclomol, in combination with miglustat, for patients with an actual body weight of:

Administer arimoclomol with or without food.

Preparation and administration instructions

Swallow arimoclomol whole. However, for patients who have difficulty swallowing capsules, administer arimoclomol in one of two ways:

Do not save the mixture for later use.

Dosage forms and strengths

Arimoclomol capsules are available as follows:

Contraindications

None.

Warnings and precautions

Hypersensitivity reactions

Hypersensitivity reactions such as urticaria and angioedema have been reported in patients treated with arimoclomol during Trial 1: two patients reported both urticaria and angioedema (6%), and one patient (3%) experienced urticaria alone. The reactions occurred within the first 2 months of treatment. Discontinue arimoclomol in patients who develop severe hypersensitivity reactions. If a mild or moderate hypersensitivity reaction occurs, stop arimoclomol and treat promptly. Monitor the patient until signs and symptoms resolve.

Embryofetal toxicity

Based on findings from animal reproduction studies, arimoclomol 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.

Increased creatinine without affecting glomerular function

Across clinical trials of arimoclomol consisting of patients with Niemann-Pick disease type C, 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 arimoclomol 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.

During arimoclomol 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 arimoclomol discontinuation.

Adverse reactions

The following clinically significant adverse reactions are described below and elsewhere in the labeling:

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 arimoclomol was evaluated in a randomized, double-blind, placebo-controlled, 12-month trial (Trial 1), which included 50 patients 2 to 19 years old with Niemann-Pick disease type C. Patients received weight-adjusted doses of arimoclomol (31 to 124 mg orally three times daily); 28 of the patients were exposed to arimoclomol for 1 year. In Trial 1, 78% of patients received miglustat. Forty-one out of 50 patients who were enrolled in Trial 1 continued into an open-label extension trial, which included 39 patients treated with arimoclomol for more than 1 year, 34 patients treated with arimoclomol for more than 2 years, and 17 patients treated with arimoclomol for more than 5 years.

The most common adverse reactions in Trial 1 (≥ 15%) in arimoclomol-treated patients who also received miglustat were upper respiratory tract infection, diarrhea, and decreased weight. Three (6%) of the arimoclomol-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 arimoclomol-treated patients in Trial 1 were hypersensitivity reactions including urticaria and angioedema.

Table 1shows common adverse reactions in Trial 1 that occurred in at least 8% of arimoclomol-treated patients who also received miglustat.

Table 1. Adverse Reactions in ≥ 8% of Patients with Niemann-Pick disease type C Treated with Arimoclomol in Trial 1 (Subgroup Who Also Received Miglustat)

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 arimoclomol 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 6 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 Niemann-Pick disease type C, healthy subjects, and patients with other diseases, increases in serum creatinine (mean increase was 10% to 20%) occurred mainly within the first month of dosing and were reversible upon treatment discontinuation.

Drug interactions

Effect of arimoclomol 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. When arimoclomol is used concomitantly with OCT2 substrates, monitor for adverse reactions and reduce the dosage of the OCT2 substrate.

Use in specific populations

Pregnancy

Risk summary. Based on findings from animal reproduction studies, arimoclomol may cause embryofetal harm when administered during pregnancy. There are no available data on arimoclomol 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 defects, 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.

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

Females and males of reproductive potential

Arimoclomol may cause embryofetal harm when administered to a pregnant female.

Contraception.

Females. Consider pregnancy planning and prevention for females of reproductive potential.

Infertility. Based on findings from animal studies, arimoclomol 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.

Pediatric use

The safety and effectiveness of arimoclomol in combination with miglustat for the treatment of neurologic manifestations of Niemann-Pick disease type C have been established in pediatric patients 2 years of age and older. Use of arimoclomol in combination with miglustat for this indication is supported by evidence from a randomized, double-blind, placebo-controlled 12-month trial (Trial 1).

The safety and effectiveness of arimoclomol 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.

Geriatric use

Niemann-Pick disease type C is largely a disease of pediatric and young adult patients. Clinical trials of arimoclomol in combination with miglustat in patients with Niemann-Pick disease type C did not include patients aged 65 years or older.

Renal impairment

The recommended arimoclomol 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. The recommended dosage of arimoclomol 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.

The pharmacokinetics of arimoclomol have not been evaluated in patients with eGFR < 15 mL/minute.

Clinical pharmacology

Mechanism of action

The mechanism(s) by which arimoclomol exerts its clinical effects in patients with Niemann-Pick disease type C is unknown.

Pharmacodynamics

The effect of arimoclomol (744 mg/day for 28 days) on serum creatinine was assessed in 16 healthy male subjects. A reversible increase in mean serum creatinine of 19% was observed after 21 days of treatment. No effect on glomerular function (GFR, 125I-iothalamate clearance) or renal hemodynamics (effective renal plasma flow (ERPF); 131I-hippuran clearance) was observed.

Cardiac electrophysiology. The effect of arimoclomol 124 mg and 372 mg (three3 times the maximum recommended dosage) administered three times a day (372 mg/day and 1116 mg/day) on ECG was evaluated in a randomized, partially double-blind, placebo-, and positive-controlled (moxifloxacin 400 mg), multipledose, 4-way crossover trial in 34 healthy male subjects. In this trial, arimoclomol did not prolong the QTc interval to a clinically relevant extent.

Pharmacokinetics

Arimoclomol exhibited linear and dose-proportional pharmacokinetics following oral administration of doses ranging from 62 to 372 mg (three times the maximum recommended dosage) three times a day in healthy subjects. The plasma C_max and AUC_0-8hr of arimoclomol at the 248 mg dose (two times the maximum recommended dosage) are summarized in Table 2.

Table 2. Geometric Mean (CV%) Pharmacokinetic Parameters of Arimoclomol Following Oral Administration in Healthy Subjects

Absorption. The absolute bioavailability of arimoclomol following oral administration has not been determined. The median time to reach maximum plasma arimoclomol concentration (t max) was approximately 0.5 hours.

Effect of food. No clinically significant difference in arimoclomol pharmacokinetics was observed following administration of a high-fat meal (1000 calories, 60% fat) to healthy subjects.

Distribution. The mean apparent volume of distribution (V Z/F) of arimoclomol at steady state in healthy adult subjects is 211 L. A dose-dependent increase in arimoclomol cerebral spinal fluid concentrations was seen at steady state. Plasma protein binding of arimoclomol is approximately 10%.

Elimination. The elimination half-life of arimoclomol is approximately 4 hours. The mean apparent clearance of arimoclomol (CL/F) at steady state is 34 L/hr in healthy adult subjects.

Metabolism. Arimoclomol is predominantly metabolized through glutathionation, O-glucuronidation, and NO-oxime cleavage.

Excretion. Following a single dose of radiolabeled arimoclomol 100 mg to healthy male subjects under fasted conditions, approximately 12% of the dose was recovered in feces and 77.5% in urine (42% unchanged).

Drug interaction studies.

In vitro studies. Cytochrome P450 (CYP) Enzymes: Arimoclomol is not an inhibitor or inducer of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4/5.

Transporter systems. Arimoclomol is an inhibitor of OCT2 and may cause relevant changes in exposure of OCT2 substrates, including the endogenous substrate creatinine. Arimoclomol is not an inhibitor of P-gp, BCRP, OATP1B1, OATP1B3, OAT1, OAT3, MATE1, and MATE2-K transporters. Arimoclomol is a substrate of MATE1 and MATE2-K transporters; MATE1 and MATE2-K inhibitors are not expected to have a clinically relevant effect on arimoclomol exposure.

Specific populations.

Pediatric patients. In pediatric patients with Niemann-Pick disease type C who received the recommended dosing regimens, the estimated steady state mean ± SD serum C_trough and C_max arimoclomol concentrations are 206 ± 60 and 523 ± 194 ng/mL, respectively.

Patients with renal impairment. In a renal impairment study, subjects with moderate to severe renal impairment (estimated glomerular filtration rate [eGFR] 15 to 49 mL/minute) had an approximately 2-fold increase in total exposure to arimoclomol (AUC _inf) compared to subjects with normal renal function (eGFR ≥ 90 mL/minute). There was no clinically meaningful difference in exposure to arimoclomol in subjects with an eGFR of ≥ 50 mL/minute. Arimoclomol was not evaluated in patients with eGFR < 15 mL/minute.

Patients with hepatic impairment. No clinically relevant differences in arimoclomol pharmacokinetics were observed in patients with mild to moderate hepatic impairment (Child-Pugh Score A or B) compared to subjects with normal hepatic function. Arimoclomol has not been studied in patients with severe hepatic impairment (Child-Pugh Criteria C).

Nonclinical toxicology

Carcinogenesis, mutagenesis, and impairment of fertility

Carcinogenesis. In a 2-year carcinogenicity study in Han Wistar rats and a 26-week carcinogenicity study in Transgenic rasH2 mice, oral administration of arimoclomol did not increase the incidence of tumors at systemic exposures that were approximately 8-fold and 11-fold the human exposure, based on AUC at the MRHD.

Mutagenesis. Arimoclomol was not mutagenic or clastogenic in a standard battery of genotoxicity tests (bacterial mutagenicity [Ames], chromosomal aberration in Chinese Hamster Ovary cells, mouse lymphoma forward mutation, mouse and rat bone marrow micronucleus).

Impairment of fertility. In a fertility and early embryonic development study in rats, once daily oral arimoclomol doses were administered to males for 4 weeks prior to and throughout mating (for a total of 10 weeks) and to females for 2 weeks before mating and to gestation day 6. A reduction in fertility and fecundity indices was noted for both sexes at 9-fold the human exposure, based on AUC at the MRHD. At the same dose level, a reduction in the number of corpora lutea was observed in females, and reduced sperm motility, immotile sperm, reduced sperm count and increased sperm abnormalities were observed in males. A dose-dependent increase in preimplantation loss was noted across all treated groups (equal to or greater than 5-fold the human exposure, based on AUC at the MRHD), which resulted in a reduction in the number of live embryos.

Clinical studies

Safety and effectiveness of arimoclomol were assessed in Trial 1, a randomized, double-blind, placebocontrolled, 12-month trial in patients 2 to 19 years of age who had a molecularly confirmed diagnosis of Niemann-Pick disease type C (NCT02612129). Fifty patients were randomized 2:1 to treatment with weight-adjusted arimoclomol (31 to 124 mg) or placebo orally three times per day. The randomization was stratified by miglustat use status at baseline.

Efficacy assessments, including the rescored 4-domain Niemann-Pick disease type C Clinical Severity Scale (R4DNPCCSS) score, were performed at baseline and every 3 months until 12 months of treatment. The R4DNPCCSS is a measure of Niemann-Pick disease type C progression that consists of the four items assessing ambulation, speech, swallow, and fine motor skills that patients with Niemann-Pick disease type C and their caregivers and physicians have identified as most relevant with higher scores representing greater severity of disease.

In Trial 1, 76% and 81% of patients in the arimoclomol and placebo groups, respectively, received miglustat 6 months or longer prior to the time of enrollment. For the subgroup of patients who also received miglustat at enrollment, the mean age was 11.6 years, the mean time since first Niemann-Pick disease type C symptom was 8.5 years, and the mean age at onset of first neurologic symptom was 4.9 years. In this subgroup, 56% of patients were females, 87% were white, 5% were Asian, 3% were native Hawaiian or other Pacific Islander, and 5% were unknown. The mean baseline R4DNPCCSS score was higher in the arimoclomol group (n=26; mean=8.9) than the placebo group (n=13; mean=7), with an overall mean R4DNPCCSS score of 8.3.

In the arimoclomol group, four patients discontinued the study: one patient due to consent withdrawal and three patients due to adverse reactions. In the placebo group, one patient discontinued the study due to an adverse event.

See Table 3 and Figure 1 in the DAILYMED drug label information for more details from the clinical study.

There were insufficient data to determine the effectiveness of the use of arimoclomol without miglustat for the treatment of neurologic manifestations in patients with Niemann-Pick disease type C.

How supplied/storage and handling

How supplied. Arimoclomol capsules are supplied in high-density polyethylene bottles with child-resistant closure as follows:

Storage and handling. Store arimoclomol at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F). Store in original container. Protect from light.

Patient counseling information

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

Drug interactions. Advise the patient to inform his/her healthcare provider if he/she is taking, or plan to take, any prescription or over-the-counter medications and supplements because of the potential for drug interactions.

Hypersensitivity reactions. Advise the patient or caregiver to contact his/her healthcare provider immediately if urticaria (hives), shortness of breath, persistent cough, or facial swelling develop in response to arimoclomol treatment.

Embryofetal toxicity. Arimoclomol may cause embryo-fetal harm. Advise the 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. Counsel females of reproductive potential about pregnancy planning and prevention.

Infertility. Advise females and males of reproductive potential that arimoclomol may impair fertility.

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.