Nulibry Drug Information

is indicated to reduce the risk of mortality in patients with molybdenum cofactor deficiency (MoCD) Type A. NULIBRY is cyclic pyranopterin monophosphate (cPMP) indicated to reduce the risk of mortality in patients with molybdenum cofactor deficiency (MoCD) Type A.

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. Overview of Safety Evaluation The safety of NULIBRY was assessed in 37 pediatric patients and healthy adults who received at least one intravenous infusion of NULIBRY or an E. coli derived non-salt, anhydrous form of cPMP (recombinant cPMP or rcPMP, which has the same active moiety and therefore the same biologic activity as NULIBRY). Of these 37 patients/healthy adults, 13 were pediatric patients with MoCD Type A in Studies 1, 2, and 3 , 6 were pediatric patients with presumptive MoCD Type A but who were later confirmed to not have MoCD Type A, and 18 were healthy adults (without MoCD Type A) in a Phase 1 study. Adverse Reactions Assessment of adverse reactions for NULIBRY is based on data from two open-label, single-arm studies, Study 1 (n=8) and Study 2 (n=1), in patients with a confirmed diagnosis of MoCD Type A (8 of the 9 patients were previously treated with rcPMP). In these studies, patients received a daily intravenous infusion of NULIBRY. The median exposure to NULIBRY was 4.3 years and ranged from 8 days to 5.6 years.

In these studies, 44% of patients were males and 56% were females, 67% were White and 33% were Asian. The mean age was 14 days and ranged from 1 day to 69 days at time of first infusion. Table 2 presents the most common adverse reactions that occurred in NULIBRY-treated patients in Studies 1 and 2. Table 2 Common Adverse Reactions Reported in Two or More NULIBRY-Treated Patients with MoCD Type A (Studies 1 and 2) Adverse Reactions NULIBRY-Treated Patients (N=9) n (%) Abbreviations: MoCD = molybdenum cofactor deficiency 1 Catheter-related complications included complication associated with device, catheter site abscess, catheter site discharge, catheter site extravasation, catheter site pain, catheter site infection, catheter site inflammation, device dislocation, device leakage, device occlusion, and vascular device infection.

Catheter-related complications 1 8 (89%) Pyrexia 7 (78%) Viral infection 5 (56%) Pneumonia 4 (44%) Otitis Media 4 (44%) Vomiting 4 (44%) Cough/Sneezing 4 (44%) Upper viral respiratory infection 3 (33%) Gastroenteritis 3 (33%) Diarrhea 3 (33%) Bacteremia 3 (33%) Abdominal pain 2 (22%) Influenza 2 (22%) Lower respiratory tract infection 2 (22%) Viral tonsillitis 2 (22%) Oropharyngeal pain 2 (22%) Rash maculo-papular 2 (22%) Anemia 2 (22%) Eye swelling 2 (22%) Seizure 2 (22%) Agitation 2 (22%) Safety data are also available from 10 patients with MoCD Type A who received rcPMP in Study 3 (an observational study). The median time on rcPMP treatment was 1.5 years and ranged from 6 days to 4.4 years. In Study 3, the patient population was evenly distributed between males and females with a mean age of 18 days (range 1, 69) at time of first infusion, 70% were White, and 30% were Asian. In Study 3, one patient died of necrotizing enterocolitis.

Adverse reactions for the rcPMP-treated patients were similar to the NULIBRY-treated patients, except for the following additional adverse reactions that were reported in more than one patient: sepsis, oral candidiasis, varicella, fungal skin infection, and eczema.

Pregnancy Risk Summary There are no available data on NULIBRY use in pregnant females to evaluate for a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. In animal reproduction studies, no adverse developmental outcomes occurred at dose exposures 32-89 times the human exposure at the maximum recommended human dose (MRHD) of 0.9 mg/kg/day (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, intravenous administration of fosdenopterin to pregnant rabbits once daily during the period of organogenesis (GD 7 to GD 20) at doses up to 200 mg/kg/day (approximately 89 times the human exposure at the MRHD, based on AUC) did not result in adverse developmental effects. In a pre- and postnatal development study, subcutaneous administration of fosdenopterin to pregnant mice once daily throughout pregnancy and lactation (GD 6 to Lactation Day 20) at doses of 50, 100, or 200 mg/kg/day (up to 32 times the human exposure at the MRHD, based on AUC) did not result in adverse developmental effects.

Pediatric Use Safety and effectiveness of NULIBRY for the treatment of MoCD Type A have been established in pediatric patients starting from birth. Use of NULIBRY for this indication is supported by evidence from two open-label studies (Studies 1 and 2) and one observational study (Study 3), in which 13 pediatric patients aged birth to 6 years of age were treated with NULIBRY or rcPMP. Pediatric use information is discussed throughout the labeling. Animal studies have identified that NULIBRY has phototoxic potential.

Advise NULIBRY-treated patients or their caregivers to avoid patient exposure to direct sunlight and artificial UV light exposure (i.e., UVA or UVB phototherapy) and adopt precautionary measures.