Nulibry

1 INDICATIONS AND USAGE NULIBRY 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. ( 1 )

2 DOSAGE AND ADMINISTRATION Start NULIBRY if known or presumed MoCD Type A. Promptly discontinue if MoCD Type A is not confirmed by genetic testing. ( 2.1 ) NULIBRY is intended for administration by a healthcare provider. If deemed appropriate by a healthcare provider, NULIBRY may be administered at home by the patient's caregiver. ( 2.2 ) See the table below for the recommended dosage in patients less than one year of age. Administer NULIBRY by intravenous infusion once daily. For dose volumes less than 2 mL, consider administering by slow intravenous push. ( 2.3 ) Titration Duration Preterm Neonates (Gestational Age Less than 37 Weeks) Term Neonates (Gestational Age 37 weeks and Above) Initial Dosage 0.4 mg/kg once daily 0.55 mg/kg once daily Dosage at Month 1 and Month 2 0.7 mg/kg once daily 0.75 mg/kg once daily Dosage at Month 3 to Month 12 0.9 mg/kg once daily 0.9 mg/kg once daily Recommended Dosage in Patients One Year of Age or Older: 0.9 mg/kg given as an intravenous infusion once daily. ( 2.3 ) 2.1 Patient Selection Start NULIBRY if the patient has a diagnosis or presumptive diagnosis of MoCD Type A. In patients with a presumptive diagnosis of MoCD Type A, confirm the diagnosis of MoCD Type A immediately after initiation of NULIBRY treatment. In such patients, discontinue NULIBRY if the MoCD Type A diagnosis is not confirmed by genetic testing. 2.2 Important Recommendation Prior to NULIBRY Treatment NULIBRY is intended for administration by a healthcare provider. If deemed appropriate by a healthcare provider, NULIBRY may be administered at home by the patient's caregiver. If NULIBRY can be administered by a caregiver/patient, advise them to read the detailed instructions on the preparation, administration, storage, and disposal of NULIBRY for caregivers [see Instructions for Use ]. 2.3 Recommended Dosage and Administration Recommended Dosage and Administration in Patients Less Than One Year of Age (by gestational age) The recommended dosage regimen of NULIBRY in patients less than one year of age (by gestational age), is based on actual body weight as shown in Table 1 . Administer NULIBRY by intravenous infusion once daily. For dose volumes less than 2 mL, consider administering by slow intravenous push using syringe administration [ see Dosage and Administration ( 2.4 ) ] . Table 1 Recommended Initial Dosage and Titration Schedule of NULIBRY for Patients Less Than One Year of Age by Gestational Age Titration Duration Preterm Neonates (Gestational Age Less than 37 Weeks) Term Neonates (Gestational Age 37 Weeks and Above) Initial Dosage 0.4 mg/kg once daily 0.55 mg/kg once daily Dosage at Month 1 and Month 2 0.7 mg/kg once daily 0.75 mg/kg once daily Dosage at Month 3 to Month 12 0.9 mg/kg once daily 0.9 mg/kg once daily Recommended Dosage and Administration in Patients One Year of Age or Older For patients one year of age or older, the recommended dosage of NULIBRY is 0.9 mg/kg (based on actual body weight) administered as an intravenous infusion once daily. Missed Dose If a NULIBRY dose is missed, administer the missed dose as soon as possible. Administer the next scheduled dose at least 6 hours after the administration of the missed dose. 2.4 Preparation and Administration Instructions Preparation NULIBRY must be reconstituted prior to use. Use aseptic technique during preparation and follow these instructions: Calculate the dose based on the patient's weight to determine the number of vials needed and total reconstituted dose volume. More than one vial may be needed to achieve the calculated dose. Remove the required number of vials from the freezer to allow them to reach room temperature (by hand warming for 3 to 5 minutes or exposing to ambient air for approximately 30 minutes). Reconstitute each NULIBRY vial with 5 mL of Sterile Water for Injection, USP. Gently swirl the vial continuously until the powder is completely dissolved. DO NOT shake. After reconstitution, the final concentration of NULIBRY reconstituted solution is 9.5 mg/5 mL (1.9 mg/mL). Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Reconstituted NULIBRY is a clear and colorless to pale yellow solution. Do not use if there are particles present or if the solution is discolored. Withdraw the calculated dose volume from the vial(s) using a syringe. Discard any unused solution remaining in the vial(s). Administration If reconstituted NULIBRY solution in the vial is refrigerated, allow it to come to room temperature (by hand warming for 3 to 5 minutes or exposing to ambient air for approximately 30 minutes) before administration. Administer NULIBRY as an intravenous infusion using an infusion pump at a rate of 1.5 mL per minute. Use non-DEHP tubing and a 0.2 micron filter to administer the total reconstituted dose volume. For dose volumes less than 2 mL, consider administering by slow intravenous push over 1 to 2 minutes using syringe administration. Complete administration of NULIBRY within 4 hours of reconstitution [ see Dosage and Administration ( 2.6 ) ] . Do not mix NULIBRY with other drugs. Do not administer as an infusion with other drugs. 2.5 Home Administration If deemed appropriate by a healthcare provider, NULIBRY may be administered at home by the patient's caregiver. If NULIBRY can be administered by a caregiver/patient, advise them to read the detailed instructions on the preparation, administration, storage, and disposal of NULIBRY for caregivers [see Instructions for Use ]. 2.6 Storage of Reconstituted Solution If the reconstituted NULIBRY solution in the vial is not used immediately, store at room temperature at 15°C to 25°C (59°F to 77°F) or refrigerate at 2°C to 8°C (36°F to 46°F) for up to 4 hours (inclusive of infusion time), or discard. Do not heat. Do not re-freeze NULIBRY after reconstitution. Do not shake.

4 CONTRAINDICATIONS None. None. ( 4 )

5 WARNINGS AND PRECAUTIONS Potential for Photosensitivity : Advise patients/caregivers to avoid patient exposure to sunlight, and to have the patient wear sunscreen, protective clothing, and sunglasses when exposed to the sun. If photosensitivity occurs, advise caregivers/patients to seek medical attention immediately and consider a dermatological evaluation. ( 5.1 , 13.2 ) 5.1 Potential for Photosensitivity Animal studies have identified that NULIBRY has phototoxic potential [ see Nonclinical Toxicology ( 13.2 ) ]. Advise NULIBRY-treated patients or their caregivers to avoid or minimize patient exposure to direct sunlight and artificial UV light exposure (i.e., UVA or UVB phototherapy) and adopt precautionary measures (e.g., have the patient wear protective clothing and hats, use broad spectrum sunscreen with high sun protection factor (SPF) in patients 6 months of age and older, and wear sunglasses when exposed to the sun). If photosensitivity occurs, advise caregivers/patients to seek medical attention immediately and consider a dermatological evaluation.

6 ADVERSE REACTIONS The most common adverse reactions (>25%) were catheter-related complications, pyrexia, viral infection, pneumonia, otitis media, vomiting, cough/sneezing, viral upper respiratory infection, gastroenteritis, bacteremia, and diarrhea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Sentynl Therapeutcis, Inc. at 888-507-5206 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. 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 [ see Clinical Studies ( 14 )] , 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 [ see Clinical Studies ( 14 )]. 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) [ see Clinical Studies ( 14 )]. 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.

8.1 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.