BRIEF SUMMARY

FOSDENOPTERIN -(Feb 2021)

Indn-  To treat patients with the rare genetic disease molubdenum cofactor deficiency  Type A

Comp- For injection: 9.5 mg of fosdenopterin as a lyophilized powder or cake in a single-dose vial for reconstitution.                                                                       Administer as an intravenous infusion once daily at a rate of 1.5 mL/minute with non-DEHP tubing with a 0.2 micron filter. Volumes below 2 mL may require syringe administration through slow intravenous push.

ADR- most common adverse reactions  were catheter-related complications, pyrexia, viral infection, pneumonia, otitis media, vomiting, cough/sneezing, viral upper respiratory infection, gastroenteritis, bacteremia, and diarrhea. 

CI- None.

WARNINGS - 

­ 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. 

Pat Inform-

Photosensitivity-                                                                                                      Advise patients and/or caregivers of the potential for photosensitivity reactions and to ensure that the patient avoids or minimizes exposure to sunlight and artificial UV light exposure (i.e., UVA or UVB phototherapy) during use

Instruct patients/caregivers to seek medical attention immediately if the patient develops a rash or if they notice symptoms of photosensitivity reactions (redness, burning sensation of the skin, blisters

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U.S. FDA APPROVED DRUGS SURING 2021                                          

Serial No 9

Name of the Drug-    NULIBRY

Active Ingredient -    Fosdenopterin

Pharmacological Classification-   To treat patients with the rare genetic disease                                                                 molubdenum cofactor deficiency  Type A                                                                                                                                                           Date of Approval-          2/26/2021

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use                                 NULIBRY™ safely and effectively.                                                                                See full prescribing information for NULIBRY. NULIBRY (fosdenopterin) for injection, for intravenous use

Initial U.S. Approval: 2021

INDICATIONS AND USAGE

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

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. 

CONTRAINDICATIONS-                                                                                                         ­ None.

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) -------------------------------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)

DOSAGE AND ADMINISTRATION

­ • Start NULIBRY if known or presumed MoCD Type A. Promptly discontinue if MoCD Type A is not confirmed by genetic testing.

 • Reconstitute before use and complete infusion within 4 hours of reconstitution.

 • Administer as an intravenous infusion once daily at a rate of 1.5 mL/minute with non-DEHP tubing with a 0.2 micron filter. Volumes below 2 mL may require syringe administration through slow intravenous push.

 • See Full Prescribing Information for additional important preparation instructions and administration instructions.

 • See the table below for the recommended dosage in patients less than one year of age

 Titration Schedule-                                                                                                    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 Month 1 0.7 mg/kg once daily 0.75 mg/kg once daily Month 3 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.

DOSAGE FORMS AND STRENGTHS-                                                                               ­ For injection: 9.5 mg of fosdenopterin as a lyophilized powder or cake in a single-dose vial for reconstitution. (

PATIENT COUNSELING INFORMATION-

Advise patients/caregivers to read the FDA-approved patient labeling (Instructions for Use) and complete the treatment logs as appropriate.

Photosensitivity-                                                                                                      Advise patients and/or caregivers of the potential for photosensitivity reactions and to ensure that the patient avoids or minimizes exposure to sunlight and artificial UV light exposure (i.e., UVA or UVB phototherapy) during use of NULIBRY, uses broad spectrum sunscreen with high sun protection factor (patients 6 months of age and older), and wears clothing, a hat, and sunglasses that protects against sun exposure.

Instruct patients/caregivers to seek medical attention immediately if the patient develops a rash or if they notice symptoms of photosensitivity reactions (redness, burning sensation of the skin, blisters

Manufactured by: Alcami Carolinas Corporation, Charleston, SC              Distributed by: Origin Biosciences, Inc., Boston, MA

 CLINICAL PHARMACOLOGY

1. Mechanism of Action- Patients with MoCD Type A have mutations in the MOCS1 gene leading to deficient MOCS1A/B dependent synthesis of the intermediate substrate, cPMP.

Substrate replacement therapy with NULIBRY provides an exogenous source of cPMP, which is converted to molybdopterin. Molybdopterin is then converted to molybdenum cofactor, which is needed for the activation of molybdenum-dependent enzymes, including sulfite oxidase (SOX), an enzyme that reduces levels of neurotoxic sulfites.

2. Pharmacodynamics-                                                                                                    In MoCD Type A, the lack of effective SOX leads to elevated levels of the neurotoxic sulfite, S-sulfocysteine (SSC). Treatment with NULIBRY resulted in a reduction in the level of urinary SSC normalized to creatinine and the reduction was sustained with long-term treatment with NULIBRY 

. Cardiac Electrophysiology A thorough QT study of NULIBRY has not been conducted.

3. Pharmacokinetics -                                                                                                  The pharmacokinetics of fosdenopterin in healthy adult subjects following a single intravenous NULIBRY infusion are summarized.                                                                The area under the plasma concentration-time curve (AUC) and the maximum plasma concentration (Cmax) of fosdenopterin increased in an approximately proportional manner with increasing doses. 

Distribution -                                                                                                                     The volume of distribution (Vd) of fosdenopterin was approximately 300 mL/kg. The plasma protein binding of fosdenopterin ranged from 6 to 12%.

Elimination -                                                                                                                      The mean total body clearance (CL) of fosdenopterin ranged from 167 to 195 mL/h/kg. The mean half-life of fosdenopterin ranged from 1.2 to 1.7 hours.

Metabolism Fosdenopterin is predominantly metabolized through nonenzymatic degradation processes to Compound Z, an inactive oxidation product of endogenous cPMP.

Excretion Renal clearance of fosdenopterin accounts for approximately 40% of total body clearance.

Specific Populations The effect of renal and hepatic impairment on the pharmacokinetics of fosdenopterin is unknown. Pediatric Patients Pharmacokinetic properties of fosdenopterin in pediatric MoCD Type A patients are similar to healthy adult subjects.

Drug Interaction Studies In Vitro Studies Cytochrome P450 (CYP) Enzymes: Fosdenopterin does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4/5.

Fosdenopterin does not induce CYP1A2, CYP2B6, or CYP3A4. Transporter Systems: Fosdenopterin is a weak inhibitor of MATE2-K and OAT1, but does not inhibit P-gp, BCRP, OATP1B1, OATP1B3, OCT2, OAT1, OAT3, MATE1, and MATE2-K.

Fosdenopterin is a weak substrate for MATE1, but is not a substrate of P-gp, BCRP, OATP1B1, OATP1B3, OCT2, OAT1, OAT3, or MATE2-K.

 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy                                                                                                                    -Risk Summary- There are no available data on NULIBRY use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes

. Animal reproduction toxicology studies have not been conducted with fosdenopterin.

The estimated 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 are 2% to 4% and 15% to 20%, respectively.

8.2 Lactation -                                                                                                                    Risk Summary- There are no human or animal data available to assess the presence of NULIBRY or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production for the mother.

The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for NULIBRY and any potential adverse effects on the breastfed infant from NULIBRY or from the underlying maternal condition.

3. 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..

4.Geriatric Use-                                                                                                            MoCD Type A is largely a disease of pediatric patients. Clinical studies of NULIBRY did not include patients 65 years of age and older.

 Adult Use -The safety and effectiveness of NULIBRY for the treatment of adults with MoCD Type A have been established. Use of NULIBRY in adults for this indication is based on an adequate and well- controlled clinical investigation in pediatric patients