Fosdenopterin is a cyclic pyranopterin monophosphate (cPMP) indicated to reduce the risk of mortality in patients with molybdenum cofactor deficiency (MoCD) type A. Fosdenopterin is given intravenously and replaces the missing cPMP that is not found in these patients. Patients with MoCD type A experience severe and rapidly progressive neurologic damage including intractable seizures, feeding difficulties, and muscle weakness from the accumulation of toxic sulfite metabolites in the central nervous system. Most patients die in early childhood from infections. In patients treated with fosdenopterin, survival at 3 years was 84% compared to 55% for untreated patients. Catheter-related complications were the most common adverse reaction reported during fosdenopterin clinical trials.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. Reconstituted fosdenopterin is a clear and colorless to pale yellow solution. Do not use if there are particles present or the solution is discolored.
-If a dose is missed, administer it as soon as possible. Administer the next scheduled dose at least 6 hours after the administration of the missed dose.
Intravenous Administration
Preparation
-Allow vials to warm to room temperature (by hand warming for 3 to 5 minutes or exposing to ambient air for approximately 30 minutes).
-Reconstitute each vial with 5 mL of Sterile Water for Injection.
-Gently swirl the vial continuously until powder is completely dissolved. Do not shake.
-The final concentration after reconstituiton is 1.9 mg/mL.
-Administer the total reconstituted dose immediately, completing the infusion with 4 hours of reconstitution.
-Storage: Discard unused reconstituted solution 4 hours after reconstitution. If immediate use is not possible, store reconstituted solution at room temperature [15 to 25 degrees C (59 to 77 degrees F)] or refrigerated [2 to 8 degrees C (36 to 46 degrees F)]. If reconstituted solution 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. Do not heat. Do not re-freeze after reconstitution. Do not shake.
Intermittent IV Infusion
-Administer through an infusion pump at a rate of 1.5 mL per minute using non-DEHP tubing with a 0.2-micron filter.
-Dose volumes below 2 mL may require syringe administration through slow intravenous push.
-Complete administration within 4 hours of reconstitution.
-Do not mix fosdenopterin with other drugs. Do not administer as an infusion with other drugs.
The assessment of adverse reactions for fosdenopterin is based on data from 2 open-label, single-arm studies, study 1 (n = 8) and study 2 (n = 1), in patients with a confirmed diagnosis of molybdenum cofactor deficiency (MoCD) type A (8 of the 9 patients were previously treated with recombinant cyclic pyranopterin monophosphate (rcPMP)). Additional safety data are also available from an observational study in patients with MoCD type A who received rcPMP (study 3, n = 10).
Infectious and respiratory adverse reactions reported in fosdenopterin treated patients included viral infection (56%), pneumonia (44%), otitis media (44%), upper viral respiratory infection (33%), bacteremia (33%), influenza (22%), lower respiratory tract infection (22%), viral tonsillitis (22%), and pharyngitis or oropharyngeal pain (22%).
Injection site reaction or catheter-related complications was reported in 89% of fosdenopterin treated patients. Reported reactions included complications 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.
Gastrointestinal adverse reactions reported in patients receiving treatment with fosdenopterin during clinical trials include vomiting (44%), diarrhea (33%), gastroenteritis (33%), and abdominal pain (22%).
Neurologic adverse reactions reported in patients receiving treatment with fosdenopterin during clinical trials include seizures (22%) and agitation (22%).
Fever or pyrexia was reported in 78% of patients receiving treatment with fosdenopterin during clinical trials. Additional reactions reported include cough/sneezing (44%), anemia (22%), eye swelling (22%), and maculopapular rash (22%).
Adverse reactions reported in more than 1 patient treated with recombinant cyclic pyranopterin monophosphate (rcPMP) (contains the same active moiety and biologic activity of fosdenopterin) were necrotizing enterocolitis, sepsis, oral candidiasis, varicella, fungal skin infection, and eczema.
Animal studies have shown that fosdenopterin has the potential of causing a skin photosensitivity disorder. Advise fosdenopterin-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.
There are no available data on fosdenopterin use in pregnancy to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.
There are no human or animal data available to assess the presence of fosdenopterin or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production for the mother. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated maternal condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.
General Dosing Information
-Start fosdenopterin if the patient has a diagnosis or presumptive diagnosis of molybdenum cofactor deficiency (MoCD) type A.
-In patients with a presumptive diagnosis of MoCD type A, confirm the diagnosis immediately after the initiation of fosdenopterin treatment. Discontinue fosdenopterin if the diagnosis is not confirmed by genetic testing.
For the reduction of mortality in patients with molybdenum cofactor deficiency type A:
NOTE: Fosdenopterin has been designated as an orphan drug for this indication by the FDA.
Intravenous dosage:
Adults: 0.9 mg/kg/dose IV once daily.
Children and Adolescents: 0.9 mg/kg/dose IV once daily.
Infants: Initially, 0.55 mg/kg/dose IV once daily. After 1 month, increase to 0.75 mg/kg/dose IV once daily. After 3 months, increase to 0.9 mg/kg/dose IV once daily.
Neonates 37 weeks gestational age and older: Initially, 0.55 mg/kg/dose IV once daily. After 1 month, increase to 0.75 mg/kg/dose IV once daily. After 3 months, increase to 0.9 mg/kg/dose IV once daily.
Premature Neonates younger than 37 weeks gestational age: Initially, 0.4 mg/kg/dose IV once daily. After 1 month, increase to 0.7 mg/kg/dose IV once daily. After 3 months, increase to 0.9 mg/kg/dose IV once daily.
Maximum Dosage Limits:
-Adults
0.9 mg/kg/day IV.
-Geriatric
Safety and efficacy have not been established.
-Adolescents
0.9 mg/kg/day IV.
-Children
0.9 mg/kg/day IV.
-Infants
0.9 mg/kg/day IV.
-Neonates
0.9 mg/kg/day IV.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
*non-FDA-approved indication
There are no drug interactions associated with Fosdenopterin products.
Molybdenum cofactor deficiency (MoCD) type A patients have mutations in the MOCS1 gene leading to deficient MOCS1A/B dependent synthesis of the intermediate substrate, cyclic pyranopterin monophosphate (cPMP). Substrate replacement therapy with fosdenopterin 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 concentrations of neurotoxic sulfites that are the predominant cause of symptom manifestation.
Fosdenopterin is administered intravenously. The volume of distribution Vd is 300 mL/kg. Protein binding ranges from 6% to 12%. Fosdenopterin is predominantly metabolized through nonenzymatic degradation processes to compound Z, an inactive oxidation product of endogenous cyclic pyranopterin monophosphate (cPMP). It is excreted in the urine at approximately 40% of total body clearance with a plasma clearance of 167 to 195 mL/kg/hour and an elimination half-life of 1.2 to 1.7 hours.
Affected cytochrome P450 isoenzymes and drug transporters: MATE2-K and OAT1
Based on in vitro studies, fosdenopterin is a weak inhibitor of MATE2-K and OAT1. It does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4/5, P-gp, BCRP, OATP1B1, OATP1B3, OCT2, OAT3, and MATE1. Fosdenopterin does not induce CYP1A2, CYP2B6, or CYP3A4. It is a weak substrate for MATE1, but is not a substrate of P-gp, BCRP, OATP1B1, OATP1B3, OCT2, OAT1, OAT3, or MATE2-K.
-Route-Specific Pharmacokinetics
Intravenous Route
The AUC and Cmax of fosdenopterin increased in an approximately proportional manner with increasing doses in healthy adult subjects.
-Special Populations
Hepatic Impairment
The effect of hepatic impairment on the pharmacokinetics of fosdenopterin is unknown.
Renal Impairment
The effect of renal impairment on the pharmacokinetics of fosdenopterin is unknown.
Pediatrics
The pharmacokinetic properties of fosdenopterin in pediatric molybdenum cofactor deficiency (MoCD) type A patients are similar to healthy adults subjects.
Geriatric
Fosdenopterin has not been studied in geriatric patients given the prevalence of the disease in pediatric patients.