Sephience (sepiapterin)
Phenylketonuria Tx - Cofactors of Phenylalanine Hydroxylase Oral Powder In Packet (Ea)
Last reviewed · Source: First Databank (FDB) drug data
Overview
Sepiapterin is a precursor of tetrahydrobiopterin (BH4), an enzymatic cofactor that activates phenylalanine hydroxylase (PAH).
Sepiapterin is a phenylalanine hydroxylase (PAH) activator that is converted to tetrahydrobiopterin (BH4), an essential cofactor for PAH. By increasing BH4 availability, sepiapterin enhances PAH activity in patients with sepiapterin responsive phenylketonuria (PKU), promoting the conversion of phenylalanine to tyrosine and lowering blood phenylalanine concentrations.
After oral administration, sepiapterin reaches peak plasma concentrations at approximately 2 hours and is rapidly converted to BH4, the pharmacologically active metabolite; sepiapterin exposure is generally <2% of BH4exposure. No BH4 accumulation was observed after repeated once daily dosing up to 60 mg/kg in healthy adults. Administration of sepiapterin with food increased BH4 exposure compared with fasting.
With a low-fat meal, BH4 exposure increased by 162-173%. With a high-fat, high-calorie meal, BH4 exposure increased by 221-284%. Sepiapterin has low plasma protein binding and BH4 has low-to-moderate plasma protein.
Seriapterin is rapidly converted to BH4, with sepiapterin concentrations generally declining below the limit of quantitation by 12 hours postdose. The terminal half-life of BH4is approximately 5 hours. Sepiapterin is metabolized by sepiapterin reductase/carbonyl reductase and dihydrofolate reductase to BH4, which is metabolized through enzymatic and nonenzymatic pathways in various tissues.
Following radio-labeled sepiapterin administration, 6.7% of radioactivity was recovered in urine and 26.2% in feces by 240 hours. No clinically significant pharmacokinetic differences were observed based on age, sex, race/ethnicity, or breast cancer resistance protein (BCRP) genotype; the effects of renal impairment, hepatic impairment, and pregnancy on sepiapterin or tetrahydrobiopterin pharmacokinetics are unknown. Sepiapterin pharmacokinetics have not been evaluated in pediatric patients <2 years of age.
USES: This medication is used along with diet changes for long-term treatment of a certain inherited disorder (phenylketonuria-PKU). It helps remove a certain chemical (phenylalanine) from the body. Too much phenylalanine in the body can cause brain damage.
Generic name: sepiapterin
Pronunciation: (SE-pi-AP-ter-in)
Drug class: Phenylketonuria Tx - Cofactors of Phenylalanine Hydroxylase
Therapeutic class: Metabolic Modifiers
Reference product & biosimilars
No reference, biosimilar or interchangeable associated with this drug.
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Indications
The following indications are listed for Sephience:
- Hyperphenylalaninemia
Dosing
No dosing information is available for this tab.
No dosing information is available for this tab.
| Drug label | Dosing type | Instructions |
|---|---|---|
| Sephience 250 Mg Powder Packet | Maintenance | Take 60 mg/kg by oral route once daily with food; mix packet(s) as directed. |
| Sephience 1,000 Mg Powder Pkt | Maintenance | Take 60 mg/kg by oral route once daily with food; mix packet(s) as directed. |
No dosing information is available for this tab.
Drug interactions
Sepiapterin and its active metabolite, tetrahydrobiopterin (BH4), are substrates and inhibitors of breast cancer resistance protein (BCRP) in vitro. Coadministration of sepiapterin with curcumin, a BCRP inhibitor, increased BH4exposure by approximately 20-24% after a single dose; coadministration with rosuvastatin, a BCRP substrate, did not affect rosuvastatin exposure.
Sepiapterin showed no apparent in vitro inhibition of cytochrome P-450 (CYP) enzymes including CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4 and no induction of CYP1A2, CYP2B6, or CYP3A4. Although BH4 was not directly assessed as a CYP inhibitor or inducer, clinically relevant CYP-mediated drug interactions are not expected.
Sepiapterin is not a P-glycoprotein substrate; BH4 is a P-glycoprotein substrate and inhibitor in vitro. Clinically relevant P-glycoprotein-mediated interactions are not expected.
There are no contraindication interactions for this drug.
Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
Sepiapterin/Dihydrofolate Reductase Inhibitors
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Dihydrofolate reductase (DHFR) inhibitors (e.g., trimethoprim, methotrexate, trimetrexate, pemetrexed, pralatrexate) may decrease conversion of sepiapterin to its active metabolite, tetrahydrobiopterin (BH4).(1)
CLINICAL EFFECTS: Concurrent use of DHFR inhibitors and sepiapterin may result in decreased levels of BH4 (the active metabolite of sepiapterin) and reduced or loss of efficacy.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The concurrent use of DHFR inhibitors and sepiapterin should be avoided. If concurrent use cannot be avoided, monitor blood phenylalanine levels.(1)
DISCUSSION: Sepiapterin is metabolized by dihydrofolate reductase (DHFR) to its pharmacologically active form, tetrahydrobiopterin (BH4). Inhibitors of DHFR may reduce the metabolism of sepiapterin to BH4.(1) DHFR inhibitors linked to this monograph include: methotrexate, pemetrexed, pralatrexate, raltitrexed, trimethoprim, and trimetrexate.
There are no moderate interactions for this drug.
Contraindications
*None
There are no contraindication contraindications for this drug.
- Hemorrhage
There are no moderate contraindications for this drug.
Adverse reactions
Most common adverse reactions with sepiapterin (>=2% and greater than placebo) were diarrhea, headache, abdominal pain, hypophenylalaninemia, feces discoloration, and oropharyngeal pain.
There are no severe adverse reactions for this drug.
Less Frequent
- Acute abdominal pain
- Diarrhea
- Discolored feces
- Headache disorder
- Hypophenylalaninemia
- Pain in oropharynx
Rare or Very Rare
- Hemorrhage
Precautions
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Safety and effectiveness of sepiapterin have been established in pediatric patients >=1 month of age with PKU. Use is supported by one adequate and well-controlled trial in 63 pediatric patients 1 to <17 years of age and additional safety and efficacy data from an ongoing open-label trial in adult and pediatric patients.
Safety and effectiveness have not been established in pediatric patients <1 month of age.
Available pregnancy data are insufficient to evaluate the risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes with sepiapterin. Uncontrolled blood phenylalanine levels before and during pregnancy are associated with adverse pregnancy and fetal outcomes. In animal studies, oral sepiapterin given during organogenesis produced no adverse developmental effects at exposures up to 9 times the human exposure in pregnant rats and up to 6 times the human exposure in pregnant rabbits at the maximum recommended human dose.
Uncontrolled blood phenylalanine levels before and during pregnancy are associated with adverse pregnancy and fetal outcomes. To reduce the risk of hyperphenylalaninemia related fetal harm, maintain blood phenylalanine concentrations between 120-360 micromol/L during pregnancy and for 3 months before conception.
Data from the Maternal Phenylketonuria Collaborative Study showed that uncontrolled phenylalanine concentrations >600 micromol/L during pregnancy were associated with increased risks of major birth defects, including microcephaly and major cardiac malformations, intrauterine growth restriction, and future intellectual disability with low IQ.
Patients who may become pregnant require preconception counseling and close monitoring because elevated maternal phenylalanine is teratogenic to the fetal brain and heart.
There are no data on sepiapterin in human or animal milk, its effects on the breastfed infant, or its effects on milk production. Consider the benefits of breastfeeding, the mother's need for sepiapterin, and potential risks to the breastfed infant from sepiapterin or the underlying maternal condition.
No dosage adjustment recommendation is provided by the manufacturer for geriatric patients; studies did not include patients >=65 years of age.
Clinical studies did not include patients >=65 years of age to determine whether they respond differently from younger adults.
ICD codes
| Code | Type | Description |
|---|---|---|
| Hyperphenylalaninemia | ||
| E70.1 | ICD10CM | Other hyperphenylalaninemias |
ICD code information from First Databank (FDB).
Formulary status
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Last reviewed · Source: First Databank (FDB) drug data
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