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SEPHIENCE (sepiapterin) contains the drug substance sepiapterin, a PAH activator. Sepiapterin is a yellow to orange powder. Sepiapterin is slightly soluble in water with the solubility at 1.4 mg/mL.
The chemical name of sepiapterin is (S)-2-amino-6-(2-hydroxypropanoyl)-7,8-dihydropteridin-4(3H)-one. The molecular formula is C9H11N5O3 and the molecular weight is 237.22 g/mol. The structural formula is:
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SEPHIENCE oral powder contains either 250 mg or 1,000 mg of sepiapterin to be administered orally. The inactive ingredients are: colloidal silicon dioxide, croscarmellose sodium, isomalt, magnesium stearate, mannitol, microcrystalline cellulose, sucralose, and xanthan gum.
The following clinically significant adverse reactions are described elsewhere in the labeling:
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.
The safety of SEPHIENCE was evaluated in Trial 1 [Part 1 (open label); Part 2, (placebo-controlled)]; and Trial 2 (open-label). The two trials included a total of 215 SEPHIENCE-treated patients with PKU: 10 (5%) were <2 years old, 118 (55%) were ≥2 and <17 years old, and 87 (40%) were ≥17 years old. All patients received SEPHIENCE from 7.5 mg/kg/day up to 60 mg/kg/day and the median duration of treatment (in weeks) was 25.5 [see Clinical Studies (14.1)]
Trial 1 included a total of 157 patients (85 male and 72 female, aged 1 year to 61 years old) with PKU across both parts of the trial. The patients received dosages from 20 mg/kg up to 60 mg/kg daily and the median duration of treatment was 8 weeks.
Table 4 lists the most common adverse reactions that were reported in ≥2% of patients treated with SEPHIENCE and greater than that of the placebo group in Part 2 of Trial 1.
Table 4: Adverse Reactions for SEPHIENCE in Adult and Pediatric Patients with PKU that Occurred in ≥2% of Sepiapterin-Treated Patients and Greater than Placebo (Trial 1 Part 2)
|
Adverse Reaction |
SEPHIENCE |
Placebo |
|
Diarrhea |
4 (7) |
1 (2) |
|
Headache |
4 (7) |
1 (2) |
|
Abdominal paina |
3 (5) |
1 (2) |
|
Hypophenylalaninemia |
2 (4) |
0 |
|
Feces discoloration |
2 (4) |
0 |
|
Oropharyngeal pain |
2 (4) |
1 (2) |
|
a Includes Abdominal pain; Abdominal pain upper; Abdominal discomfort. |
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Adverse reactions were similar across both adult and pediatric populations except for hypophenylalaninemia (see Description of Selected Adverse Reactions).
Increased Bleeding
In Trial 1 Part 2, a case of heavy menstrual bleeding was reported in a SEPHIENCE-treated patient. Less than 2% of patients in Trial 2 experienced increased bleeding, which included heavy menstrual bleeding, non- traumatic superficial hematomas, and prolonged bleeding.
Hypophenylalaninemia
In Trial 1 Part 2, hypophenylalaninemia was seen in 5% (2/37) of sepiapterin-treated pediatric patients and in no adult patients. Some pediatric patients in Trial 2 had multiple low blood Phe levels.
Avoid concomitant use of drugs known to inhibit folate synthesis dihydrofolate reductase (DHFR) (e.g., trimethoprim, methotrexate, trimetrexate, pemetrexed, pralatrexate, raltitrexed, and piritrexim) while taking SEPHIENCE. Concomitant administration of such drugs may reduce sepiapterin metabolism to tetrahydrobiopterin (BH4). If concomitant use is not avoidable, monitor blood Phe levels.
Avoid concomitant use of sepiapterin reductase (SR) inhibitors with SEPHIENCE. Concomitant administration of such drugs may reduce sepiapterin metabolism to BH4. If concomitant use is not avoidable, monitor blood Phe levels.
SEPHIENCE may increase the availability of tyrosine, a precursor of levodopa. Neurologic events were reported postmarketing in patients receiving another PAH activator and levodopa concomitantly for a non-PKU indication. Monitor patients for a change in neurologic status when levodopa is administered with SEPHIENCE [see Warnings and Precautions (5.3)].
SEPHIENCE and PDE-5 inhibitors induce vasorelaxation, thus concomitant use of SEPHIENCE with PDE-5 inhibitors may reduce blood pressure even further. Monitor for signs and symptoms of hypotension with concomitant use of SEPHIENCE with drugs that affect nitric oxide-mediated vasorelaxation (e.g., PDE-5 inhibitors such as sildenafil, vardenafil, or tadalafil).
Included as part of the PRECAUTIONS section.
SEPHIENCE may increase the risk of bleeding. Bleeding events, including superficial hematomas, prolonged bleeding, and heavy menstrual bleeding have occurred in patients treated with SEPHIENCE [see Adverse Reactions (6.1)]. One patient with non-traumatic superficial hematomas and prolonged bleeding was re- challenged at a lower dose of SEPHIENCE with recurrence of symptoms, which led to treatment discontinuation. The patient experienced symptoms 15 days after initial exposure and two days after rechallenge. The patient had normal blood counts and coagulation studies at the time of the bleeding. Inform the patient about the increased risk of bleeding associated with SEPHIENCE and to follow up with his/her healthcare provider if he/she experiences any signs of increased bleeding. Consider treatment interruption with SEPHIENCE in patients with active bleeding.
In clinical trials of SEPHIENCE, some pediatric PKU patients experienced hypophenylalaninemia (low blood Phe), including some patients with multiple low blood Phe levels, during treatment with SEPHIENCE [see Adverse Reactions (6.1)]. Prolonged levels of blood Phe that are too low have been associated with catabolism and endogenous protein breakdown, which has been associated with adverse developmental outcomes.
Monitor blood Phe levels during treatment and if needed, modify the dosage of SEPHIENCE and/or dietary protein and Phe intake to ensure adequate blood Phe level control. Frequent blood Phe monitoring is recommended in the pediatric population [see Dosage and Administration (2.2)].
In a 10-year post-marketing safety surveillance program for a non-PKU indication using another drug that is a phenylalanine hydroxylase (PAH) activator, 3 patients with underlying neurological disorders experienced seizures, exacerbation of seizures, over-stimulation, and irritability during co-administration with levodopa. Monitor patients who are receiving levodopa for changes in neurological status during treatment with SEPHIENCE [see Drug Interactions (7.2)].
In a 6-month carcinogenicity study in Tg.rasH2 mice, sepiapterin did not increase the incidence of tumors in male or female transgenic mice at approximately 12- and 16-fold, respectively, the human exposure (AUC0-24h) at the MRHD.
Based on the weight of evidence, SEPHIENCE is not genotoxic. SEPHIENCE was negative in the Ames assay. SEPHIENCE was positive in an in vitro chromosomal aberration assay without metabolic activation but not with metabolic activation. SEPHIENCE was negative in the in vivo (micronucleus and comet) assays in rats.
SEPHIENCE was found to have no effect on fertility and reproductive function of male and female rats when given prior to and throughout mating in male and female rats and continuing to gestation day (GD) 7 in females at oral doses up to 300 mg/kg/day (approximately 7.5-fold the plasma exposure (AUC) at MRHD).
Repeated administration of SEPHIENCE in rats for 26 weeks at doses greater than 100 mg/kg/day (approximately 3-fold the plasma exposure (AUC) at MRHD) caused renal toxicity, including renal tubular degeneration associated with crystal formation. However, renal toxicity was not noted in monkeys following repeated administration of SEPHIENCE for 39 weeks up to 300 mg/kg/day (approximately 7-fold the plasma exposure (AUC) at MRHD).
No information provided.
No information provided.
SEPHIENCE is a precursor of the enzymatic co-factor tetrahydrobiopterin (BH4) which activates PAH.
At the recommended SEPHIENCE dose of 60 mg/kg orally once daily, clinically significant QTc interval prolongation was not observed.
Following oral administration, sepiapterin reached the maximum concentration in plasma at 2 hours post- treatment and converted to pharmacologically active metabolite BH4 with the exposures of sepiapterin generally less than 2% of those of BH4 (Table 5).
There was no accumulation for BH4 following repeated once daily dose up to 60 mg/kg administered in adult healthy volunteers.
When administered with a high-fat, high-calorie meal in adult healthy volunteers, BH4 exposures increased less than dose proportionally (with slopes 0.87 and 0.84 for Cmax and AUC0-last, respectively) in the dose range 5 to 20 mg/kg and less than dose proportionally (with slopes 0.1957 and 0.3189 for Cmax and AUC0-last, respectively) in the dose range 20 to 60 mg/kg.
The pharmacokinetics of sepiapterin and its active metabolite BH4 following oral administration of sepiapterin at 60 mg/kg with food in adult patients with PKU are summarized in Table 5.
Table 5: Summary of Pharmacokinetic Parameters of Sepiapterin and BH4 Following Oral Administration of Sepiapterin at 60 mg/kg with Fooda in Adult Patients (Age ≥17 Years) with PKU
|
Analyte |
Tmax (hr) |
Cmax(ng/mL) |
AUCinf |
AUC24 |
|
|
Sepiapterin |
N |
29 |
29 |
27 |
|
|
Results |
2 |
2.9 (1.6) |
NC |
19.9 (18.3) |
|
|
(0.5, 6.1) |
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|
BH4 |
N |
30 |
30 |
19 |
30 |
|
Results |
4 |
432 (177) |
3,626 (1267) |
3,618 (1,699) |
|
|
(2, 8) |
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a Sepiapterin was administered with dietary Phe restriction. NC: not calculated. Sepiapterin plasma concentration quickly declines to below lower limit of quantitation by 12 hours post dose and AUCinf were not estimable for the majority of patients. |
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The time to maximum plasma concentration (Tmax) of sepiapterin is approximately 1 to 3 hours after oral administration. Plasma sepiapterin is rapidly metabolized to BH4 and peak BH4 concentrations are achieved approximately 4 hours after the oral administration of sepiapterin.
Effect of Food
Administration of SEPHIENCE with food results in increased exposure to sepiapterin and BH4. When SEPHIENCE was administered at 20 or 60 mg/kg daily with a low-fat meal in healthy adult subjects, BH4 exposures were 169% to 172% higher for Cmax and 162% to 173% higher for AUC0-24h compared to administration under fasted conditions. When sepiapterin at 20 or 60 mg/kg was administered with a high-fat, high-calorie meal, BH4 exposures were 221% to 226% higher for Cmax and 251% to 284% higher for AUC0-24h compared to administration under fasted conditions [see Dosage and Administration (2.2)].
Sepiapterin mean human plasma protein binding was 15.4% in the presence of 0.1% dithiothreitol (DTT) in the concentration range of 0.1 to 10 μM. BH4 mean human plasma protein binding was between 24.1% and 41.3% in the concentration range 2 to 15 μM in the presence of 0.5% β-mercaptoethanol. Sepiapterin apparent volume of distribution could not be estimated reliably as sepiapterin is converted to BH4 post oral administration and plasma concentration declines to below lower limit of quantitation generally by 12 hours postdose. BH4 apparent volume of distribution is 11433 (5790) L in adult patients with PKU. Increase of BH4 in cerebrospinal fluid was detected after oral administration of sepiapterin 60 mg/kg QD for 7 days in healthy adult subjects.
Following oral administration, sepiapterin is quickly absorbed and converted to BH4. Sepiapterin plasma concentration is remarkably lower than BH4 and declines rapidly to below the limit of quantitation generally by 12 hours post dose. The terminal half-life of BH4 is approximately 5 hours and the apparent clearance is 1498 (848) L/h in adult patients with PKU.
Metabolism
Sepiapterin is metabolized by SR/carbonyl reductase (CR) and DHFR in a 2-step unidirectional process to form pharmacologically active metabolite BH4. BH4 is further metabolized non-enzymatically or enzymatically mediated by aromatic amino acid hydroxylases, such as PAH, tyrosine hydroxylase (TH), tryptophan hydroxylase (TPH), pterin-4α-carbinolamine dehydratase (PCD), dihydropteridine reductase (DHPR), xanthine oxidase (XO), and nitric oxide synthase (NOS) in various tissues.
Extensive metabolism of sepiapterin was observed in humans following a single oral dose of 14C-sepiapterin. Absorbed sepiapterin was converted to the active metabolite BH4, with Cmax and AUC0-24h of sepiapterin generally less than 2% of those of BH4.
Excretion
Following a single oral dose of radiolabeled sepiapterin 4,000 mg to healthy adult subjects, a mean of 6.7% was recovered in urine and 26.2% recovered in feces with a combined total recovery of 32.9% by 240 hours. The low total mass recovery is likely due to formation of volatile metabolites in human intestine. Sepiapterin was a minor component in urine and was one of the prominent radioactive components in feces.
No clinically significant difference in pharmacokinetics of sepiapterin were observed based on age (range 0.5 to 61 years), sex (female 52%, male 48%), race/ethnicity (White 74%, Asian 16%, Other or not specified 7%, or American Indian or Alaska Native 3%) or ABCG2 genotype (BCRP p.Gln141Lys). The effect of renal impairment, hepatic impairment, or pregnancy on pharmacokinetics of sepiapterin or BH4 is unknown.
Pediatric Patients
The pharmacokinetics of sepiapterin and BH4 following oral administration of sepiapterin at 60 mg/kg with food in PKU patients ≥2 years old are summarized in Table 6.
Table 6: Summary of Pharmacokinetic Parameters of Sepiapterin and BH4 Following Oral Administration of Sepiapterin at 60 mg/kg with Fooda in Pediatric Patients ≥2 Years Old with PKU
|
Analyte |
Tmax (hr) |
Cmax (ng/mL) |
AUCinf (ng*hr/mL) |
AUC24 (ng*hr/mL) |
|
|
Sepiapterin |
N |
19 |
19 |
NA |
18 |
|
Results |
1.05 (0.5, 4) |
2.5 (2.1) |
NA |
13.8 (15.1) |
|
|
BH4 |
N |
21 |
21 |
16 |
21 |
|
Results |
4 (1.9, 8) |
350 (191.9) |
3,466 (1,792) |
3,023 (1,637) |
|
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a Sepiapterin was administered with dietary Phe restriction. |
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The pharmacokinetics of sepiapterin have not been evaluated in pediatric patients younger than 2 years of age.
Both sepiapterin and BH4 were a substrate and inhibitor of efflux transporter breast cancer resistance protein (BCRP) in vitro.
Oral coadministration of curcumin, a BCRP inhibitor, and sepiapterin in healthy adult subjects resulted in increases in mean AUCs and Cmax of BH4 by approximately 20% to 24%, after a single dose.
In healthy adult subjects, oral coadministration of sepiapterin and rosuvastatin, a BCRP substrate, had no impact on rosuvastatin exposures.
The pharmacokinetics of sepiapterin and BH4 following sepiapterin oral administration may be affected by inhibitors of SR and/or DHFR [see Drug Interactions (7.1)].
Sepiapterin may increase the availability of tyrosine, a precursor of levodopa [see Drug Interactions (7.2)].
Advise the patient and/or caregiver to read the FDA-approved patient labeling (Patient Information and Instructions for Use).
Inform the patient about the increased risk of bleeding associated with SEPHIENCE and to follow up with his/her healthcare provider if he/she experiences any symptoms of increased bleeding.
Advise the patient to inform his/her healthcare provider if he/she is taking, or plan to take, any prescription or over-the-counter medications and supplements because of the potential for drug interactions [see Drug Interactions (7) and Clinical Pharmacology (12.3)].
Advise patients that SEPHIENCE may cause feces to have a yellow or orange discoloration.
Manufactured by
Allphamed PHARBIL Arzneimittel GmbH
Hildebrand str. 12,
37081 Gottingen,
Germany (DEU)
Manufactured for:
PTC Therapeutics, Inc.
Warren, NJ 07059
INSTRUCTIONS FOR USE
SEPHIENCE (seh-FIGH-ence)
(sepiapterin) oral powder
This Instructions for Use contains information on how to prepare, take, or give SEPHIENCE.
Ask your healthcare provider or pharmacist if you have any questions on how to prepare, take, or give SEPHIENCE.
The preparation steps differ based on the prescribed dose. Follow the steps specific to the dose your healthcare provider has prescribed. See the section called:
Each SEPHIENCE carton contains:
 |
Important Information you need to know before taking or giving SEPHIENCE:
Storing SEPHIENCE:
Keep SEPHIENCE and all medicines out of the reach of children.
Preparing to mix SEPHIENCE oral powder:
Instructions for SEPHIENCE Doses Less Than 1,000 mg:
Your healthcare provider or pharmacist will tell you the amount of:
Water or apple juice needed to mix 1 dose of SEPHIENCE.
SEPHIENCE mixture (after mixed with water or apple juice) to give in milliliters (mL).
You may need to measure a smaller amount of mixture than you prepared to take or give the correct prescribed dose of SEPHIENCE.
Supplies needed to mix and give SEPHIENCE doses less than 1,000 mg (see Figure A):
Supplies not included with the SEPHIENCE oral powder packet carton(s):
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Ask your pharmacist for a container for mixing SEPHIENCE and an oral dosing syringe if you do not have these supplies.
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Step 1: Find a clean, flat work surface. Place the following items on your clean, flat work surface:
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Step 2: Check the label on the SEPHIENCE oral powder packet(s) to make sure you have the number of packets for the prescribed dose. Open the SEPHIENCE oral powder packet(s) by folding and tearing at the tear notch, or using scissors to cut the packet(s) open at the dotted line. Empty the entire contents of each SEPHIENCE oral powder packet(s) into the container for mixing (see Figure B). |
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Step 3: Place the tip of the oral dosing syringe into the cup containing the water or apple juice. Pull back on the plunger and draw up the amount of water or apple juice needed to prepare the packet(s) for the prescribed dose. Use 9 mL of water or apple juice for each 250 mg packet. For example:
If you are using one 1,000 mg packet to prepare the prescribed dose, you will need to add 36 mL of water or apple juice. Slowly add the water or apple juice to the container for mixing containing the SEPHIENCE oral powder. Repeat until the entire amount of water or apple juice that is needed to mix the number of SEPHIENCE oral powder packets has been added to the container for mixing (see Figure C). |
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Step 4: Stir the SEPHIENCE oral powder mixed with water or apple juice well for 30 seconds or more with a small spoon until the SEPHIENCE mixture is free of lumps (see Figure D). SEPHIENCE oral powder is not expected to dissolve completely. This is normal. |
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Step 5: Place the tip of the oral dosing syringe into the mixture inside the container used for mixing. Pull back on the plunger until the edge of the plunger lines up with the marking for the dose as instructed by your healthcare provider in mL (milliliters) (see Figure E). |
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Step 6: Take the oral dosing syringe out of the container used for mixing. Carefully turn the oral dosing syringe so that the tip is pointing up. Check the syringe marking to make sure that the amount of SEPHIENCE mixture in the oral dosing syringe lines up with the prescribed SEPHIENCE dose in mL (milliliters) (see Figure F). Your dose may be different than the dose shown in Figure F. Give SEPHIENCE mixture right away after it is drawn up into the syringe. |
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Step 7: Place the tip of the oral dosing syringe into your child’s mouth. Point the tip of the oral dosing syringe toward either cheek (see Figure G). Push on the plunger slowly, until all the mixture in the oral dosing syringe is given. If the prescribed dose is more than 10 mL, repeat Step 5 to Step 7 until you give the total amount of prescribed dose in mL (milliliters) by your healthcare provider. |
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Step 8: If there is any mixture left in the oral dosing syringe, draw up more water or apple juice into the oral dosing syringe and give until no mixture is left in the oral dosing syringe. |
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Step 9: Throw away any SEPHIENCE mixture remaining in the container used for mixing in the household trash. See Throwing away (disposing of) SEPHIENCE. Remove the plunger from the barrel of the oral dosing syringe. Wash the oral dosing syringe and container used for mixing with warm water and air dry. When the oral dosing syringe is dry, put the plunger back into the barrel. Store the oral dosing syringe and container used for mixing for the next use. |
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Instructions for SEPHIENCE Doses 1,000 mg or Greater:
Supplies needed to mix and take or give SEPHIENCE doses 1,000 mg or greater (see Figure A):
Supplies not included with the SEPHIENCE oral powder packet carton(s):
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Your healthcare provider will tell you the number of packets, and the amount of water, apple juice, strawberry jam, or applesauce needed to mix 1 dose of SEPHIENCE per Table 1 below.
Table 1: Number of SEPHIENCE Packets to Prepare a SEPHIENCE Mixture for Doses of 1,000 mg or Greater
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Find your prescribed number of packets: |
Choose one of the following:
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|
Number of 1,000 mg packets |
Number of 250 mg packets |
Amount of water, apple juice, strawberry jam, or applesauce to mix the packet(s) |
|
1 |
0 |
2 Tbsp or 30 mL |
|
1 |
1 |
4 Tbsp or 60 mL |
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1 |
2 |
4 Tbsp or 60 mL |
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1 |
3 |
4 Tbsp or 60 mL |
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2 |
0 |
4 Tbsp or 60 mL |
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2 |
1 |
6 Tbsp or 90 mL |
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2 |
2 |
6 Tbsp or 90 mL |
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2 |
3 |
6 Tbsp or 90 mL |
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3 |
0 |
6 Tbsp or 90 mL |
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3 |
1 |
8 Tbsp or 120 mL |
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3 |
2 |
8 Tbsp or 120 mL |
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3 |
3 |
8 Tbsp or 120 mL |
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4 |
0 |
8 Tbsp or 120 mL |
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4 |
1 |
10 Tbsp or 150 mL |
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4 |
2 |
10 Tbsp or 150 mL |
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4 |
3 |
10 Tbsp or 150 mL |
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5 |
0 |
10 Tbsp or 150 mL |
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5 |
1 |
12 Tbsp or 180 mL |
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5 |
2 |
12 Tbsp or 180 mL |
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5 |
3 |
12 Tbsp or 180 mL |
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6 |
0 |
12 Tbsp or 180 mL |
Ask your pharmacist for a container for mixing SEPHIENCE if you do not have these supplies.
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Step 1: Find a clean, flat work surface. Place the following items on your clean, flat work surface:
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Step 2: Check the label on the SEPHIENCE oral powder packet(s) to make sure you have the number of packets for the prescribed dose. Open the SEPHIENCE oral powder packet(s) by folding and tearing at the tear notch or using scissors to cut the packet(s) open at the dotted line. Empty the entire contents of each SEPHIENCE oral powder packet(s) into the container for mixing (see Figure B). |
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Step 3: Mix the SEPHIENCE oral powder packet(s) with water, apple juice, strawberry jam, or applesauce. See Table 1 above. Slowly add the water, apple juice, strawberry jam, or applesauce to the container for mixing containing the SEPHIENCE oral powder. Repeat until the entire amount of water, apple juice, strawberry jam, or applesauce that is needed to mix the number of SEPHIENCE oral powder packets has been added to the container for mixing (see Figure C). |
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Step 4: If you used water or apple juice to mix the SEPHIENCE oral powder packet(s), stir the mixture well for 30 seconds or more with the tablespoon until the SEPHIENCE mixture is free of lumps (see Figure D). SEPHIENCE oral powder is not expected to dissolve completely. or If you used strawberry jam or applesauce to mix the SEPHIENCE oral powder packet(s), stir the mixture well for 60 seconds or more with the tablespoon. |
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Step 5: Give or take all of the SEPHIENCE mixture from the container used for mixing. |
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Step 6: If any SEPHIENCE mixture remains in the container used for mixing, rinse the container with water or apple juice (at least 15 mL). Swallow the rinse right away. Repeat this step until no mixture remains in the container used for mixing. |
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Step 7: Wash the container used for mixing with warm water and air dry. Store the container used for mixing for the next use. |
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Throwing away (disposing of) SEPHIENCE:
Manufactured by:
Allphamed PHARBIL Arzneimittel GmbH
Hildebrand str. 12,
37081 Gottingen,
Germany (DEU)
Manufactured for:
PTC Therapeutics, Inc.
Warren, NJ 07059
This Instructions for Use has been approved by the U.S. Food and Drug Administration.
Approved: 07/2025
