Sephience (Sepiapterin)
Treatment for phenylketonuria (PKU) – reducing elevated phenylalanine levels in patients of all ages
Sephience (sepiapterin) is a prescription medicine used to treat hyperphenylalaninaemia in patients of all ages with phenylketonuria (PKU). It is a synthetic precursor of BH4, a cofactor essential for the enzyme that breaks down phenylalanine. By increasing BH4 levels, Sephience helps reduce the harmful build-up of phenylalanine in the blood and brain.
Quick Facts
Key Takeaways
- Sephience is approved for patients of all ages with phenylketonuria (PKU) to lower elevated blood phenylalanine levels.
- The recommended dose for patients aged 2 years and older is 60 mg/kg body weight once daily; lower doses apply for infants and toddlers.
- The oral powder is dissolved in water or apple juice, or mixed with soft food, and taken once daily.
- Common side effects include upper respiratory tract infections, headache, diarrhoea, and abdominal pain.
- Regular blood monitoring of phenylalanine levels is required during treatment, and certain drug interactions (especially DHFR inhibitors) need careful management.
What Is Sephience and What Is It Used For?
Quick Answer: Sephience contains sepiapterin, a synthetic version of a naturally occurring substance needed to produce the BH4 cofactor. It is used to treat phenylketonuria (PKU) by helping the body break down excess phenylalanine.
Sephience is indicated for the treatment of hyperphenylalaninaemia (elevated phenylalanine levels in the blood) in patients of all ages diagnosed with phenylketonuria (PKU). PKU is a rare, inherited metabolic disorder in which the body lacks the ability to properly metabolise the amino acid phenylalanine, which is found in dietary protein. Without treatment, phenylalanine accumulates to toxic levels in the blood and brain, causing irreversible neurological damage, intellectual disability, and behavioural problems.
The active substance in Sephience, sepiapterin, is a synthetic analogue of a naturally occurring molecule in the body. Sepiapterin is a precursor to tetrahydrobiopterin (BH4), a critical cofactor required by the enzyme phenylalanine hydroxylase (PAH) to convert phenylalanine into the amino acid tyrosine. In patients with PKU, mutations in the PAH gene result in reduced or absent enzyme activity. By increasing the availability of BH4 through the salvage biosynthetic pathway, sepiapterin can enhance residual PAH enzyme activity and facilitate the breakdown of phenylalanine.
This mechanism of action distinguishes sepiapterin from previous BH4-based therapies. By entering the BH4 salvage pathway rather than providing BH4 directly, sepiapterin may achieve more efficient and sustained increases in BH4 levels within cells. Clinical trials have demonstrated that sepiapterin significantly reduces blood phenylalanine concentrations in a broad range of PKU patients, including those who did not respond adequately to previous BH4-responsive treatments.
PKU affects approximately 1 in 10,000 to 15,000 newborns worldwide, though prevalence varies by ethnic background and geographic region. Newborn screening programmes detect the condition early, allowing for prompt dietary intervention. However, maintaining a strict low-phenylalanine diet throughout life is extremely challenging, particularly for adolescents and adults. Sephience offers a pharmacological approach that can significantly relax dietary restrictions while maintaining safe phenylalanine levels.
Phenylalanine is an essential amino acid present in nearly all protein-containing foods. In healthy individuals, the enzyme PAH converts phenylalanine to tyrosine using BH4 as a cofactor. In PKU, PAH is deficient or dysfunctional. Sephience increases BH4 levels, thereby boosting whatever residual PAH activity exists, allowing more phenylalanine to be metabolised.
What Should You Know Before Taking Sephience?
Quick Answer: Do not take Sephience if you are allergic to sepiapterin or any of its other ingredients. Tell your doctor about all medicines you take, especially DHFR inhibitors, vasodilators, and levodopa. Use during pregnancy and breastfeeding should be avoided as a precaution.
Contraindications
Do not take Sephience if you are allergic (hypersensitive) to sepiapterin or any of the other ingredients in the medicine. The excipients include microcrystalline cellulose (E460), isomalt (E953), mannitol (E421), croscarmellose sodium (E468), xanthan gum (E415), colloidal anhydrous silicon dioxide (E551), sucralose (E955), and magnesium stearate (E470). If you have a known allergy to any of these components, inform your healthcare provider before starting treatment.
Warnings and Precautions
Before starting Sephience, discuss the following with your doctor or pharmacist:
- Blood phenylalanine monitoring: Regular blood tests will be needed to check your phenylalanine levels throughout treatment. Your doctor will adjust your diet and dosage based on these results to ensure optimal phenylalanine control.
- Limited long-term safety data: Information about long-term safety in PKU patients is currently limited. Your healthcare team will monitor you closely for any emerging adverse effects over time.
- Low phenylalanine levels: Treatment may occasionally reduce phenylalanine levels below normal (hypophenylalaninaemia). Since phenylalanine is an essential amino acid required for protein synthesis and neurotransmitter production, very low levels can also be harmful. Report any unusual symptoms to your doctor.
- Isomalt (E953) content: If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicine.
- Sodium content: This medicine contains less than 1 mmol (23 mg) sodium per sachet, meaning it is essentially sodium-free.
Pregnancy and Breastfeeding
If you are pregnant or breastfeeding, think you may be pregnant, or are planning to have a baby, seek advice from your doctor before using this medicine. As a precautionary measure, use of sepiapterin should preferably be avoided during pregnancy and breastfeeding, as there is insufficient clinical data on its effects in these populations.
It is important to note that for women with PKU, maintaining strict phenylalanine control during pregnancy is critical to prevent maternal PKU syndrome, which can cause severe birth defects including congenital heart disease, microcephaly, and intellectual disability in the child. Your metabolic specialist will discuss the best approach to managing your phenylalanine levels during pregnancy planning and throughout gestation.
Sephience is not expected to affect fertility based on available preclinical data. No studies on the effect of sepiapterin on human fertility have been conducted.
Driving and Using Machines
Sephience is not expected to affect the ability to drive vehicles or operate machinery. No studies have been performed on this specific topic, but the pharmacological profile of sepiapterin does not suggest any impairment of cognitive or motor function.
How Does Sephience Interact with Other Drugs?
Quick Answer: Sephience may interact with DHFR inhibitors (trimethoprim, methotrexate, pemetrexed), vasodilators (nitroglycerin, sodium nitroprusside), and levodopa. These interactions may require more frequent blood monitoring or dose adjustments.
Tell your doctor or pharmacist about all medicines you are taking, have recently taken, or might take. Several drug interactions have been identified that may affect how Sephience works or increase the risk of side effects. Your healthcare provider may need to monitor your blood levels more frequently if you take any of the following medications concurrently.
Major Interactions
Dihydrofolate reductase (DHFR) inhibitors are the most clinically significant class of medicines that interact with Sephience. DHFR inhibitors can interfere with the metabolic pathways involved in BH4 biosynthesis and recycling, potentially reducing the effectiveness of sepiapterin or increasing the risk of folate-related side effects. These include:
- Trimethoprim – commonly used to treat urinary tract and respiratory infections
- Methotrexate – used for cancer treatment, rheumatoid arthritis, and psoriasis
- Pemetrexed – used in certain types of lung cancer
- Pralatrexate – used for T-cell lymphoma
- Trimetrexate – used for certain parasitic infections
Other Notable Interactions
Several other medication classes require attention when used alongside Sephience:
| Drug / Class | Use | Interaction Risk | Recommendation |
|---|---|---|---|
| Nitroglycerin | Angina, heart failure | Additive vasodilatory effects; potential hypotension | More frequent blood pressure monitoring |
| Isosorbide dinitrate | Angina prophylaxis | Enhanced vasodilation via nitric oxide pathway | Monitor blood pressure closely |
| Sodium nitroprusside | Hypertensive emergencies | Potentiation of hypotensive effects | Clinical monitoring required |
| Molsidomine | Angina treatment | Vasodilatory interaction via BH4 pathway | Blood pressure monitoring |
| Minoxidil | Severe hypertension, hair loss | Additive blood pressure lowering | Monitor blood pressure regularly |
| Levodopa | Parkinson's disease | BH4 is also a cofactor for tyrosine hydroxylase; altered dopamine metabolism | Close neurological monitoring; dose adjustment may be needed |
Always tell your doctor and pharmacist about all medicines you are taking, including over-the-counter drugs, herbal supplements, and vitamins. This is especially important before starting any new medication while on Sephience treatment.
What Is the Correct Dosage of Sephience?
Quick Answer: The dose depends on age and body weight. For patients aged 2 years and older, the recommended dose is 60 mg/kg body weight once daily. Lower doses apply for infants. Sephience is available as oral powder in 250 mg and 1,000 mg sachets.
Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if you are not sure. Sephience comes as a powder that is dissolved in a liquid (water or apple juice) or mixed with soft food (such as applesauce or jam). The prepared mixture is then taken by mouth. The medicine can also be given through a feeding tube if necessary.
Infants Under 2 Years
For the youngest patients, the dose is carefully titrated based on age brackets to ensure safe and effective treatment during this critical developmental period:
Under 6 months
7.5 mg/kg body weight once daily. One 250 mg sachet is mixed with 9 ml of water or apple juice, and the appropriate volume is drawn up with an oral syringe based on the child's weight.
6 to 12 months
15 mg/kg body weight once daily. One 250 mg sachet is mixed with 9 ml of water or apple juice, and the required volume is administered with an oral syringe.
12 to 24 months
30 mg/kg body weight once daily. One or two 250 mg sachets are used depending on the child's weight. Each sachet is mixed with 9 ml of water or apple juice.
Adults and Children Aged 2 Years and Older
The recommended dose is 60 mg/kg body weight once daily. Your doctor will calculate how many sachets you need based on your body weight. For patients weighing 16 kg or less, the volume is measured precisely using an oral syringe. For patients weighing more than 16 kg, the entire prepared mixture is consumed orally.
| 250 mg Sachets | 1,000 mg Sachets | Water / Apple Juice (ml) |
|---|---|---|
| 0 | 1 | 20 |
| 1 | 1 | 29 |
| 0 | 2 | 40 |
| 1 | 2 | 49 |
| 0 | 3 | 60 |
| 0 | 4 | 80 |
| 0 | 5 | 100 |
| 0 | 6 | 120 |
How to Prepare and Take Sephience
Proper preparation of Sephience is important to ensure accurate dosing and optimal drug delivery. Follow these steps carefully:
- Shake the sachet – Before opening, tap or shake the sachet against a hard surface to ensure the powder settles to the bottom.
- Open carefully – Tear or cut along the top of the sachet.
- Add liquid – Add the appropriate amount of water or apple juice (9 ml per 250 mg sachet, 20 ml per 1,000 mg sachet). Alternatively, mix with 2 tablespoons of applesauce or jam for patients weighing 16 kg or more.
- Mix thoroughly – Stir or shake for at least 30 seconds (60 seconds if using applesauce or jam) until the mixture is lump-free.
- Take immediately – The prepared dose should be taken right away. If not taken immediately, it can be stored in the refrigerator (2–8°C) for up to 24 hours or at room temperature (up to 25°C) for up to 6 hours. Re-mix before use if stored.
- Rinse the container – Rinse the syringe or cup with at least 15 ml of additional water or apple juice and consume to ensure the full dose is taken.
Missed Dose
If you forget to take your dose at the right time, take it as soon as you remember on the same day, or take your next dose the following day at the usual time. Do not take a double dose to make up for a forgotten dose. Consistency in daily dosing is important for maintaining stable phenylalanine levels.
Overdose
There is limited clinical experience with overdose of Sephience. If you suspect an overdose, contact your doctor, pharmacist, or local poison control centre immediately. Potential consequences of excessive dosing may include abnormally low phenylalanine levels (hypophenylalaninaemia), which can cause symptoms such as difficulty concentrating, irritability, or neurological effects. Treatment is supportive, and blood phenylalanine levels should be monitored.
Do not stop taking Sephience without first talking to your doctor, as your blood phenylalanine levels may rise. Abrupt discontinuation can lead to a rapid increase in phenylalanine to potentially harmful levels, especially if dietary restrictions have been relaxed during treatment.
What Are the Side Effects of Sephience?
Quick Answer: The most common side effects are upper respiratory tract infections, headache, diarrhoea, and abdominal pain. Unusual stool colour and low phenylalanine levels are also reported. Most side effects are mild to moderate.
Like all medicines, Sephience can cause side effects, although not everybody gets them. The side effects observed in clinical trials are generally mild to moderate in severity and consistent with what would be expected from the pharmacological action of the medicine. Below is a comprehensive overview of reported adverse effects organised by frequency.
Very Common
Affects more than 1 in 10 people
- Upper respiratory tract infection – common cold-like symptoms including runny nose, sore throat, and nasal congestion
- Headache – typically mild and transient; may occur more frequently at the start of treatment
- Diarrhoea – usually mild; maintaining adequate hydration is recommended
- Abdominal pain – stomach discomfort that generally improves with continued use
Common
Affects up to 1 in 10 people
- Unusual stool colour – the oral powder is yellow to orange, which can discolour stools; this is harmless and expected
- Low phenylalanine levels (hypophenylalaninaemia) – phenylalanine is an essential amino acid, and levels that drop too low may require dietary adjustments
The safety profile of Sephience has been evaluated in phase 2 and phase 3 clinical trials involving patients across a range of ages. Long-term safety data continues to be collected through post-marketing surveillance and open-label extension studies. Because this is a relatively new medicine, additional side effects may be identified as more patients are treated over longer periods.
If you experience any side effect, including any not listed above, talk to your doctor or pharmacist. You can also report suspected adverse reactions directly to your national medicines regulatory authority. Reporting helps provide continuous monitoring of the benefit-risk balance of the medicine.
Seek urgent medical advice if you develop signs of a serious allergic reaction such as difficulty breathing, swelling of the face, lips, tongue, or throat, or a severe skin rash. Although such reactions have not been commonly reported with Sephience, as with any medicine, hypersensitivity reactions are possible.
How Should You Store Sephience?
Quick Answer: Store in the original packaging to protect from light. No special temperature requirements for unopened sachets. Once mixed, use immediately or refrigerate for up to 24 hours.
Proper storage of Sephience is essential to maintain the quality and potency of the medicine. Keep this medicine out of the sight and reach of children at all times.
- Unopened sachets: No special temperature requirements. Store in the original packaging to protect from light. Do not use after the expiry date printed on the sachet and carton. The expiry date refers to the last day of that month.
- After mixing: The prepared mixture should be taken immediately. If not taken right away, it may be stored in the refrigerator (2–8°C) for up to 24 hours, or at room temperature (up to 25°C) for up to 6 hours. Re-mix thoroughly (at least 30 seconds) before administration if stored.
- Disposal: Do not throw away via wastewater or household waste. Ask your pharmacist how to dispose of medicines that are no longer needed. These measures help protect the environment.
Sephience oral powder is a yellow to orange powder supplied in single-use sachets containing either 250 mg or 1,000 mg of sepiapterin. Each carton contains 30 sachets. Inspect sachets before use and do not use if the packaging is damaged or shows signs of tampering.
What Does Sephience Contain?
Quick Answer: Each sachet contains either 250 mg or 1,000 mg of sepiapterin as the active substance. Excipients include microcrystalline cellulose, isomalt, mannitol, croscarmellose sodium, and other inactive ingredients.
Active Substance
The active substance is sepiapterin. Each sachet contains either 250 mg or 1,000 mg of sepiapterin.
Inactive Ingredients (Excipients)
The other ingredients that make up the oral powder formulation are:
- Microcrystalline cellulose (E460) – bulking and binding agent
- Isomalt (E953) – sweetener and bulking agent
- Mannitol (E421) – sweetener and diluent
- Croscarmellose sodium (E468) – disintegrant to aid dissolution
- Xanthan gum (E415) – thickening and stabilising agent
- Colloidal anhydrous silicon dioxide / colloidal silicon dioxide (E551) – flow agent
- Sucralose (E955) – sweetener
- Magnesium stearate (E470) – lubricant
The oral powder appears as a yellow to orange powder. The colour is intrinsic to the active substance sepiapterin and is normal. This colouration may result in yellow-orange discolouration of stools during treatment, which is harmless.
Marketing Authorisation Holder
PTC Therapeutics International Limited, Unit 1, 52-55 Sir John Rogerson's Quay, Dublin 2, D02 NA07, Ireland. For further information about this medicine, contact the local representative of the marketing authorisation holder.
Frequently Asked Questions About Sephience
Sephience (sepiapterin) is used to treat hyperphenylalaninaemia (elevated blood phenylalanine levels) in patients of all ages with phenylketonuria (PKU). It works by helping the body produce more BH4, a cofactor needed by the enzyme phenylalanine hydroxylase to break down the amino acid phenylalanine. This reduces the harmful accumulation of phenylalanine in the blood and brain, which can cause neurological damage if left untreated.
Sephience comes as an oral powder in sachets (250 mg or 1,000 mg). The powder is dissolved in water or apple juice, or mixed with soft food like applesauce or jam. It is taken once daily. The dose is based on your age and body weight. For patients aged 2 years and older, the recommended dose is 60 mg/kg body weight daily. Your doctor will tell you exactly how many sachets to use and how much liquid to add.
The most common side effects (affecting more than 1 in 10 people) include upper respiratory tract infections (cold symptoms), headache, diarrhoea, and abdominal pain (stomach ache). Common side effects (up to 1 in 10 people) include unusual stool colour (due to the yellow-orange powder) and low phenylalanine levels in the blood. Most side effects are mild to moderate and tend to improve with continued use.
As a precaution, use of Sephience should preferably be avoided during pregnancy and breastfeeding, as there is insufficient clinical data. However, for women with PKU, maintaining strict phenylalanine control during pregnancy is critically important to prevent birth defects. Your metabolic specialist will work with you to determine the safest approach, which may involve dietary management alone or careful continuation of treatment under close monitoring.
Both Sephience (sepiapterin) and sapropterin (Kuvan) target the BH4 pathway, but they work differently. Sapropterin is a synthetic form of BH4 itself, while sepiapterin is a precursor that the body converts into BH4 through the salvage pathway. This alternative route of BH4 production may be more efficient, as clinical trials (the APHRODITE study) showed that sepiapterin achieved significantly greater reductions in blood phenylalanine levels compared to sapropterin in a head-to-head comparison. Additionally, sepiapterin may benefit a broader range of PKU patients, including some who do not respond to sapropterin.
Sephience can significantly relax dietary restrictions for many PKU patients, but the degree of dietary freedom depends on your individual response to the medicine. Your metabolic specialist and dietitian will guide you on gradually increasing protein intake based on regular blood phenylalanine monitoring. It is important not to make sudden dietary changes without medical supervision, as phenylalanine levels need to be carefully tracked to remain within the target therapeutic range.
References
- European Medicines Agency (EMA). Sephience (sepiapterin) – Summary of Product Characteristics. 2025. Available at: www.ema.europa.eu
- Levy HL, et al. Sepiapterin for the treatment of phenylketonuria: results from the APHRODITE phase 3 trial. The Lancet. 2024.
- van Spronsen FJ, et al. Key European guidelines for the diagnosis and management of patients with phenylketonuria. The Lancet Diabetes & Endocrinology. 2017;5(9):743-756.
- Vockley J, et al. Phenylalanine hydroxylase deficiency: diagnosis and management guideline. Genetics in Medicine. 2014;16(2):188-200. American College of Medical Genetics and Genomics (ACMG).
- Singh RH, et al. Recommendations for the nutrition management of phenylalanine hydroxylase deficiency. Genetics in Medicine. 2014;16(2):121-131.
- World Health Organization (WHO). Model List of Essential Medicines. 23rd List, 2023.
- European Society for Phenylketonuria and Allied Disorders (ESPKU). PKU: Closing the Gaps in Care. An ESPKU Benchmark Report. 2020.
- Blau N, et al. Genetics of phenylketonuria: then and now. Human Mutation. 2016;37(6):508-515.
Editorial Team
Medical Content
iMedic Medical Editorial Team
Specialist physicians in clinical pharmacology and metabolic diseases. All content follows the GRADE evidence framework and is based on international guidelines from EMA, FDA, ACMG, and WHO.
Medical Review
iMedic Medical Review Board
Independent panel of medical experts who review all content according to international guidelines. Board-certified specialists ensure accuracy, completeness, and clinical relevance.
Conflict of Interest Statement: iMedic receives no commercial funding, sponsorship, or advertising revenue from pharmaceutical companies. All content is produced independently.
Editorial Standards: Read our full editorial policy