SEPHIENCE Oral powder Ref.[115495] Active ingredients: Sepiapterin

Dietary intake

Patients treated with Sephience should undergo regular clinical assessments to align with their health care provider on appropriate dietary Phe intake (such as monitoring of blood Phe and tyrosine levels and nutritional intake).

Concomitant use with dihydrofolate reductase (DHFR) inhibitors

Co-administration of sepiapterin with DHFR inhibitors (e.g. trimethoprim, methotrexate, pemetrexed, pralatrexate, and trimetrexate) may require more frequent monitoring of blood Phe levels (see section 4.5).

Long-term safety data

Long-term safety data in patients with PKU are limited (see section 4.8 for adverse reactions evaluated to date for sepiapterin).

Excipients with known effect

Sodium content

This medicinal product contains less than 1 mmol sodium (23 mg) per sachet, that is to say essentially 'sodium-free'.

Isomalt content

Patients with rare hereditary problems of fructose intolerance should not take this medicinal product.

Sepiapterin reductase (SR) inhibitors

Orally administered sepiapterin is quickly absorbed and rapidly and extensively converted by SR and carbonyl reductase to 7,8-dihydrobiopterin (BH2), which is then unidirectionally converted to BH4 by DHFR. Co-administration of a SR inhibitor is expected to have minimal effect on biotransformation of sepiapterin due to the compensatory effect of carbonyl reductase. Normal blood Phe levels were reported in patients with SR deficiency. Neverthless, caution and more frequent monitoring of blood Phe are recommended when Sephience is co-administered with SR inhibitors, such as sulphasalazine or sulphamethoxazole.

DHFR inhibitors

DHFR mediates the conversion of BH2 to BH4, inhibition of DHFR could potentially result in lower BH4 concentration. However, the impact on sepiapterin concentration is expected to be minimal due to the existence of multiple pathways for the elimination. Caution and more frequent monitoring of blood Phe are required in patients when sepiapterin is co-administered with a DHFR inhibitor, such as trimethoprim, methotrexate, pemetrexed, pralatrexate, and trimetrexate (see section 4.4).

Vasodilatory medicinal products

Caution is recommended during concomitant use of Sephience with medicinal products that cause vasodilation by affecting nitric oxide (NO) metabolism or action, including classical NO donors (e.g. glyceryl trinitrate [GTN], isosorbide dinitrate [ISDN], sodium nitroprusside [SNP], and molsidomin), phosphodiesterase type 5 (PDE-5) inhibitors (e.g. sildenafil, vardenafil, or tadalafil), and minoxidil. In animal studies, BH4 administered orally in combination with a PDE-5 inhibitor had no effect on blood pressure.

Levodopa

Caution should be exercised when prescribing Sephience to patients receiving treatment with levodopa to monitor neurological disorders such as exacerbation of convulsion, increased excitability and irritability, seizures, and exacerbation of seizures.

Pregnancy

There are is a limited amount of data from the use of sepiapterin in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). There are no adequate and well-controlled studies with sepiapterin in pregnant women. As a precautionary measure, it is preferable to avoid the use of Sephience during pregnancy.

Breast-feeding

It is unknown whether sepiapterin/metabolites are excreted in human milk. A risk to the newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Sephience therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

No clinical studies on the effect on human fertility have been conducted for sepiapterin. Animal studies do not indicate direct or indirect harmful effects with respect to fertility (see section 5.3).

Sephience has no or negligible influence on the ability to drive and use machines.

Summary of the safety profile

As presented in the table below, the most frequent adverse reactions were: upper respiratory tract infection (19.8%); headache (15.3%); diarrhoea (14.9%); followed by abdominal pain (12.2%); faeces discoloured (4.5%) and hypophenylalaninaemia (2.7%).

Tabulated list of adverse reactions

The selection of adverse reactions to sepiapterin was based on evidence from clinical trials. The frequency of adverse reactions, as presented below in the tabulated list, was calculated based on pooled data from the 2 pivotal clinical studies in patients with PKU (study PTC923-MD-003-PKU and study PTC923-MD-004-PKU). These data included 222 patients who were exposed to sepiapterin up to 60 mg/kg/day of which: 15 (6.8%) were <2 years old, 25 (11.3%) were 2 to <6 years old, 46 (20.7%) were 6 to <12 years old, 55 (24.8%) were 12 to <18 years old, and 81 (36.5%) were ≥18 years old, and the median duration of treatment (in weeks) was 34.286.

Adverse reactions are listed below (Table 6) by MedDRA System Organ Class (SOC). Within each SOC adverse reactions are presented in order of decreasing frequency. Frequencies are defined as follows: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1 000 to <1/100); rare (≥1/10 000 to <1/1 000); very rare (<1/10 000); and not known (cannot be estimated from available data).

Table 6. Adverse reactions:

^* Grouping of 3 MedDRA Preferred Terms: Abdominal pain, Abdominal pain upper, Abdominal discomfort.

Paediatric population

Overall, in PKU clinical studies, sepiapterin was well tolerated in paediatric patients. Frequency, type, and severity of adverse reactions in all age groups of paediatric patients were consistent with those in adults. Long-term safety data are limited.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Not applicable.