Trofinetide

Plasma concentrations of OATP1B1 and OATP1B3 substrates may be increased if given concomitantly with trofinetide. Avoid the concomitant use of trofinetide with OATP1B1 and OATP1B3 substrates for which a small change in substrate plasma concentration may lead to serious toxicities.

Based on in vitro data, the potential for trofinetide to inhibit MATE1 and MATE2-K cannot be excluded, which may increase the plasma concentration of MATE1 and MATE2-K substrates (e.g., metformin).

Η τροφινετίδη είναι ένας ασθενής αναστολέας του CYP3A4 και της P-gp. Συνεπώς, οι συγκεντρώσεις των υποστρωμάτων του CYP3A4 ή/και της P-gp στο πλάσμα μπορεί να αυξηθούν εάν χορηγούνται ταυτόχρονα με την τροφινετίδη. Μια κλινική μελέτη φαρμακευτικής αλληλεπίδρασης σε υγιή άτομα που εκτιμά την επίδραση της τροφινετίδης στη φαρμακοκινητική της λοπεραμίδης, ενός υποστρώματος τόσο του CYP3A4 όσο και της P-gp, έδειξε ότι η ταυτόχρονη χορήγηση οδήγησε σε αύξηση του C_max της λοπεραμίδης κατά 1,95 φορές και της AUC κατά 1,73 φορές.

Συνιστάται στενή παρακολούθηση όταν η τροφινετίδη χρησιμοποιείται σε συνδυασμό με από στόματος χορηγούμενα ευαίσθητα υποστρώματα του CYP3A4 ή/και της P-gp (π.χ. κυκλοσπορίνη, διγοξίνη) για τα οποία μια μικρή μεταβολή στη συγκέντρωση του υποστρώματος στο πλάσμα μπορεί να οδηγήσει σε σοβαρές ανεπιθύμητες ενέργειες.

The recommended dosage of trofinetide for patients with moderate renal impairment (eGFR 30 to 59 mL/min/1.73 m²) is described in the following table:

Recommended dosage of trofinetide in patients with moderate renal impairment:

Administration of trofinetide to patients with severe renal impairment (eGFR 15 to 29 mL/min/1.73 m²) is not recommended.

There are no data from the use of trofinetide in pregnant women. Animal studies are insufficient with respect to reproductive toxicity. Trofinetide is not recommended during pregnancy or in women of childbearing potential not using contraception.

It is unknown whether trofinetide is excreted in human milk. There is insufficient information on the excretion of trofinetide in animal milk. A risk to the newborns/infants cannot be excluded.

Women of childbearing potential

Women of child-bearing potential should be advised to use effective contraception during treatment.

Fertility

There are no human data on the effect of trofinetide on fertility. Animal studies are insufficient with respect to fertility risk.

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

Summary of the safety profile

The most commonly observed adverse reactions in ACP-2566-003 (Study 1), a 12-week, randomized, double-blind, placebo-controlled study were diarrhoea (80.6%) and vomiting (26.9%).

In Study 1 and open-label extension studies up to 144 weeks, 43.3% of patients discontinued treatment due to adverse reactions. The most common adverse reactions leading to discontinuation included diarrhoea (25.8%), vomiting (6.7%), seizures (2.8%), weight loss (2.2%), and decreased appetite (2.2%).

Tabulated list of adverse reactions

The table below presents the adverse reactions in trofinetide-treated patients identified in Study 1 within the MedDRA system organ class and frequency grouping. Frequencies are defined as follows: very common (≥1/10); common (≥1/100 to <1/10).

Adverse reactions reported in patients with Rett syndrome:

^a Includes partial seizure
^b Includes retching

Description of selected adverse reactions

Diarrhoea

Diarrhoea occurred in 80.6% of patients treated with trofinetide in Study 1. The mean onset for diarrhoea was 7 days with a mean duration of 51 days. Diarrhoea severity was mild in 52% of cases, moderate in 45.3% of cases, and severe in 2.7% of cases. In Study 1 and open-label extension studies, 53.3% of patients had either persistent diarrhoea or recurrence after resolution despite dose interruptions, reductions, or concomitant antidiarrhoeal therapy.

Vomiting

Vomiting occurred in 26.9% of patients treated with trofinetide in Study 1. The mean onset for vomiting was 20 days with a mean duration of 26 days. Vomiting severity was mild in 72% of cases, moderate in 24% of cases, and severe in 4% of cases. In Study 1 and open-label extension studies, 36.4% of patients had recurrence of vomiting after resolution.

Weight loss

In Study 1, 12.9% of patients treated with trofinetide experienced weight loss of greater than 7% from baseline, compared to 4.7% of patients who received placebo.

Seizure

In Study 1, seizure was reported in 8.6% of patients treated with trofinetide and 6.4% of patients treated with placebo reported seizure or partial seizures. Seizure severity was mild in 37.5% of patients treated with trofinetide, and moderate in 62.5% of patients treated with trofinetide.