DAYBU Oral solution Ref.[116869] Active ingredients: Trofinetide

Diarrhoea

Patients should be advised to stop taking laxatives before starting trofinetide. Patients who experience diarrhoea during treatment with trofinetide should be managed using antidiarrhoeal treatment, and monitored for hydration status and oral fluids should be increased, if needed. An interruption, a reduction in dose, or discontinuation of trofinetide should be considered if severe diarrhoea occurs or dehydration is suspected (see section 4.2).

Vomiting

Patients with Rett syndrome are at risk for aspiration and aspiration pneumonia. Aspiration and aspiration pneumonia have been reported following vomiting in patients being treated with trofinetide. An interruption, a reduction in dose, or discontinuation of trofinetide should be considered if vomiting is severe or occurs despite medical management (see section 4.2).

Weight loss

Patient's weight should be monitored. An interruption, a reduction in dose, or discontinuation of trofinetide should be considered if significant weight loss occurs (see section 4.2).

Interactions with sensitive CYP3A4 and/or P-gp substrates

Close monitoring is recommended when trofinetide is used in combination with orally administered CYP3A4 and/or P-gp sensitive substrates (e.g., cyclosporine, digoxin) for which a small change in substrate plasma concentration may lead to serious adverse reactions (see section 4.5).

Excipients with known effect

This medicinal product contains 30 mg maltitol in each mL. Patients with rare hereditary problems of fructose intolerance should not take this medicine.

This medicinal product contains 4.9 mg propylene glycol in each mL.

This medicinal product contains 1.12 mg of sodium methyl parahydroxybenzoate and 0.25 mg of sodium propyl parahydroxybenzoate in each mL. Those excipients may cause allergic reactions (possibly delayed).

This medicinal product contains Allura Red AC. This excipient may cause allergic reactions.

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

Effect of trofinetide on pharmacokinetics of other medicinal products

Trofinetide is a weak inhibitor of CYP3A4 and P-gp; therefore, plasma concentrations of CYP3A4 and/or P-gp substrates may be increased if given concomitantly with trofinetide. A clinical drug-drug interaction study in healthy subjects assessing the effect of trofinetide on the pharmacokinetic of loperamide, a substrate of both CYP3A4 and P-gp, showed that concomitant administration resulted in an increase in loperamide C_max by 1.95-fold and AUC by 1.73-fold.

Close monitoring is recommended when trofinetide is used in combination with orally administered CYP3A4 and/or P-gp sensitive substrates (e.g., cyclosporine, digoxin) for which a small change in substrate plasma concentration may lead to serious adverse reactions.

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).

Women of childbearing potential

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

Pregnancy

There are no data from the use of trofinetide in pregnant women. Animal studies are insufficient with respect to reproductive toxicity (see section 5.3). Trofinetide is not recommended during pregnancy or in women of childbearing potential not using contraception.

Breast-feeding

It is unknown whether trofinetide is excreted in human milk. There is insufficient information on the excretion of trofinetide in animal milk (see section 5.3). A risk to the newborns/infants cannot be excluded.

Fertility

There are no human data on the effect of trofinetide on fertility. Animal studies are insufficient with respect to fertility risk (see section 5.3).

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%) (see section 4.4).

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

Table 3 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).

Table 3. 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.

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.

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

The compatibility of trofinetide with G-tube or G-port of the GJ tubes made of other materials than those mentioned in section 6.6 has not been established.