Recommendations for the management of diarrhea with trofinetide use in Rett syndrome

Figures & data

Table 1. Incidence, severity, time to onset, and duration of diarrhea TEAEs by age group at baseline in the phase 3 LAVENDER trial (safety analysis set).

				Maximum severity
Treatment and age group, y	N	Participants with diarrhea, n (%)	Diarrhea events, n	Mild, n (%)	Moderate, n (%)	Severe, n (%)	Mean time to onset, days (min, max)	Mean event duration, days (min, max)
Placebo
5–10	52	10 (19.2)	11	9 (17.3)	1 (1.9)	0	11.8 (2, 33)	13.8 (1, 78)
11–15	24	4 (16.7)	4	3 (12.5)	1 (4.2)	0	23.0 (1, 78)	5.8 (2, 12)
16–20	18	4 (22.2)	5	3 (16.7)	1 (5.6)	0	19.0 (8, 36)	33.5 (3, 77)
Trofinetide
5–10	49	39 (79.6)	48	26 (53.1)	13 (26.5)	0	6.6 (1, 38)	52.2 (1, 92)
11–15	25	22 (88.0)	28	9 (36.0)	12 (48.0)	1 (4.0)	8.4 (1, 49)	50.6 (4, 89)
16–20	19	14 (73.7)	27	4 (21.1)	9 (47.4)	1 (5.3)	3.4 (1, 8)	50.6 (8, 84)

Note: TEAE: treatment-emergent adverse event.

Table 2. Recommendations for diarrhea management for individuals being treated with trofinetide.

Prior to initiating trofinetide
1	Obtain a 7- day baseline of bowel activity (stool frequency and consistency, presence of blood) and provide caregiver education on diarrhea management
Upon initiation of trofinetide
2	Upon the start of trofinetide, stop or reduce all constipation medications
3	At initiation of trofinetide, examine any concomitant medications and switch as many liquid medications that contain sugar alcohols as possible to pill form
4	Start fiber (e. g. psyllium, wheat dextrin, flaxseed) as a stool normalizer when starting trofinetide according to the following dosing instructions: Children: 0.5–1 tsp 1–3 times daily in 4 oz water Adolescents/adults: 1–2 tsp 1–4 times daily in 8 oz water Continue fiber to promote bowel health, even in the absence of diarrhea or if diarrhea resolves
Upon occurrence of diarrhea
5	At the onset of diarrhea, start oral loperamide according to the following dosing instructions: Children 2–<12 years of age : ○ 2–5 years of age and/or weighing 13–<21 kg: initially 1 mg with first loose stool, followed by 1 mg/dose every 8 hours; maximum: 3 mg/day ○ 6–8 years of age and/or weighing 21–27 kg: initially 2 mg with first loose stool, followed by 1 mg/dose every 8 hours; maximum: 4 mg/day ○ 9–11 years of age and/or weighing 27.1–43 kg: initially 2 mg with first loose stool, followed by 1–2 mg/dose every 8 hours; maximum: 6 mg/day Children ≥12 years of age and adolescents weighing >43 kg: ○ Initially 4 mg with first loose stool, followed by 2 mg/dose every 8 hours; maximum: 8 mg/day Adults: ○ Initially 4 mg with first loose stool, followed by 4 mg/dose every 6 hours; maximum: 16 mg/day Use the lowest effective dose of loperamide that maintains symptomatic control If no bowel movement occurs for 24 hours, withhold loperamide until a bowel movement occurs If bloody diarrhea occurs, loperamide is contraindicated and should not be used Other antidiarrheal medications to consider include bismuth subsalicylate and cholestyramine; anticholinergic medication may be considered for severe cramping. Consult with the individual’s gastroenterologist
6	If diarrhea occurs, ask the caregiver to contact the prescriber and to begin tracking the consistency and frequency of bowel movements or the occurrence of new fecal incontinence. If diarrhea persists despite the discontinuation of constipation medications and the initiation of fiber supplements, a 50% dose reduction of trofinetide may be considered. Following resolution of the diarrhea, trofinetide may be titrated back up to the full dose
Other
7	Initiate the following dietary and hydration measures: Diet ○ For a child who is not dehydrated, continue a regular diet ○ Regular milk, yogurt, complex carbohydrates (e. g. bread, potatoes, rice, wheat), fruits, vegetables, and lean meats are recommended ○ High-fat foods should be avoided ○ Food should be provided in smaller and more frequent volumes ○ Fruit juice should be given at half-strength (i. e. mixed with an equal amount of water) Hydration ○ Review daily fluid requirements and intake in light of potential increased fluid output due to diarrhea ○ Monitor for dehydration Signs of mild dehydration include increased thirst, a slightly dry mouth, and slightly decreased urination Signs of moderate or severe dehydration include dry mouth, significantly decreased urination, lack of tears, and sunken eyes Administer an oral rehydration solution (e. g. Pedialyte® or generic) for mild dehydration 5 tsp/lb should be given over 4 hours Small volumes of the dose can be given as frequently as every few minutes or as tolerated Contact the prescriber in the event of moderate or severe dehydration
8	If the individual has stopped constipation medications and does not have diarrhea or a bowel movement for 24 hours, regular constipation medications may be resumed as needed

Data availability statement

The data that support the findings of this study are available from the corresponding author KJM upon reasonable request.