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Trofinetide (Acadia’s Daybue) FDA-Approved for Rett syndrome

Trofinetide Rett Syndrome

Generic Name: Trofinetide

Brand Name: Daybue

Manufacturer: Acadia Pharmaceuticals

FDA Approval Date: 10th March 2023

Indications: Rett Syndrome

Trofinetide was approved by the U.S. Food and Drug Administration (FDA) on 10th March 2023, making it the first-ever treatment for Rett syndrome, a rare genetic neurodevelopmental condition that shares some traits with autism [Ref]

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What is Rett syndrome?

Rett syndrome is a rare genetic disorder that affects the development of the brain, resulting in severe mental and physical disabilities.

The clinical features of Rett syndrome can vary from person to person, but some of the most common features include:

  • Developmental regression:

Children with Rett syndrome typically develop normally for the first few months of life, but then begin to lose previously acquired skills such as the ability to crawl, walk, or use their hands.

  • Communication difficulties:

Many children with Rett syndrome have severe communication difficulties, including the inability to speak or communicate effectively with others.

  • Repetitive hand movements:

People with Rett syndrome often exhibit repetitive hand movements such as wringing, clapping, or tapping.

  • Breathing problems:

Rett syndrome can cause breathing difficulties, including hyperventilation, breath-holding, and irregular breathing patterns.

  • Seizures:

Many people with Rett syndrome experience seizures, which can be difficult to control with medication.

  • Cognitive impairment:

People with Rett syndrome typically have intellectual disabilities and may have difficulty learning new information or performing tasks that require problem-solving or reasoning skills.

  • Social withdrawal:

Many people with Rett syndrome exhibit social withdrawal and avoid interacting with others, although they may be affectionate with family members.

  • Scoliosis:

Rett syndrome can cause scoliosis, a curvature of the spine, which can lead to breathing difficulties and other complications.

It’s important to note that the severity and range of symptoms can vary widely among individuals with Rett syndrome, and some people may have milder or more severe symptoms than others.

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How is Rett syndrome treated?

There is currently no cure for Rett syndrome, and treatment focuses on managing the symptoms and improving the quality of life for individuals with the condition.

Some of the medications and therapies that may be used to treat Rett syndrome include:

  • Anticonvulsants:

These medications are used to control seizures, which is a common symptom of Rett syndrome.

  • Gastrointestinal medications:

Rett syndrome can cause gastrointestinal problems such as constipation, reflux, and swallowing difficulties.

Medications such as laxatives, antacids, and prokinetics may be used to manage these symptoms.

  • Behavioral therapies:

Behavioral therapies such as speech therapy, occupational therapy, and physical therapy can help improve communication skills, motor function, and daily living skills.

  • Communication aids:

Individuals with Rett syndrome may benefit from using communication aids such as sign language, communication boards, or electronic devices that allow them to communicate with others.

  • Nutritional support:

Some individuals with Rett syndrome may require nutritional support, such as a feeding tube, to ensure that they are receiving adequate nutrition.

  • Psychotropic medications:

In some cases, medications such as antidepressants, antipsychotics, or mood stabilizers may be used to treat behavioral or emotional symptoms such as anxiety, depression, or aggression.

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Trofinetide for Rett Syndrome: Indications:

Trofinetide (DAYBUE) has been approved for the treatment of Rett syndrome in both adults and children who are at least 2 years old.

It is not a cure for Rett syndrome but may help alleviate the symptoms of Rett syndrome. It may improve motor function, communication skills, and other aspects of daily life for people with Rett syndrome.

Dose of Trofinetide (DAYBUE) for the treatment of Rett Syndrome:

Dosage and VolumePatient Weight RangeAdministration
5,000 mg twice daily, 25 mL twice daily9 kg to < 12 kgOral or gastrostomy tube
6,000 mg twice daily, 30 mL twice daily12 kg to < 20 kgOral or gastrostomy tube
8,000 mg twice daily, 40 mL twice daily20 kg to < 35 kgOral or gastrostomy tube
10,000 mg twice daily, 50 mL twice daily35 kg to < 50 kgOral or gastrostomy tube
12,000 mg twice daily, 60 mL twice daily50 kg or moreOral or gastrostomy tube

Note: DAYBUE should not be used with other medications. It can be taken with or without food. It is important to use a calibrated measuring device, such as an oral syringe or dosing cup, to ensure accurate measurement and delivery of the prescribed dose. Unused DAYBUE oral solution should be discarded after 14 days of first opening the bottle.

  • If a dose is missed . . .

If a dose of DAYBUE is missed, it should not be doubled to make up for it. Patients should take the next scheduled dose at the appropriate time to avoid unintended side effects.

If vomiting occurs after taking DAYBUE, patients should continue with the regular dosing schedule and not take an extra dose to avoid the risk of an overdose.

Patients should follow up with their healthcare provider if vomiting persists or if they have concerns about their response to the medication.

  • Dosage modification for weight loss or diarrhea:

Patients should discontinue the use of any laxatives before starting treatment with DAYBUE. A combination of laxatives and DAYBUE can cause diarrhea, leading to dehydration and weight loss.

Severe diarrhea, dehydration, or significant weight loss may require interruption or reduction of DAYBUE dosage or discontinuation of treatment.

Patients should inform their healthcare provider if they experience any changes in bowel habits while taking DAYBUE to adjust the treatment plan.

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Contraindications to Trofinetide (DAYBUE):

There is no contraindication given in the FDA prescribing information

Warning & Precaution:

  • Diarrhea:

85% of patients in Study 1 and long-term studies experienced diarrhea as a side effect of DAYBUE.

If diarrhea occurs, patients should discontinue laxatives and consider using antidiarrheal medication.

Severe diarrhea or suspected dehydration may require interruption, dosage reduction, or discontinuation of DAYBUE treatment.

  • Weight Loss:

12% of patients in Study 1 experienced weight loss of greater than 7% from baseline compared to 4% of patients who received a placebo.

It is recommended to monitor weight and interrupt, reduce dosage, or discontinue DAYBUE if significant weight loss occurs.

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Side effects caused by Trofinetide (Daybue):

Side Effect

Prevalence in Clinical Studies


Diarrhea85%Notify healthcare provider, consider antidiarrheal medication, monitor hydration status; may require dose interruption, reduction, or discontinuation
VomitingNot commonDo not take an additional dose, continue with next scheduled dose
Weight loss12%Monitor weight; may require interruption, dose reduction, or discontinuation
InfectionsMore frequent than placeboMonitor for symptoms and seek medical attention if necessary
Vascular disordersHigher incidence than placeboMonitor blood pressure and seek medical attention if necessary
Adverse reactions at the injection site4%Monitor for adverse reactions and seek medical attention if necessary
CNS effectsHigher incidence than placeboMonitor for symptoms and seek medical attention if necessary

Side effects reported in Clinical Trials:

  • Adverse reaction rates cannot be directly compared between drugs or reflect rates observed in practice
  • 260 patients with Rett syndrome, ages 2 to 40, were treated with DAYBUE in controlled and uncontrolled trials
  • 109 patients were treated for more than 6 months
  • 69 patients were treated for more than 1 year
  • 4 patients were treated for more than 2 years
  • However, it is important to note that adverse reaction rates cannot be compared between different drugs or reflect rates observed in actual practice.
PopulationStudy DesignNumber of PatientsTreatment DurationAdverse Reactions Leading to Discontinuation
Adult and pediatric (≥5 y)Randomized, double-blind, placebo-controlledDAYBUE: 93

Placebo: 94

12 weeks19% of DAYBUE patients; diarrhea (15%)
Pediatric (2-4 y)Open-label studyDAYBUE: 13

Placebo: 9

≥12 weeks/≥6 monthsSimilar adverse reactions to adult and pediatric patients (≥5 y) in Study 1

Summary of side effects of Trofinetide:

The safety of DAYBUE was evaluated in two studies in patients with Rett syndrome.

Study 1 included adult and pediatric patients aged 5 years and older and showed that 19% of DAYBUE patients experienced adverse reactions leading to discontinuation, with diarrhea being the most common.

The open-label study included pediatric patients aged 2 to 4 years and reported similar adverse reactions to those in Study 1.

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Trofinetide Drug Interaction:

Drug interactionDAYBUE is a weak CYP3A4 inhibitor, and concomitant use with orally administered CYP3A4 substrates may increase plasma concentrations.
Closely monitor for serious toxicities with orally administered CYP3A4 substrates.
Concomitant use of DAYBUE with OATP1B1 and OATP1B3 substrates may increase plasma concentrations.
RecommendationAvoid concomitant use of DAYBUE with OATP1B1 and OATP1B3 substrates that may cause serious toxicities due to small changes in substrate plasma concentration.
Monitor closely for serious toxicities with orally administered CYP3A4 substrates when used with DAYBUE.

Using Trofinetide in specific populations:



PregnancySafety for pregnant women has not been adequately studied.

Animal studies showed no adverse effects on fetal development with lower doses of Trofinetide.

Potential risks for major birth defects and miscarriage are unknown.

LactationThe effects of Trofinetide on the breastfed infant are unknown.

The decision to breastfeed should be based on the benefits of breastfeeding and the mother’s need for DAYBUE along with possible side effects on the infant or maternal condition.

ChildrenSafe and effective in treating Rett syndrome in patients aged 2 years and older.

Safety and effectiveness are established in pediatric patients aged 5 years and older.

Safety data in 13 patients aged 2 to 4 years treated with DAYBUE for 12 weeks supports its use in this age group.

Safety and effectiveness are not established in pediatric patients less than 2 years of age.

Old AgeNo studies conducted on patients aged 65 years and older to determine if they respond differently.

Monitor kidney function in elderly patients as DAYBUE is mostly eliminated through the kidneys.

Kidney ProblemNot recommended for people with moderate or severe kidney problems as DAYBUE is mainly eliminated through the kidneys.

No specific research on how it affects people with kidney problems.

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Mechanism of action of Trofinetide (Daybue):

The way Trofinetide works to help patients with Rett syndrome is not yet understood.

However, at the highest recommended dose for healthy adults, DAYBUE does not have any significant effect on the QT interval, which measures the electrical activity of the heart.

Trofinetide Pharmacokinetics



KineticsLinear kinetics with no time- or dose-dependent effect
Systemic exposureDose-proportional across the studied dose range; minimal to no accumulation
AbsorptionTime to maximum drug concentration (Tmax) is about 2 to 3 hours after administration; at least 84% of the administered dose was absorbed following oral administration of 12,000 mg trofinetide
Effect of FoodCoadministration with a high-fat meal had no impact on the total exposure (AUC0-inf) of Trofinetide and reduced the peak plasma concentration (Cmax) by approximately 20%
DistributionThe apparent volume of distribution of Trofinetide in adult healthy subjects was approximately 80 L; protein binding in human plasma is less than 6%
EliminationThe effective elimination half-life of orally administered Trofinetide in healthy subjects is about 1.5 hours
MetabolismNot significantly metabolized by CYP450 enzymes; hepatic metabolism is not a significant route of Trofinetide elimination
ExcretionPrimarily excreted unchanged (approximately 80% of the dose) in urine, with minor excretion in feces

Overall, Trofinetide exhibits linear pharmacokinetics with no dose-dependent effect. It is well-absorbed following oral administration with a Tmax of 2-3 hours.

Co-administration with a high-fat meal does not affect total exposure but reduces peak plasma concentration.

Trofinetide has an apparent volume of distribution of approximately 80 L, and protein binding in human plasma is less than 6%.

It has an elimination half-life of about 1.5 hours and is primarily excreted unchanged in the urine, with minor excretion in feces.

Trofinetide is not significantly metabolized by CYP450 enzymes, and hepatic metabolism is not a significant route of elimination.

How to store and handle Trofinetide?

The medication DAYBUE (Trofinetide) comes in a 500 mL bottle with a child-resistant cap and contains 450 mL of oral solution.

It is a pink-to-red, strawberry-flavored solution. It should be stored upright in the refrigerator at 2°C to 8°C (36°F to 46°F) and should not be frozen. After opening the bottle, the unused solution should be discarded after 14 days.

Patient Counseling:

The patient or caregiver should read the Patient Information Leaflet provided by the FDA. DAYBUE can be taken orally or through a gastrostomy tube, but a proper measuring device, like an oral syringe, should be used to ensure the correct dose is administered.

Unused DAYBUE should be discarded within 14 days of opening the bottle. DAYBUE can cause diarrhea, vomiting, and weight loss.

If these symptoms occur, the healthcare provider should be notified. The oral solution of DAYBUE should be stored upright in the refrigerator, but not frozen.

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What do you think?

Written by Dr. Ahmed

I am Dr. Ahmed (MBBS; FCPS Medicine), an Internist and a practicing physician. I am in the medical field for over fifteen years working in one of the busiest hospitals and writing medical posts for over 5 years.

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