DRUG INTERACTIONS-(SUMMARY)

 • Orally administered CYP3A4 sensitive substrates for which a small change in substrate plasma concentration may lead to serious toxicities: closely monitor for adverse reactions with concomitant use.

 • OATP1B1 and OATP1B3 substrates for which a small change in substrate plasma concentration may lead to serious toxicities: avoid concomitant use.

DRUG INTERACTIONS- (details)

1 Effect of DAYBUE on Other Drugs Trofinetide is a weak CYP3A4 inhibitor; therefore, plasma concentrations of CYP3A4 substrates may be increased if given concomitantly with DAYBUE 

Closely monitor when DAYBUE is used in combination with orally administered CYP3A4 sensitive substrates for which a small change in substrate plasma concentration may lead to serious toxicities.

Plasma concentrations of OATP1B1 and OATP1B3 substrates may be increased if given concomitantly with DAYBUE

Avoid the concomitant use of DAYBUE with OATP1B1 and OATP1B3 substrates for which a small change in substrate plasma concentration may lead to serious toxicities

BRIEF SUMMARY-

TROFINETIDE-(May 2023)

Indcn-  To  treat Rett syndrome      

Dose- Dosage DAYBUE Volume 9 kg to less than 12 kg 5,000 mg twice daily 25 mL twice daily 12 kg to less than 20 kg 6,000 mg twice daily

ADR- e most common adverse reactions in treated patients  were diarrhea and vomiting. 

CI-  None. WARNINGS - Diarrhea: Most patients experience diarrhea during treatment  Advise patients to stop laxatives before starting DAYBUE.

Pat inform-  may be taken with or without food . Instruct the caregiver or patient to obtain a calibrated measuring device, such as an oral syringe or oral dosing cup, from the pharmacy to measure and deliver the prescribed dose accurately.

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U.S.  APPROVED DRUGS DURING 2023                                        

Serial No 10

Name-        DAYBUE

Acive  Ingredient -  Trofinetide

 Pharmacological clssificiation-        To  treat Rett syndrome                                                                                                                                                                                          Date of Approval-         3/10/2023 

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use                                   DAYBUE safety and effectively.                                                                                      See full prescribing information for DAYBUE. DAYBUE™ (trofinetide) oral solution

Initial U.S. Approval: 2023

INDICATIONS AND USAGE-

 DAYBUE is indicated for the treatment of Rett syndrome in adults and pediatric patients 2 years of age and older.

ADVERSE REACTIONS-

 The most common adverse reactions (that occurred in at least 10% of DAYBUE-treated patients and at least 2% greater than in placebo) were diarrhea and vomiting. 

WARNINGS AND PRECUATIONS-

 • Diarrhea: Most patients experience diarrhea during treatment with DAYBUE. Advise patients to stop laxatives before starting DAYBUE.

If diarrhea occurs, patients should start antidiarrheal treatment, increase oral fluids, and notify their healthcare provider. Interrupt, reduce dose, or discontinue DAYBUE if severe diarrhea occurs or if dehydration is suspected.

 • Weight Loss: Weight loss may occur in patients treated with DAYBUE. Monitor weight and interrupt, reduce dose, or discontinue DAYBUE if significant weight loss occurs.

CONTRAINDICATIONS-

 None. 

DOSAGE AND ADMINISTRATION-

Recommended  dosage is twice daily, morning and evening, according to patient weight. DAYBUE can be given with or without food. (2.1)

Patient Weight DAYBUE-                                                                                                Dosage DAYBUE Volume 9 kg to less than 12 kg 5,000 mg twice daily 25 mL twice daily 12 kg to less than 20 kg 6,000 mg twice daily 30 mL twice daily 20 kg to less than 35 kg 8,000 mg twice daily 40 mL twice daily 35 kg to less than 50 kg 10,000 mg twice daily 50 mL twice daily 50 kg or more 12,000 mg twice daily 60 mL twice daily

• Can be given orally or via gastrostomy (G) tube; doses administered via gastrojejunal (GJ) tubes must be administered through the G-port. 

DOSAGE FORMS AND STRENGTHS-

 • Oral solution: 2

PATIENT COUNSELING INFORMATION-

 Advise the caregiver or patient to read the FDA-approved patient labeling (Patient Information).

DAYBUE Administration-                                                                                           Advise the caregiver or patient that DAYBUE may be given orally or via gastrostomy (G) tube; doses administered via gastrojejunal (GJ) tubes must be administered through the G-port.

DAYBUE may be taken with or without food [see Dosage and Administration (2.1, 2.2)]. Instruct the caregiver or patient to obtain a calibrated measuring device, such as an oral syringe or oral dosing cup, from the pharmacy to measure and deliver the prescribed dose accurately.

A household measuring cup is not an adequate measuring device. Reference ID: 5140110 10 Instruct the caregiver or patient to discard any unused DAYBUE after 14 days of first opening the bottle.

Diarrhea -                                                                                                                      Advise the caregiver or patient that DAYBUE can cause diarrhea. Instruct the patient to stop taking laxatives before starting DAYBUE

 If diarrhea occurs, patients should notify their healthcare provider, consider starting antidiarrheal treatment, and monitor hydration status and increase oral fluids, if needed 

Weight Loss-                                                                                                                Inform the caregiver or patient that DAYBUE may cause weight loss and to notify their healthcare provider if weight loss occurs .

Vomiting-                                                                                                                        Advise the caregiver or patient that DAYBUE can cause vomiting and if vomiting occurs after DAYBUE administration, do not take an additional dose, but continue with the next scheduled dose.

Storage-                                                                                                                          Keep bottles of DAYBUE oral solution upright and refrigerated before and after opening. Do not freeze [see How Supplied/Storage and Handling

 Marketed by: Acadia Pharmaceuticals Inc. San Diego, CA 92130 USA DAYBUE is a trademark of Acadia Pharmaceuticals Inc. ©2023 Acadia Pharmaceuticals Inc. All rights reserved.

CLINICAL PHARMACOLOGY -

1 Mechanism of Action-                                                                                                      The mechanism by which trofinetide exerts therapeutic effects in patients with Rett syndrome is unknown.

2. Pharmacodynamics-                                                                                           

Cardiac Electrophysiology At the maximum recommended dose in healthy adult subjects, DAYBUE does not prolong the QT interval to any clinically relevant exten

3. Pharmacokinetics-                                                                                                 Trofinetide exhibits linear kinetics with no time- or dose-dependent effect on pharmacokinetic parameters. Systemic exposure to trofinetide was dose-proportional across the studied dose range. Minimal to no accumulation was observed following multiple-dose administration.

Absorption-                                                                                                                    The time to maximum drug concentration (Tmax) is about 2 to 3 hours after administration. Based on the mass balance study, at least 84% of the administered dose was absorbed following oral administration of 12,000 mg trofinetide.

Effect of Food-                                                                                                         Coadministration of DAYBUE 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%

Distribution-                                                                                                            Following oral administration, the apparent volume of distribution of trofinetide in adult healthy subjects was approximately 80 L. Trofinetide protein binding in human plasma is less than 6%. Reference ID: 5140110 6

Elimination-                                                                                                                   The effective elimination half-life of orally administered trofinetide in healthy subjects is about 1.5 hours

Metabolism-                                                                                                                 Trofinetide is not significantly metabolized by CYP450 enzymes. Hepatic metabolism is not a significant route of trofinetide elimination.

Excretion-                                                                                                                     Trofinetide is primarily excreted unchanged (approximately 80% of the dose) in urine, with minor excretion in feces.

Specific Populations-                                                                                                   The drug exposure of trofinetide in pediatric patients ages 2 to 4 years of age is similar to children older than 4 years and adults when following the recommend dosage.

The pharmacokinetics in patients with renal impairment have not been studied..

The pharmacokinetics in patients with hepatic impairment have not been studied. However, hepatic impairment is not expected to impact the exposure of trofinetide because hepatic metabolism is not a significant route of trofinetide elimination.

Drug Interaction Studies-                                                                                               In Vitro Trofinetide is not a substrate of CYP450 enzymes, uridine diphosphate glucuronosyltransferase (UGT), or major drug transporters.

Therefore, coadministration of drugs that are inducers or inhibitors of CYP450, UGT, or major drug transporters will not significantly affect the systemic exposure of trofinetide.

Trofinetide is a weak CYP3A4 inhibitor. Using physiologically based pharmacokinetic modeling, coadministration of trofinetide with orally administered midazolam, a sensitive CYP3A4 substrate, was predicted to increase the AUC of midazolam by approximately 1.33-fold

No inhibition on CYP450 enzymes, CYP1A2, 2C8, 2C9, 2C19, and 2D6, is expected at therapeutic systemic concentrations based on the in vitro assays and the static mechanistic models. Time-dependent inhibition on CYP2B6 was inconclusive based on in vitro data.

DAYBUE inhibits UGT enzymes, UGT1A9, 2B7, and 2B15, in vitro. No inhibition was observed at therapeutic systemic concentrations on P-gp, BCRP, BSEP, OAT1, OAT3, OCT2, MATE1, and MATE2-K, based on the in vitro assays.

Trofinetide inhibits OATP1B1 and OATP1B3 in vitro

 USE IN SPECIFIC POPULATIONS

1. Pregnancy Risk Summary There are no adequate data on the developmental risks associated with the use of DAYBUE in pregnant women

The  of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

2 Lactation-                                                                                                                  Risk Summary- There is no information regarding the presence of trofinetide or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for DAYBUE and any potential adverse effects on the breastfed infant from DAYBUE or from the underlying maternal condition

3. Pediatric Use-                                                                                                           The safety and effectiveness of DAYBUE for the treatment of Rett syndrome have been established in pediatric patients aged 2 years and older.

The safety and effectiveness of DAYBUE for the treatment of Rett syndrome in pediatric patients 5 years of age and older was established in a randomized, double-blind, placebo-controlled, 12-week study (Study 1), which included 108 pediatric patients age 5 to less than 12 years of age and 47 pediatric patients age 12 to less than 17 years of age

4. Geriatric Use-                                                                                                       Clinical studies of DAYBUE did not include patients 65 years of age and older to determine whether or not they respond differently from younger patients. This drug is known to be substantially excreted by the kidney.

Because elderly patients are more likely to have decreased renal function, it may be useful to monitor renal function.

5. Renal Impairment-                                                                                                       No dedicated clinical study has been conducted to evaluate the pharmacokinetics of DAYBUE in subjects with renal impairment.

Since the drug is eliminated mainly through the kidney, administration of DAYBUE to patients with moderate or severe renal impairment is not recommended.