DRUG INTERACTIONS-(summary)

 See Full Prescribing Information for complete list of clinically significant drug interactions.

DRUG INTERACTIONS-(details)-

1. Potential for Other Drugs to Affect RELYVRIO Bile Acid Sequestering Agents-     Bile acid sequestering agents (e.g., cholestyramine, colestipol, colesevelam) may interfere with the absorption of bile acids such as taurursodiol.

Avoid use of bile acid sequestering agents with RELYVRIO and consider alternative cholesterol lowering agents.

Inhibitors of Bile Acid Transporters-                                                                        Concomitant medications that inhibit canalicular membrane bile acid transporters such as the bile salt export pump (BSEP) may exacerbate accumulation of conjugated bile salts in the liver and result in clinical symptoms.

Avoid use of strong inhibitors of BSEP with RELYVRIO. If concomitant use of a strong inhibitor of BSEP (e.g., cyclosporine) is deemed necessary, caution should be exercised and monitoring of serum transaminases and bilirubin is recommended.

Aluminum-based Antacids Aluminum-based antacids have been shown to adsorb bile acids in vitro and may interfere with the absorption of taurursodiol.

Avoid use of aluminum-based antacids with RELYVRIO and consider other acid lowering agents.

Probenecid- Avoid use of probenecid with RELYVRIO as it may affect renal excretion of sodium phenylbutyrate metabolites. HDAC Inhibitors Phenylbutyrate is a pan-histone deacetylase (HDAC) inhibitor.

Avoid use of other HDAC inhibitors with RELYVRIO. Inhibitors of Transports OATP1B3 In vitro studies showed that RELYVRIO is a substrate of OATP1B3

 Avoid use of inhibitors of OATP1B3 with RELYVRIO.

2. Potential for RELYVRIO to Affect Other Drugs OAT1 Substrates-                        Plasma concentrations of OAT1 substrates may be increased if given concomitantly with RELYVRIO.

Avoid use of OAT1 substrates for which a small change in substrate plasma concentration may lead to serious toxicities or loss of efficacy with RELYVRIO.

P-glycoprotein (P-gP) and Breast Cancer Resistance Protein (BCRP) Substrates RELYVRIO has been shown to inhibit P-gP and BCRP in vitro. Plasma concentrations of P-gP and BCRP substrates may be increased if given concomitantly with RELYVRIO.

Avoid the concomitant use of P-gP and BCRP substrates for which a small change in substrate plasma concentration may lead to serious toxicities or loss of efficacy with RELYVRIO.

Drugs that are substrates of CYP2C8, CYP1A2, CYP2B6, and CYP3A4 isoenzymes RELYVRIO inhibits CYP2C8 and CYP2B6 isoenzymes in vitro. RELYVRIO induces CYP1A2, CYP2B6, and CYP3A4 in vitro

Plasma concentrations of substrates for these enzymes may be changed if given concomitantly with RELYVRIO

Avoid use of drugs that are substrates of these CYP P450 isoenzymes in which a small change in substrate plasma concentration may lead to serious toxicities or loss of efficacy

U.S.  APPROVED DRUGS SURING 2022                                        

Serial No 25

Name-                       RELYURIO        

Active Ingredient -   Phenyl Butyrate /Taurusodiol

Pharmacological Classification- To treat Amyotrophic Lateral  Sclerosis (ALS)                                                                                                                                                    Date of Approval-         9/22/2022 

HIGHLIGHTS OF PRESCRIBING INFORMATION -

These highlights do not include all the information needed to us                                         RELYVRIO safely and effectively.                                                                                       See full prescribing information for RELYVRIO. RELYVRIO (sodium phenylbutyrate and taurursodiol), for oral suspension

Initial U.S. Approval: 2022

 INDICATIONS AND USAGE-

 RELYVRIO is indicated for the treatment of amyotrophic lateral sclerosis (ALS) in adults

ADVERSE REACTIONS-

 Most common adverse reactions (at least 15% and at least 5% greater than placebo) are diarrhea, abdominal pain, nausea, and upper respiratory tract infection.

 CONTRAINDICATIONS-

 None.

 WARNINGS AND PRECAUTIONS-

 • Risk in Patients with Enterohepatic Circulation Disorders, Pancreatic Disorders, or Intestinal Disorders: In patients with disorders that interfere with bile acid circulation, consider consulting with a specialist.

Monitor for new or worsening diarrhea in these patients. These conditions may also lead to decreased absorption of either of the components of RELYVRIO.

 Use in Patients Sensitive to High Sodium Intake: RELYRIO has a high sodium content. In patients sensitive to salt intake, consider the amount of daily sodium intake in each dose of RELYVRIO and monitor appropriately.

DOSAGE AND ADMINISTRATION-

• The recommended dosage is 1 packet (3 g sodium phenylbutyrate and 1 g taurursodiol) administered orally or via feeding tube as follows:                                 

 o Initial dosage: 1 packet daily for the first 3 weeks

 o maintenance dosage: 1 packet twice daily thereafter

• Empty contents of one packet in a cup containing 8 ounces of room temperature water and stir vigorously prior to administration.

 • Take within 1 hour of preparation.

 • Administer RELYVRIO before a snack or meal.

 DOSAGE FORMS AND STRENGTHS-                                                                          For oral suspension: 3 g sodium phenylbutyrate and 1 g taurursodiol in singledose packets

PATIENT COUNSELING INFORMATION-

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

Administration-                                                                                                        Instruct patients or caregivers to empty the contents of one packet in a cup containing 8 ounces of room temperature water and stir vigorously.

Advise them that RELYVRIO can be taken orally or administered via feeding tube, and to use or discard 10 within 1 hour of preparation. Instruct to administer RELYVRIO before a snack or meal.

Enterohepatic Circulation, Pancreatic and Intestinal Disorders -                            Inform patients about the risks and benefits with the use of RELYVRIO if they have underlying medical conditions such as enterohepatic circulation, pancreatic, or intestinal disorders and advise them to notify their healthcare provider if they have new or worsening diarrhea

Sodium Intake-                                                                                                         Inform patients that 2 packets of RELYVRIO contain 928 mg sodium (46% of WHO daily recommended intake) and patients who are sensitive to sodium. (e.g., those with congestive heart failure, severe renal insufficiency, or other conditions associated with sodium retention) should limit their sodium intake.

 Aluminum-based Antacids-                                                                                        Inform patients that aluminum-based antacids may interfere with the absorption of RELYVRIO, and therefore should not be taken during treatment with RELYVRIO

Pregnancy and Breastfeeding-                                                                                     Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during RELYVRIO therapy..

Advise patients to notify their healthcare provider if they intend to breastfeed or are breastfeeding an infant ..

Manufactured for and Distributed by: Amylyx Pharmaceuticals, Inc., 43 Thorndike Street, Cambridge, MA 02141 ©2022 Amylyx Pharmaceuticals, Inc. All Rights Reserved. AMYLYX® and RELYVRIO™ are trademarks of Amylyx Pharmaceuticals, Inc

CLINICAL PHARMACOLOGY

1. Mechanism of Action-                                                                                                 The mechanism by which RELYVRIO exerts its therapeutic effects in patients with ALS is unknown.

2. Pharmacodynamics-                                                                                         Cardiac Electrophysiology-                                                                                          At the maximum recommended dose, RELYVRIO does not cause large mean increases (>20 ms) in the QT interval.

3. Pharmacokinetics -                                                                                         Absorption-                                                                                                                  Following oral administration of a single dose of RELYVRIO in healthy subjects under fasting conditions, sodium phenylbutyrate reaches a median Tmax of 0.5 hour. Taurursodiol reaches a median Tmax of 4.5 hours.

Effect of Food- Administration of RELYVRIO in the presence of a high-fat meal resulted in both significantly slower absorption (Cmax reduced by 76%) and lower overall exposure (AUC reduced by 54%) of sodium phenylbutyrate.

A high-fat meal did not significantly affect the Cmax for taurursodiol, but AUC was increased by 39%

Distribution- Human plasma protein binding for sodium phenylbutyrate and taurursodiol is 82% and 98%, respectively.

Elimination-                                                                                                     Metabolism- No mass balance studies of sodium phenylbutyrate and taurursodiol have been conducted in humans to confirm the metabolic pathways and elimination routes. Phenylacetate was found to be a major metabolite of phenylbutyrate. Ursodiol and glyco-ursodiol were found as major metabolites of taurursodiol.

Excretion-                                                                                                                            The majority of administered sodium phenylbutyrate (~80-100%) is excreted in the urine within 24 hours as the conjugated product, phenylacetylglutamine.

Specific Populations-                                                                                                   The effect of age, gender, racial, or ethnic groups on the pharmacokinetics of RELYVRIO is unknown.

Patients with Renal Impairment-                                                                                 The effect of renal impairment on the pharmacokinetics of RELYVRIO has not been studied. There were no reports of safety issues with patients with mild renal impairment who were enrolled in Study 1. However, there is no clinical experience for subjects with moderate and severe renal impairment ..

Patients with Hepatic Impairment The effect of hepatic impairment on the pharmacokinetics of RELYVRIO has not been studied.

There were no reports of safety issues with patients with mild hepatic impairment (using National Cancer Institute Classification system) who were enrolled in Study 1.

However, there is no clinical experience for subjects with moderate and severe hepatic impairment

Drug Interaction Studies-                                                                                                  No clinical interaction studies between RELYVRIO and other medicinal products have been performed.

In vitro studies showed that the combination of sodium phenylbutyrate and taurursodiol:

• induces CYP1A2, CYP2B6, and CYP3A4 at clinically relevant concentrations • inhibits CYP2C8 and CYP2B6 at clinically relevant concentrations.

• inhibits OAT1, P-gP, and BCRP at clinically relevant concentrations

• is a substrate of OATP1B3, MATE2-K, OAT3, and BSEP

USE IN SPECIFIC POPULATIONS

1. Pregnancy Risk Summary-                                                                                   There are no available data on RELYVRIO use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

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 are no data on the presence of sodium phenylbutyrate or taurursodiol in human milk, the effects on the breastfed infant, or the effects of the drug on milk production.

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

3.Pediatric Use-                                                                                                         Safety and effectiveness of RELYVRIO in pediatric patients have not been established.

4.Geriatric Use Of the 89 patients with ALS who received RELYVRIO in Study 1, 25 patients (28%) were 65 years of age or older, while 4 patients (4.5%) were 75 years of age and older with the oldest patient being 79 years old.

No overall differences in safety or effectiveness were observed between those patients 65 years of age and older and those <65 years of age

. Although differences in responses between the elderly and younger patients were not identified, greater sensitivity of some older individuals cannot be ruled out. 8.6 Renal Impairment

No dose adjustment is needed for patients with mild renal impairment.

Avoid use in patients with moderate or severe renal impairment..

5.Hepatic Impairment No dose adjustment is needed for patients with mild hepatic impairment. Avoid use in patients with moderate or severe hepatic impairment .