RELYVRIO Powder for oral suspension Ref.[50247] Active ingredients: Sodium phenylbutyrate Ursodoxicoltaurine

5.1 Risk in Patients with Enterohepatic Circulation Disorders, Pancreatic Disorders, or Intestinal Disorders

RELYVRIO contains taurursodiol, which is a bile acid. In patients with disorders that interfere with bile acid circulation, there may be an increased risk for worsening diarrhea, and patients should be monitored appropriately for this adverse reaction. Pancreatic insufficiency, intestinal malabsorption, or intestinal diseases that may alter the concentration of bile acids, may also lead to decreased absorption of either of the components of RELYVRIO. Because different enterohepatic circulation, pancreatic, and intestinal disorders have varying degrees of severity, consider consulting with a specialist. Patients with disorders of enterohepatic circulation (e.g., biliary infection, active cholecystitis, etc.), severe pancreatic disorders (e.g., pancreatitis), and intestinal disorders that may alter concentrations of bile acids (e.g., ileal resection, regional ileitis, etc.) were excluded from the study, therefore there is no clinical experience in these conditions.

5.2 Use in Patients Sensitive to High Sodium Intake

RELYVRIO has a high salt content. Each initial daily dosage of one packet contains 464 mg of sodium; each maintenance dosage of two packets daily contains 928 mg of sodium. In patients sensitive to salt intake (e.g., those with heart failure, hypertension, or renal impairment), consider the amount of daily sodium intake in each dose of RELYVRIO and monitor appropriately.

The following clinically significant adverse reactions are described elsewhere in the labeling:

• Risk in Patients with Enterohepatic Circulation Disorders, Pancreatic Disorders, or Intestinal Disorders [see Warnings and Precautions (5.1)]
• Use in Patients Sensitive to High Sodium Intake [see Warnings and Precautions (5.2)]

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of RELYVRIO was evaluated in Study 1 which enrolled 137 adult patients with ALS randomized (2:1) to RELYVRIO (n=89) or placebo (n=48) for 24 weeks.

In Study 1, there were 5 (6%) RELYVRIO-treated patients and 2 (4%) placebo patients who died during the 24-week study. The deaths appeared to be related to ALS disease progression.

The most common adverse reactions (at least 15% and at least 5% greater than placebo) with RELYVRIO were diarrhea, abdominal pain, nausea, and upper respiratory tract infection. Gastrointestinal-related adverse reactions occurred throughout the study but were more frequent during the first 3 weeks of treatment.

Table 1 lists the common adverse reactions that occurred in more than 5% of patients taking RELYVRIO and were at least 5% greater than in patients taking placebo in Study 1.

Table 1. Adverse Reactions Reported in More than 5% of RELYVRIO-Treated Patients with ALS and at least 5% Greater than Placebo (Study 1):

Adverse Reaction	RELYVRIO (N=89) %	Placebo (N=48) %
Diarrhea*	25	19
Abdominal pain*	21	13
Nausea	18	13
Upper respiratory tract infection*	18	10
Fatigue*	12	6
Salivary hypersecretion	11	2
Dizziness	10	4

^* Adverse reaction is composed of several similar terms.

7.1 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.

Probenicid

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.

7.2 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.

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. In animal studies, administration of sodium phenylbutyrate and taurursodiol to rats throughout pregnancy and lactation resulted in increased offspring mortality at all doses tested, which were less than or similar to the clinical doses.

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.

Data

Animal Data

Oral administration of the combination of sodium phenylbutyrate and taurursodiol (0, 375, 750, or 1500 mg/kg/day, containing sodium phenylbutyrate and taurursodiol in a 3:1 ratio) to pregnant mice during the period of organogenesis was not associated with any adverse effects. At the highest dose of the combination of sodium phenylbutyrate and taurursodiol tested, the doses of sodium phenylbutyrate and taurursodiol were similar to the maximum recommended dose (6 g sodium phenylbutyrate and 2 g taurursodiol) in humans (MRHDs), based on body surface area (mg/m²).

Oral administration of the combination of sodium phenylbutyrate and taurursodiol (0, 375, 750, or 1500 mg/kg/day) to pregnant rats during the period of organogenesis was not associated with any adverse effects. At the highest dose of the combination of sodium phenylbutyrate and taurursodiol tested, the doses of sodium phenylbutyrate and taurursodiol were approximately 2-fold the MRHDs, based on mg/m².

Oral administration of the combination of sodium phenylbutyrate and taurursodiol (0, 375, 750, or 1500 mg/kg/day) to rats throughout pregnancy and lactation resulted in increases in stillbirth at all doses and pup deaths at the highest dose tested. A no effect dose for adverse developmental effects in rats was not identified. At the lowest dose of the combination of sodium phenylbutyrate and taurursodiol tested, the doses of sodium phenylbutyrate and taurursodiol were less than the MRHDs, based on mg/m².

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.

Safety and effectiveness of RELYVRIO in pediatric patients have not been established.

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.

No dose adjustment is needed for patients with mild renal impairment. Avoid use in patients with moderate or severe renal impairment [see Clinical Pharmacology (12.3)].

No dose adjustment is needed for patients with mild hepatic impairment. Avoid use in patients with moderate or severe hepatic impairment [see Clinical Pharmacology (12.3)].