Livdelzi (seladelpar lysine)

Dosage of seladelpar lysine is expressed in terms of seladelpar.

Seladelpar lysine is administered orally without regard to meals.

In patients taking bile acid sequestrants, administer seladelpar at least 4 hours before or 4 hours after taking a bile acid sequestrant, or at as great an interval as possible.

Seladelpar should be stored at 20-25degreesC (excursions permitted between 15-30degreesC).

No dosing information is available for this tab.

In vitro studies indicate that seladelpar lysine is primarily metabolized by cytochrome P-450 (CYP) 2C9, and to a lesser extent, by CYP2C8 and CYP3A4. Seladelpar is also a substrate of breast cancer resistance protein (BCRP), P-glycoprotein (P-gp), and organic anion transporter (OAT) 3. Seladelpar is not a substrate of multidrug and toxin extrusion (MATE) 1, MATE2-K, OAT1, organic anion transporting polypeptide (OATP) 1B1, OATP1B3, organic cation transporter (OCT) 1, or OCT2 transporters.

In vitro studies indicate that seladelpar and its metabolites do not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C19, CYP2D6, or CYP3A4. Seladelpar does not induce CYP1A2, CYP2B6, or CYP2C8.

In vitro studies indicate that seladelpar and its metabolites do not inhibit UDP-glucuronosyltransferases (UGTs).

In vitro studies indicate that seladelpar and its metabolites do not inhibit P-gp, MATE1, MATE2-K, OCT1, OCT2, OAT1, or OAT3.

Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Seladelpar/Probenecid

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Probenecid may inhibit the renal elimination of seladelpar.(1,2)

CLINICAL EFFECTS: Concurrent use of probenecid may result in an increase in both the therapeutic and toxic effects of seladelpar, such as hepatotoxicity.(1) Symptoms can include nausea, vomiting, jaundice, dark urine, abdominal pain, and unexplained fatigue.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of seladelpar states that concurrent administration of seladelpar with probenecid should be avoided.(1)

DISCUSSION: In a study in healthy subjects, concurrent administration of seladelpar (single 10 mg dose) with probenecid (500 mg) resulted in approximately a 2-fold increase in area-under-curve (AUC) and a 4.69-fold increase in concentration maximum (Cmax) of seladelpar.(1)

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Agents That Increase Cpk/Aumolertinib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Aumolertinib may increase blood CPK levels leading to myopathy and rhabdomyolysis. Other agents that also increase CPK may contribute to additive effects on CPK levels.(1) In addition, aumolertinib may prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1) Taletrectinib and zidesamtinib may prolong the QTc interval.

CLINICAL EFFECTS: Concurrent use of aumolertinib and other agents that also increase CPK levels may increase the risk of myopathy or rhabdomyolysis, which is characterized by progressive muscle weakness and pain in the presence of a normal neurological exam.(1) In addition, the concurrent use of aumolertinib with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1) Taletrectinib and zidesamtinib may prolong the QTc interval.

PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may also be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis. Patients on fluvastatin who are CYP2C9 intermediate or poor metabolizers may have increased fluvastatin concentrations and risk of myopathy. Patients on rosuvastatin with ABCG2 polymorphisms leading to decreased or poor BCRP transporter function may have increased rosuvastatin concentrations and risk of myopathy. The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, and advanced age.(1,2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: Concurrent use of aumolertinib and other agents that increase CPK levels should be avoided. Prior to initiation of aumolertinib, blood CPK levels should be obtained and periodically monitored during treatment and as clinically indicated.(1) If the patient develops elevated CPK levels or rhabdomyolysis, the following is recommended: For Grade 3 with muscular symptoms: - Withhold aumolertinib for up to 2 weeks. - If muscular symptoms resolve and CPK increase is <= Grade 3, resume at 110 mg dose for the first occurrence; resume at 55 mg for the second occurrence. - Permanently discontinue aumolertinib if symptoms/signs recur at anytime while on the reduced dose. - If muscular symptoms do not resolve and CPK increase does not improve to <= Grade 2, permanently discontinue aumolertinib. For Grade 4 with or without muscular symptoms: - Withhold aumolertinib for up to 2 weeks. - If muscular symptoms resolve and CPK increase is <= Grade 3, resume at 55 mg for the first occurrence. - Permanently discontinue aumolertinib if symptoms/signs recur at anytime while on the reduced dose. - If muscular symptoms do not resolve and CPK remains >= Grade 3, permanently discontinue aumolertinib. If rhabdomyolysis occurs, hold aumolertinib and initiate treatment for rhabdomyolysis.(1) In concurrent use is warranted, carefully monitor for myopathy or rhabdomyolysis. Patients should be instructed to report any symptoms of myopathy such as unexplained muscle aches, tenderness, weakness, or the onset of tingling/numbness in the fingers or toes.(1) The manufacturer of aumolertinib states that concurrent use of other drugs that are known to prolong the QTc interval should be avoided. Taletrectinib and zidesamtinib may also prolong the QTc interval. If a suitable alternative is not available, consider increasing the frequency of ECG and electrolyte monitoring.(1) Consider obtaining serum calcium, magnesium, and potassium levels and correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. If QTc prolongation occurs, follow recommended dose modifications: - Grade 2 (QTc interval >480 to 500 ms): Withhold aumolertinib for up to 2 weeks. If QTc interval has not recovered to <= 480 ms, permanently discontinue aumolertinib. If QTc interval recovers to <= 480 ms or within 30 ms of baseline, resume aumolertinib treatment at 110 mg. Monitor ECGs at least weekly for 2 weeks following return to <= 480 ms. Monitor and correct electrolytes and/or change concomitant medications. - Grade 3 (QTc interval > 500 ms or QTc interval increase of > 60 ms from baseline): Withhold aumolertinib for up to 2 weeks. If QTc interval has not recovered to <= 480 ms or within 30 ms of baseline, permanently discontinue aumolertinib. If QTc interval recovers to <= 480 ms and it is the first occurrence, resume treatment at 110 mg dose. If QTc interval recovers to <= 480 ms and it is the second occurrence or the first occurrence in patients with risk factors, resume treatment at 55 mg dose. Permanently discontinue aumolertinib if signs or symptoms recur at any time on the 55 mg dose. Monitor ECGs at least weekly for 2 weeks following return to <= 480 ms. Monitor and correct electrolytes and/or change concomitant medications. - QT interval prolongation associated with torsade de pointes, polymorphic ventricular tachycardia, or signs/symptoms of other serious arrhythmia: permanently discontinue aumolertinib.(1)

DISCUSSION: Aumolertinib increased blood CPK levels in 31.7% of patients in clinical studies at recommended doses. Patients developed Grade 3 CPK elevations with muscular symptoms (7.5% of patients) and Grade 4 CPK elevations with or without muscular symptoms. Elevated CPK levels led to interruption or dose reduction in 6.1% and 2.0% of patients, respectively. Rhabdomyolysis occurred in 2.6% of patients.(1) A concentration-QT analysis predicted a QTc interval prolongation at 110 mg aumolertinib of 9.06 ms (upper confidence interval = 11.01 ms) in 49 subjects.(1) In clinical studies (n=545), QT prolongation was reported in 51 patients (9.4%) treated with aumolertinib 110 mg. Seven patients (1.3%) had symptomatic events, including cardiac arrest, syncope, and ventricular arrhythmia. One patient with cardio-respiratory arrest and one patient with sudden cardiac death died. QTcF increase >60 ms occurred in 4.2% of patients, and increase in QTcF to >500 ms occurred in 0.9% of patients.(1) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(3)

Moderate Interaction: Assess the risk to the patient and take action as needed.

Seladelpar/Bile Acid Sequestrants

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Bile acid sequestrants may bind to seladelpar in the gut, resulting in decreased absorption of seladelpar.(1)

CLINICAL EFFECTS: Coadministration of bile acid sequestrants with seladelpar may result in reduced efficacy of seladelpar.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of seladelpar states to administer bile acid sequestrants (cholestyramine, colesevelam, and colestipol) at least 4 hours before or 4 hours after administration of seladelpar, or at as great an interval as possible.(1)

DISCUSSION: Bile acid sequestrants are known to bind to drugs when given concurrently. Administration with seladelpar may result in decreased systemic absorption.(1)

*None.

• Hepatic failure

There are no severe contraindications for this drug.

There are no moderate contraindications for this drug.

The most common adverse reactions (reported in >=5% of patients and higher compared to placebo) with seladelpar in clinical studies were headache, abdominal pain, nausea, abdominal distension, and dizziness.

There are no severe adverse reactions for this drug.

More Frequent

• Abdominal distension
• Abnormal hepatic function tests
• Acute abdominal pain
• Dizziness
• Headache disorder
• Nausea

Less Frequent

• Alopecia
• Anemia
• Cough
• Dyspepsia
• Fracture
• Kidney disease with reduction in glomerular filtration rate (GFr)
• Skin rash

No enhanced messaging available.

Safety and efficacy of seladelpar have not been established in pediatric patients <18 years of age.

Human data regarding seladelpar use during pregnancy are inadequate to inform a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.

In animal studies, no malformations or effects on embryofetal survival occurred in pregnant rats or rabbits following seladelpar treatment exposures up to 176-times and 49-times the recommended dose, respectively. Reduction of fetal growth associated with maternal toxicity occurred in pregnant rabbits at 49-times the recommended dose, but not at 3-times the recommended dose. In a study in pregnant rats during organogenesis through lactation, postnatal growth and pre-weaning survival of offspring was reduced at 115-times the recommended dose, but not at 16-times the recommended dose.

Pregnancies in seladelpar-treated patients should be reported to Gilead Sciences, Inc. at 1-800-445-3235.

It is not known whether seladelpar is distributed into human milk. Effects of the drug on breastfed infants or milk production are also not known. Consider the developmental and health benefits of breastfeeding along with the mother's clinical need for seladelpar and any potential adverse effects on the breastfed infant from the drug or the underlying maternal condition.

No dosage adjustment is recommended for patients >=65 years of age.

In the RESPONSE trial, 23% of patients were >=65 years of age and 2% of patients were >=75 years of age. No differences in safety or efficacy were observed between older patients between 65 and 75 years of age and younger patients, and no dosage adjustments are recommended. Due to limited clinical experience with patients >=75 years of age, close monitoring of adverse events is recommended.