Iqirvo
(elafibranor)Dosage & Administration
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Iqirvo Prescribing Information
IQIRVO is indicated for the treatment of primary biliary cholangitis (PBC) in combination with ursodeoxycholic acid (UDCA) in adults who have had an inadequate response to UDCA, or as monotherapy in patients unable to tolerate UDCA.
This indication is approved under accelerated approval based on reduction of alkaline phosphatase (ALP) [see Clinical Studies (14)]. Improvement in survival or prevention of liver decompensation events have not been demonstrated. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).
Limitations of Use
Use of IQIRVO is not recommended in patients who have or develop decompensated cirrhosis (e.g., ascites, variceal bleeding, hepatic encephalopathy) [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)].
Recommended Evaluation Before Initiating IQIRVO
Before initiating IQIRVO:
- Evaluate for muscle pain or myopathy [see Warnings and Precautions (5.1)].
- Verify that females of reproductive potential are not pregnant prior to initiating treatment with IQIRVO [see Warnings and Precautions (5.3), Use in Specific Populations (8.1, 8.3)].
Recommended Dosage and Administration
The recommended dosage of IQIRVO is 80 mg taken orally once daily with or without food [see Clinical Pharmacology (12.3)].
Administration Modification for Bile Acid Sequestrants
Administer IQIRVO at least 4 hours before or 4 hours after administering the bile acid sequestrant, or at as great an interval as possible [see Drug Interactions (7.2)].
Tablets: 80 mg, round, orange, film-coated tablets, debossed with "ELA 80" on one side and plain on the other side.
Pregnancy
Risk Summary
Based on data from animal reproduction studies, IQIRVO may cause fetal harm when administered during pregnancy. Treatment of pregnant rats with elafibranor during organogenesis through lactation resulted in stillbirths, reduced survival, decrease in pup body weight, and/or blue/black discoloration of the caudal section of body, which occurred at maternal plasma drug exposures lower than or approximately equal to human exposure at the recommended dose (see Data). There are insufficient data from human pregnancies exposed to IQIRVO to allow an assessment of a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes.
The 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 2-4% and 15-20%, respectively.
Report pregnancies to Ipsen Pharmaceuticals, Inc. Adverse Event reporting line at 1-855-463-5127 and [https://www.ipsen.com/contact-us/].
Data
Animal Data
No effects on embryo-fetal development were observed in pregnant rats treated orally with up to 300 mg/kg/day elafibranor (15-times the recommended dose based on combined AUC [area under the plasma concentration-time curve] for elafibranor and GFT1007) during the period of organogenesis.
No adverse effects on embryo-fetal development were observed in pregnant rabbits treated orally with doses up to 100 mg/kg/day elafibranor, which produced systemic exposures (combined AUC for elafibranor and GFT1007) during the period of organogenesis that were less than the human exposure. Administration of 300 mg/kg/day (3.9-times the recommended dose based on combined AUC for elafibranor and GFT1007) produced marked maternal toxicity, embryo-lethality, reduced fetal weight, and a low incidence of fetal malformations. Variations in ossification of distal limb bones occurred at 100 mg/kg/day, which was associated with strong signs of maternal toxicity (e.g., body weight loss).
A pre- and postnatal development study was performed using oral administration of 10, 30, or 100 mg/kg/day elafibranor in female rats during organogenesis through lactation. All doses produced a reduction in pup survival (during postnatal days 1-4 at 100 mg/kg/day and postnatal days 5-21 at 10 mg/kg/day and higher), a decrease in pup body weight (dose-dependent, up to -28% on postnatal day 1), blue/black discoloration of the caudal section of body, and developmental delays based on evaluation of physical landmarks and functional tests. The developmental delays were likely caused by the decrease in body weight. Adverse effects in the offspring occurred at maternal exposures at or above 0.6-times the recommended dose based on combined AUC for elafibranor and GFT1007. Stillbirths were observed in the 30 and 100 mg/kg/day groups (1.3 and 4.9-times the recommended dose, respectively, based on combined AUC for elafibranor and GFT1007). Aortic or iliac arterial thrombosis was found in decedent pups from females treated with 30 or 100 mg/kg/day. The surviving adult offspring showed no effects on learning and memory, reflex development, or reproductive capability.
Lactation
Risk Summary
There are no data available on the presence of elafibranor or its metabolites in human or animal milk, or on effects of the drug on the breastfed infant or the effects on milk production. Because of the potential for serious adverse reactions in the breastfed infant, advise patients not to breastfeed during treatment with IQIRVO, and for 3 weeks after the last dose.
Females and Males of Reproductive Potential
Based on animal data, IQIRVO may cause fetal harm when administered during pregnancy [see Use in Specific Populations (8.1)].
Pregnancy Testing
For females of reproductive potential, verify that the patient is not pregnant prior to initiating IQIRVO.
Contraception
Females
Advise females of reproductive potential to use effective contraception (non-hormonal) or add a barrier method of contraception when using hormonal contraceptives during treatment with IQIRVO and for 3 weeks after the last dose.
Pediatric Use
The safety and effectiveness of IQIRVO have not been established in pediatric patients.
Geriatric Use
Of the 108 IQIRVO-treated patients with PBC, 25 (23%) were 65 years of age and older, while 1 (1%) was 75 years of age and older. No overall differences in effectiveness of IQIRVO has been observed in patients 65 years of age and older compared to younger adult patients. In healthy elderly subjects (age range 75-80 years), mean systemic exposure (AUC) of elafibranor and the major active metabolite, GFT1007 was 23% and 52% higher, respectively, than those in healthy young subjects (age range 26 to 42 years).
No dosage adjustment for patients 65 years of age and older is necessary. However, because of limited clinical experience with IQIRVO in patients older than 75 years old, closer monitoring of adverse events in patients older than 75 years is recommended [see Clinical Pharmacology (12.3)].
Renal Impairment
The recommended dosage in patients with mild, moderate, or severe renal impairment is the same as in patients with normal kidney function [see Clinical Pharmacology (12.3)].
Hepatic Impairment
No dosage adjustment is recommended for patients with mild hepatic impairment (Child-Pugh A) [see Clinical Pharmacology (12.3)].
The safety and efficacy of IQIRVO in patients with decompensated cirrhosis have not been established. Use of IQIRVO is not recommended in patients who have or develop decompensated cirrhosis (e.g., ascites, variceal bleeding, hepatic encephalopathy). Monitor patients with cirrhosis for evidence of decompensation. Consider discontinuing IQIRVO if the patient progresses to moderate or severe hepatic impairment (Child-Pugh B or C).
None.
Myalgia, Myopathy, and Rhabdomyolysis
Rhabdomyolysis resulting in acute kidney injury occurred in one IQIRVO-treated patient who had cirrhosis at baseline and was also taking a stable dose of an HMG-CoA reductase inhibitor (statin). Myalgia or myopathy, with or without CPK elevations, occurred in patients treated with IQIRVO alone or treated concomitantly with a stable dose of an HMG-CoA reductase inhibitor [see Adverse Reactions (6.1)].
Assess for myalgia and myopathy prior to IQIRVO initiation. Consider periodic assessment (clinical exam, CPK measurement) during treatment with IQIRVO, especially in those who have signs and symptoms of new onset or worsening of muscle pain or myopathy. Interrupt IQIRVO treatment if there is new onset or worsening of muscle pain, or myopathy, or rhabdomyolysis.
Fractures
Fractures occurred in 6% of IQIRVO-treated patients compared to no placebo-treated patients [see Adverse Reactions (6.1)].
Consider the risk of fracture in the care of patients treated with IQIRVO and monitor bone health according to current standards of care.
Adverse Effects on Fetal and Newborn Development
Based on findings from animal reproduction studies, IQIRVO may cause fetal harm when administered during pregnancy. Treatment of pregnant rats with elafibranor at maternal plasma drug exposures lower than or approximately equal to human exposure at the recommended dose resulted in stillbirths, reduced survival, decrease in pup body weight, and/or blue/black discoloration of the caudal section of body.
For females of reproductive potential, verify that the patient is not pregnant prior to initiation of therapy. Advise females of reproductive potential to use effective non-hormonal contraceptives or add a barrier method when using hormonal contraceptives during treatment with IQIRVO and for 3 weeks following the last dose of IQIRVO [see Drug Interactions (7.1), Use in Specific Populations (8.1, 8.3)].
Drug-Induced Liver Injury
Drug-induced liver injury (DILI) occurred in one patient who took IQIRVO 80 mg once daily [see Adverse Reactions (6.1)] and two patients who took IQIRVO at 1.5-times the recommended dosage. In one patient who developed DILI while taking IQIRVO at 1.5-times the recommended dosage, the clinical presentation was drug-induced autoimmune-like hepatitis (DI-ALH). The median time to onset of elevation in liver tests was 85 days (range: day 57 to 288). In Study 1, increases in transaminases (alanine aminotransferase [ALT] and aspartate aminotransferase [AST] ≥ 5× ULN) occurred in 6% of IQIRVO-treated patients compared to 6% of placebo-treated patients, and total bilirubin (TB) elevation (> 3× ULN) occurred in 2% of IQIRVO-treated patients compared to no placebo-treated patients.
Obtain baseline clinical and laboratory assessments at treatment initiation with IQIRVO and monitor thereafter according to routine patient management. Interrupt IQIRVO treatment if liver tests (ALT, AST, TB, and/or alkaline phosphatase [ALP]) worsen, or the patient develops signs and symptoms consistent with clinical hepatitis (e.g., jaundice, right upper quadrant pain, eosinophilia). Consider permanent discontinuation if liver tests worsen after restarting IQIRVO.
Hypersensitivity Reactions
Hypersensitivity reactions have occurred in a clinical trial with IQIRVO at 1.5-times the recommended dosage. Three patients (0.2%) had rash or unspecified allergic reaction that occurred 2 to 30 days after IQIRVO initiation, with positive dechallenges and rechallenges. Hypersensitivity reactions resolved after discontinuation of IQIRVO and treatment with steroids and/or antihistamines.
If a severe hypersensitivity reaction occurs, permanently discontinue IQIRVO. If a mild or moderate hypersensitivity reaction occurs, interrupt IQIRVO and treat promptly. Monitor the patient until signs and symptoms resolve. If a hypersensitivity reaction recurs after IQIRVO rechallenge, then permanently discontinue IQIRVO.
Biliary Obstruction
Avoid use of IQIRVO in patients with complete biliary obstruction. If biliary obstruction is suspected, interrupt IQIRVO and treat as clinically indicated [see Adverse Reactions (6.1)].