Approved Drug Label (PDF)
5
Warnings and Precautions
5.3 Fat-Soluble
Vitamin Deficiency
Newly added
information
…
Bone
Fracture
Fracture
events have been observed with BYLVAY-treated patients in two open-label
postmarketing studies (5% in PFIC patients and 4% in ALGS patients) [see Adverse Reactions (6)]. If fracture
occurs, consider interrupting BYLVAY treatment and supplement with FSV if
indicated.
6
Adverse Reactions
6.1 Clinical
Trials Experience
Extensive changes;
please refer to label for complete information
8
Use in Specific Populations
8.1 Pregnancy
Additions and/or revisions underlined:
Risk
Summary
Limited
human
data on the use of BYLVAY in pregnant women are insufficient to
establish a drug-associated risk of major birth defects, miscarriage, or
adverse developmental outcomes. Based on findings from animal reproduction
studies, BYLVAY may cause cardiac malformations when a fetus is exposed during
pregnancy. In pregnant rabbits treated orally with odevixibat during
organogenesis, an increased incidence of malformations in fetal heart, great
blood vessels, and other vascular sites occurred at all doses; maternal
systemic exposure at the lowest dose was 2.1 times the maximum recommended dose
(see Data). Odevixibat may inhibit
the absorption of fat-soluble vitamins. FSV are essential for normal fetal
growth and development. Monitor pregnant patients for FSV deficiency and
supplement as needed. Increased supplementation of FSVs may be needed during
pregnancy [see Warnings and Precautions
(5.3) and Clinical Considerations]. Consider the woman’s need for BYLVAY,
the potential drug-related risks to the fetus, and the potential adverse
outcomes from untreated maternal PFIC and ALGS.
…
Clinical
Considerations
Fetal/Neonatal
Adverse Reactions
Odevixibat
may inhibit the absorption of fat-soluble vitamins (FSV). Monitor pregnant
patients for FSV deficiency and supplement as needed. Increased supplementation
of FSVs may be needed during pregnancy [see
Warnings and Precautions (5.3)].
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING
INFORMATION
Additions
and/or revisions underlined:
…
Fat
Soluble Vitamin (FSV) Deficiency
Advise
patients or their caregiver(s) that INR (for vitamin K) and serum levels of
vitamins A, D, E will be obtained before starting and periodically during
treatment to assess for FSV deficiency [see
Warnings and Precautions (5.3)]. Inform patients or their caregiver(s) that
they may bleed more easily, may bleed longer, or have a bone fracture.
Advise patients or their caregiver(s) to call their healthcare provider for any
signs or symptoms of bleeding or report any fractures.
Approved Drug Label (PDF)
4
Contraindications
Additions and/or
revisions underlined:
IBAT inhibitors,
including BYLVAY, are contraindicated in patients with prior or active hepatic
decompensation events (e.g., variceal hemorrhage, ascites, hepatic
encephalopathy) [see Warnings and Precautions (5.1)].
5
Warnings and Precautions
Subsection title revised:
5.1 Hepatoxicity
Additions and/or
revisions underlined:
BYLVAY treatment is
associated with a potential for drug-induced liver injury (DILI).
In the PFIC and ALGS trials,
treatment-emergent elevations of liver tests or worsening of liver tests occurred.
Of the six patients who experienced DILI, two underwent liver
transplant.
Obtain baseline liver
tests because some ALGS and PFIC patients have
abnormal liver tests at baseline. Monitor patients frequently for the
first 6 to 8 months after starting therapy and as clinically indicated
thereafter during treatment with BYLVAY. Monitor for elevation in
liver tests, for the development of liver-related adverse reactions, and for
physical signs of hepatic decompensation. If liver test abnormalities or signs
of clinical hepatitis occur in the absence of other causes, consider dose
reduction or treatment interruption.
Permanently discontinue
BYLVAY if a patient experiences the following:
- persistent
or recurrent liver test abnormalities, or
- upon
rechallenge, signs and symptoms consistent with clinical hepatitis, or
- a
hepatic decompensation event.
The safety and
effectiveness of BYLVAY have not been established in patients with
decompensated cirrhosis. Monitor patients with compensated cirrhosis or portal
hypertension more frequently and discontinue BYLVAY if hepatic decompensation
occurs. IBAT inhibitors, including BYLVAY, are contraindicated in patients with
prior or active hepatic decompensation events [see Contraindications (4)].
5.3 Fat-Soluble Vitamin
Deficiency
Additions and/or
revisions underlined:
BYLVAY may adversely
affect absorption of fat-soluble vitamins (FSV). FSV
include vitamin A, D, E, and K (measured using INR levels). PFIC and ALGS
patients can have FSV deficiency at baseline and are frequently supplemented
with FSV.
In Trial 1 in PFIC
patients, new onset or worsening of existing FSV deficiency
was reported in 1 (5%) placebo-treated patient, and 3 (16%) BYLVAY-treated 120
mcg/kg/day patients; none of the patients treated with BYLVAY dosage
40 mcg/kg/day had new onset or worsening of existing FSV deficiency.
In Trial 3 in ALGS
patients, new or worsening of existing FSV deficiency was reported in 3
(17.6%) placebo- treated patients and 3 (8.6%) BYLVAY-treated patients [see Adverse Reactions (6.1)].
Obtain serum FSV levels
at baseline and monitor during treatment, along with any clinical
manifestations of FSV deficiency. If FSV deficiency is diagnosed,
supplement with FSV. If FSV deficiency persists or worsens despite adequate FSV
supplementation, consider permanent discontinuation of BYLVAY depending on
the benefit and risk balance.
If complications of FSV
deficiency occur, consider interrupting BYLVAY treatment and reassess to ensure
adequate supplementation with FSV. Consider restarting BYLVAY once the patient
is clinically stable.
Bleeding
Interrupt treatment with
BYLVAY if bleeding occurs. Optimize treatment of FSV deficiency and consider
restarting BYLVAY once the patient is clinically stable.
6
Adverse Reactions
Additions and/or
revisions underlined:
The following adverse
reactions are discussed in greater detail in other sections of the label:
- Hepatotoxicity
[see Warnings and Precautions (5.1)]
- Diarrhea
[see Warnings and Precautions (5.2)]
- Fat-Soluble
Vitamin Deficiency [see Warnings and
Precautions (5.3)]
6.1 Clinical Trials
Experience
Additions and/or
revisions underlined:
. . .
Trial 2 is a 72-week,
open-label, single-arm trial in PFIC type 1, 2, and 3 patients. Age of the
enrolled patients ranged from 4 months to 26 years. BYLVAY 120
mcg/kg/day was administered once daily. A total of 116 PFIC patients were
enrolled, of which 56 patients were rolled over from Trial 1. In addition to
patients rolled over from Trial 1, an additional 60 patients were enrolled to
Trial 2. Treatment- emergent adverse reactions were similar as observed in
Trial 1. Adverse reactions observed in Trial 2 but not described in Trial 1
(Table 3) included increased INR (16%), epistaxis (9%), coagulopathy (3%), iron
deficiency anemia (3%), prolonged prothrombin time (2%) and variceal
hemorrhage, stoma hemorrhage, hematochezia, and rectal hemorrhage (<1% each).
The most common reason for BYLVAY treatment
interruption was liver test abnormalities (increases in ALT, AST, direct and
total bilirubin).
Of the 33 patients who
discontinued BYLVAY in Trial 2, five underwent or were referred for liver
transplantation and one patient underwent surgical biliary diversion (SBD).
There were a total of 19 patients who underwent surgical intervention in Trial
2, with one patient who had SBD followed by liver transplant, 15 patients who
underwent liver transplant alone, and three patients who underwent SBD alone.
. . .
Hepatotoxicity
BYLVAY treatment is
associated with a potential for DILI.
In the PFIC and ALGS
trials, treatment-emergent elevations of liver tests or worsening of liver
tests occurred. Of the six patients who experienced DILI, two underwent liver
transplant.
Newly added subsection:
6.2 Postmarketing
Experience
The following adverse
reactions have been identified during post-approval use of BYLVAY.
Because these reactions are reported voluntarily from a population of uncertain
size, it is not always possible to reliably estimate their frequency or
establish a causal relationship to drug exposure.
Gastrointestinal
disorders: gastrointestinal hemorrhage, gingival hemorrhage,
liver transplant
Investigations:
gamma-glutamyltransferase increased, hemoglobin decreased
Nervous system disorders: extra-axial hemorrhage (subdural
hemorrhage)
Respiratory, thoracic, and
mediastinal disorders: epistaxis
8
Use in Specific Populations
8.1 Pregnancy
Additions
and/or revisions underlined:
. . .
There is a pregnancy safety study that monitors
pregnancy outcomes in women exposed to BYLVAY during pregnancy. Pregnant women
exposed to BYLVAY, or their healthcare providers, should report BYLVAY exposure
by calling 1-855-463-5127.
. . .
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATION
Additions and/or
revisions underlined:
. . .
Hepatotoxicity
Advise patients or their
caregiver(s) that liver tests should be obtained before starting BYLVAY and
periodically during BYLVAY therapy. Inform patients or their caregiver(s) of
the potential risk of hepatotoxicity, and that they will need to
undergo monitoring for liver injury. Instruct patients or their
caregiver(s) to immediately report any signs or symptoms of severe liver injury
to their healthcare provider [see
Dosage and Administration (2.3) and Warnings and Precautions (5.1)].
.
. .
Fat
Soluble Vitamin (FSV) Deficiency
Advise
patients or their caregiver(s) that INR (for vitamin K) and serum levels of
vitamins A, D, E will be obtained before starting and periodically during
treatment to assess for FSV deficiency [see Warnings and Precautions (5.3)].
Inform patients or their
caregiver(s) that they may bleed more easily or may bleed longer. Advise
patients or their caregiver(s) to call their healthcare provider for any signs
or symptoms of bleeding.
Pregnancy
Advise patients or their caregiver(s) that there is
a pregnancy safety study that collects pregnancy outcome data in women taking
BYLVAY during pregnancy. Pregnant women exposed to BYLVAY, or their healthcare
providers, should report BYLVAY exposure by calling 1-855-463-5127 [see
Use in Specific Populations (8.1)].
Approved Drug Label (PDF)
5
Warnings and Precautions
5.1 Liver Test
Abnormalities
Extensive
changes; please refer to label for complete information
5.2 Diarrhea
Additions and/or
revisions underlined:
In
Trial 1, diarrhea in PFIC patients was reported in 2 (10%)
placebo-treated patients, 9 (39%)
BYLVAY-treated
40 mcg/kg/day patients and 4 (21%) BYLVAY-treated 120 mcg/kg/day patients.
Treatment interruption due to diarrhea occurred in 2 patients with 3 events
during treatment with BYLVAY 120 mcg/kg/day. Treatment interruption due to
diarrhea ranged between 3 to 7 days [see
Adverse Reactions (6.1)]. One patient treated with BYLVAY 120 mcg/kg/day
withdrew from Trial 1 due to persistent diarrhea.
In
Trial 3, diarrhea in ALGS patients was reported in 1 placebo-treated patient
(6%) and in 10 (29%) BYLVAY-treated patients [see Adverse Reactions (6.1)]. No patients interrupted or permanently
discontinued BYLVAY due to diarrhea.
…
5.3
Fat-Soluble Vitamin (FSV) Deficiency
Additions
and/or revisions underlined:
Fat-soluble
vitamins (FSV) include vitamin A, D, E, and K (measured using INR levels). PFIC
and ALGS patients can have FSV deficiency at baseline, as part of
their disease. BYLVAY may affect absorption of fat-soluble vitamins. In
Trial 1, new onset or worsening of existing FSV deficiency was reported in 1
(5%) placebo-treated patient, and 3 (16%) BYLVAY-treated 120 mcg/kg/day
patients; none of the BYLVAY-treated 40 mcg/kg/day patients had new onset or
worsening of existing FSV deficiency. In Trial 3, new or worsening of
existing FSV deficiency was reported in 3 (17.6%) placebo- treated patients and
3 (8.6%) BYLVAY-treated patients [see
Adverse Reactions (6.1)].
…
6
Adverse Reactions
6.1 Clinical
Trials Experience
Extensive changes; please refer to label for complete information
8
Use in Specific Populations
8.1 Pregnancy
Additions
and/or revisions underlined:
…
There
is a pregnancy safety study that monitors pregnancy outcomes in women exposed
to BYLVAY during pregnancy. Pregnant women exposed to BYLVAY, or their
healthcare providers, should report BYLVAY exposure by calling 1-855-252-4736.
8.4
Pediatric Use
Additions
and/or revisions underlined:
The
safety and effectiveness of BYLVAY have been established in pediatric patients
3 months to 17 years of age for the treatment of pruritus in PFIC. Use of
BYLVAY in this age group is supported by evidence from one randomized,
double-blind, placebo-controlled trial conducted in 62 patients with a
confirmed diagnosis of PFIC type 1 or type 2 (Trial 1), and an open-label
extension trial in PFIC patients (Trial 2) [see
Adverse Reactions (6.1) and Clinical Studies (14)].
The
safety and effectiveness of BYLVAY for the treatment of pruritus in PFIC in
pediatric patients less than 3 months of age have not been established.
The
safety and effectiveness of BYLVAY have been established in pediatric patients
12 months to 17 years of age for the treatment of pruritus in ALGS. Use of
BYLVAY in this age group is supported by evidence from one randomized,
double-blind, placebo-controlled trial conducted in 52 patients with a
confirmed diagnosis of ALGS (Trial 3) and one open-label extension trial in
ALGS patients (Trial 4) [see Adverse
Reactions (6.1) and Clinical Studies (14)].
The
safety and effectiveness of BYLVAY for the treatment of pruritus in ALGS in
pediatric patients less than 12 months of age have not been established.
8.5
Geriatric Use
Additions
and/or revisions underlined:
PFIC and ALGS are
largely diseases of pediatric and young adult patients. Clinical
studies in BYLVAY did not include patients 65 years of age and older.
8.6
Hepatic Impairment
Additions
and/or revisions underlined:
Patients
with PFIC and ALGS may have impaired hepatic function. The efficacy and
safety of BYLVAY in PFIC and ALGS patients with clinically
significant portal hypertension, and in patients with decompensated cirrhosis
have not been established [see Clinical
Studies (14), Dosage and Administration (2.3), and Warning and Precautions
(5.1)].
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATION
Additions and/or revisions underlined:
Administration
Instructions
Advise
patients or their caregivers(s) to:
…
- Take
BYLVAY at least 4 hours before or 4 hours after taking a bile acid binding
resin (e.g., cholestyramine, colesevelam, or colestipol) [see Drug Interactions (7.1)].
Liver
Test Abnormalities
Advise
patients or their caregiver(s) that liver tests should be obtained before
starting BYLVAY and periodically during BYLVAY therapy, due to the risk of
elevation in liver tests and development of liver-related adverse reactions [see Dosage and Administration (2.3) and
Warnings and Precautions (5.1)].
Diarrhea
Advise
patients or their caregiver(s) to notify their healthcare provider if they
experience new onset or worsening of diarrhea [see Warnings and Precautions (5.2)].
Fat
Soluble Vitamin (FSV) Deficiency
Advise
patients or their caregiver(s) that INR (for vitamin K) and serum levels of
vitamins A, D, E will be obtained before starting and periodically during
treatment to assess for FSV deficiency [see
Warnings and Precautions (5.3)].
Pregnancy
Advise
patients or their caregiver(s) that there is a pregnancy safety study that
collects pregnancy outcome data in women taking BYLVAY during pregnancy.
Pregnant women exposed to BYLVAY, or their healthcare providers, should report
BYLVAY exposure by calling 1-855-252-4736 [see
Use in Specific Populations (8.1)].
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