Approved Drug Label (PDF)
5
Warnings and Precautions
5.1
Risk of QTc Interval Prolongation with Higher-Than-Recommended Dosages
Subsection
title revised
Additions
and/or revisions underlined:
ORLADEYO
should not be used for treatment of acute attacks of HAE. Additional doses or
doses of ORLADEYO higher than the recommended dosage are not recommended. An
increase in QTc interval was observed in adults at dosages higher
than 150 mg once daily and was concentration dependent [see Dosage and Administration (2) and Clinical Pharmacology (12.2)].
6
Adverse Reactions
Additions
and/or revisions underlined:
The
following clinically significant adverse reaction is described elsewhere in the
labeling:
- QTc
Interval
Prolongation [see Warnings and
Precautions (5.1)]
6.1
Clinical Trials Experience
Additions
and/or revisions underlined:
.
. .
Adverse
Reactions in Adult and Pediatric Patients 12 Years of Age and Older
The
safety of ORLADEYO is primarily based on 24-week (Part 1) data from a 3-part,
double-blind, parallel-group, placebo-controlled trial (Trial 1) in 120
patients with Type I or II HAE who were randomized and dosed with either
ORLADEYO 110 mg, 150 mg, or placebo, once daily with food. After Week 24,
patients who continued in the study received active treatment through 48 weeks.
In
Trial 1, a total of 81 patients aged 12 years and older with HAE received at
least one dose of ORLADEYO in Part 1. Overall, 66% of patients were female and
93% of patients were White with a mean age of 41.6 years. The proportion
of patients who discontinued study drug prematurely due to adverse reactions
was 7% and 3% for patients treated with ORLADEYO 110 mg and 150 mg,
respectively, and 3% for placebo-treated patients. No deaths occurred in the
trial.
.
. .
Table
2 shows adverse reactions occurring in greater than or equal to 10% of adult
and pediatric patients aged 12 years and older in any ORLADEYO
treatment group that also occurred at a higher rate than in the placebo
treatment group in Trial 1.
Table
2: Adverse Reactions Observed in greater than or equal to 10% of Adult and
Pediatric Patients Aged 12 Years and Older with HAE in Any ORLADEYO
Treatment Group (Trial 1)
.
. .
Gastrointestinal
adverse reactions, including abdominal pain, vomiting, and diarrhea
occurred more frequently in patients receiving ORLADEYO 150 mg versus ORLADEYO
110 mg or placebo. These adverse reactions generally occurred early
after initiation of treatment with ORLADEYO, became less frequent with time,
and typically self-resolved. No patients in the ORLADEYO 150 mg dose group and
1 patient in the ORLADEYO 110 mg dose group discontinued treatment due to a
gastrointestinal adverse reaction.
Less Common Adverse
Reactions
Other
adverse reactions that occurred in Part 1 of Trial 1 with an incidence between
5% to <10% and at a higher incidence in ORLADEYO-treated patients compared
to placebo-treated patients included headache (9% versus 5%), fatigue
(6% versus 3%), and flatulence (6% versus 3%).
A
maculopapular drug rash was reported in less than 1% of patients treated with
ORLADEYO. The rash resolved, including in patients who continued dosing.
.
. .
Laboratory
Abnormalities
Transaminase
Elevations
In
Part 1 of Trial 1, one patient treated with ORLADEYO 150 mg
discontinued treatment due to asymptomatic elevated transaminases (ALT >8x
the upper limit of normal [ULN] and AST >3x ULN). Total bilirubin was
normal. No patient receiving ORLADEYO 110 mg or placebo developed
transaminase levels >3x ULN. In addition to this patient, 2 ORLADEYO-treated
patients developed laboratory-related hepatic adverse reactions compared
to 1 placebo-treated patient. No patient reported serious adverse reactions of
elevated transaminases.
Adverse
Reactions in Pediatric Patients 2 to Less than 12 Years of Age
The
safety of ORLADEYO was evaluated in 29 pediatric patients aged 2 to <12
years with HAE in a multicenter, single-arm, open-label safety and
pharmacokinetic study (Trial 3). Patients received ORLADEYO based on patient’s
body weight for at least 12 weeks, with 17 patients completing 48 weeks of
treatment. No new safety signals were observed in these patients.
7
Drug Interactions
7.1
Effect of Other Drugs on ORLADEYO
Subsection
title revised
Additions
and/or revisions underlined:
P-gp
Inducers
Berotralstat
is a substrate of P-gp and BCRP. P-gp inducers may decrease berotralstat plasma
concentration, leading to reduced efficacy of ORLADEYO. Avoid concomitant
use of P-gp inducers with ORLADEYO.
7.2
Effect of ORLADEYO on Other Drugs
Subsection
title revised
Additions
and/or revisions underlined:
CYP2D6
and CYP3A4 Substrates
ORLADEYO
at a dose of 150 mg is a moderate inhibitor of CYP2D6 and CYP3A4. Concomitant use
of ORLADEYO with CYP2D6 or CYP3A4 substrates can increase exposure of
the CYP2D6 or CYP3A4 substrates and may increase the risk of adverse reactions
associated with the substrates. If ORLADEYO is concomitantly used with CYP2D6
or CYP3A4 substrates where minimal increases in the concentration of the
substrates may lead to serious adverse reactions, closely monitor or
modify the dosage of the CYP2D6 or CYP3A4 substrate [see Clinical Pharmacology (12.3)]. Refer to the Prescribing
Information of the CYP2D6 or CYP3A4 substrate.
Desogestrel
Concomitant
use of ORLADEYO
with desogestrel increases exposure to etonogestrel, the active metabolite of
desogestrel, and may increase the risk of desogestrel-associated adverse
reactions. Consider the benefits and risks when using
ORLADEYO concomitantly with desogestrel [see Clinical Pharmacology (12.3)].
P-gp
Substrates
ORLADEYO
at 2-times the maximum recommended dose of 150 mg is a P-gp
inhibitor and can increase exposure of P-gp substrates, leading to
increased risk of adverse reactions associated with the substrates.
Higher-than-recommended dosages of ORLADEYO are not recommended [see Warnings and Precautions (5.1)]. If
ORLADEYO is concomitantly used with P-gp substrates where minimal increases in
the concentration of the substrates may lead to serious adverse reactions,
closely monitor or modify the dosage of the P-gp substrate [see Clinical Pharmacology (12.3)]. Refer
to the Prescribing Information of the P-gp substrate.
8
Use in Specific Populations
8.4
Pediatric Use
Additions
and/or revisions underlined:
The
safety and effectiveness of ORLADEYO for prophylaxis to prevent attacks of
hereditary angioedema have been established in pediatric patients aged 2
and older.
The use of ORLADEYO in pediatric
patients aged 12 to <18 years with HAE is supported by evidence from an
adequate and well-controlled trial (Trial 1) that included adults and a
total of 6 pediatric patients aged 12 to <18 years. The safety
profile and attack rate in the study were similar to those observed in
adults [see Adverse Reactions (6.1),
Clinical Pharmacology (12.3), and Clinical Studies (14)]. An additional 10 pediatric
patients aged 12 to <18 years were enrolled in the open-label study (Trial
2).
The
use of ORLADEYO in pediatric patients aged 2 to <12 years with HAE is
supported by efficacy data from an adequate and well-controlled study in adults
and pediatric patients aged 12 years and older (Trial 1), and pharmacokinetic
and safety data from 29 pediatric patients aged 2 to less than 12 years
enrolled in a multicenter, single-arm, open-label study with additional support
from population pharmacokinetic analyses. Pediatric patients aged 2 to less
than 12 years received a dosage of ORLADEYO based on the patient’s body weight,
which showed no clinically significant difference in drug exposures from those
observed in adults treated with ORLADEYO 150 mg [see Clinical Pharmacology (12.3)]. Pediatric patients aged 2 to
less than 12 years were treated for at least 12 weeks, with 17 patients
completing 48 weeks of treatment. No new safety signals were observed in
pediatric patients aged 2 to less than 12 years [see Adverse Reactions (6.1)].
The
safety and effectiveness of ORLADEYO have not been established in pediatric
patients younger than 2 years of age.
8.5
Geriatric Use
Additions
and/or revisions underlined:
Of
the total number of
patients in clinical studies of ORLADEYO, 9 patients were 65
years of age and over in Trial 1, and 5 patients were 65 years of
age and over in Trial 2 (open-label safety study). No overall differences
in safety or effectiveness of ORLADEYO have been observed between
patients 65 years of age and older and younger adult patients [see Adverse Reactions (6.1), Clinical
Pharmacology (12.3), and Clinical Studies (14)].
8.6
Renal Impairment
Additions
and/or revisions underlined:
Mild
to Moderate Renal Impairment:
Adult and
Pediatric Patients Aged 2 Years and Older
- No
dosage modification of ORLADEYO is recommended [see Clinical Pharmacology (12.3)].
Severe
Renal Impairment:
Adult and
Pediatric Patients Aged 12 Years and Older
- No
dosage modification of ORLADEYO is recommended.
Pediatric Patients
Aged 2 to Less than 12 Years
- Avoid
use of ORLADEYO. End-Stage Renal Disease:
ORLADEYO
has not been studied in patients with End-Stage Renal Disease (CLCR <15
mL/min or eGFR <15 mL/min/1.73 m2 or patients requiring
hemodialysis) and therefore is not recommended for use in these patient
populations [see Clinical Pharmacology
(12.3)].
8.7
Hepatic Impairment
Additions
and/or revisions underlined:
Mild
Hepatic Impairment (Child-Pugh Class A):
Adult and
Pediatric Patients Aged 2 Years and Older
- No
dosage modification of ORLADEYO is recommended [see Clinical Pharmacology (12.3)].
Moderate
or Severe Hepatic Impairment (Child-Pugh B or C):
Adult and
Pediatric Patients Aged 12 Years and Older
- The
recommended dosage of ORLADEYO capsules is 110 mg once daily with food [see Dosage and Administration (2.3) and
Clinical Pharmacology (12.3)].
Pediatric Patients
Aged 2 Years and Older
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT
COUNSELING INFORMATION
Additions
and/or revisions underlined:
.
. .
Not
for Acute Treatment of HAE Attacks
Advise
patients to take their usual rescue medication to treat an acute attack of HAE.
Inform patients that the safety and effectiveness of ORLADEYO has not been
established as a treatment for acute HAE attacks [see Indications and Usage (1)].
QTc
Prolongation with Higher Than Recommended Dosages
Advise
patients that they should not take daily doses higher than their prescribed
once-daily dose or additional doses of ORLADEYO to treat an acute attack
of HAE due to risk of QTc interval prolongation [see Indications and Usage (1) and Warnings and Precautions (5.1)].
Administration
Instructions for Oral Pellets
Instruct
patients that ORLADEYO oral pellets should not be chewed or crushed because
this will affect the film coating, which masks the bitter taste. Advise
patients to take ORLADEYO oral pellets by pouring one packet directly into the
mouth and swallowing with a non-acidic liquid (e.g., water or milk), or to
sprinkle one packet over one tablespoon of soft, non-acidic food and consume
immediately [see Dosage and
Administration (2.5)].
Drug
Interactions
Advise
patients that ORLADEYO may interact with other drugs [see Drug Interactions (7) and Clinical Pharmacology (12.3)].
Advise patients to report to their healthcare provider the use of any other
prescription or nonprescription medication or herbal products.
PATIENT
INFORMATION
Additions
and/or revisions underlined:
What is ORLADEYO?
- ORLADEYO
is a prescription medicine used to prevent attacks of Hereditary Angioedema
(HAE) in adults and children 2 years of age and older.
- ORLADEYO
is not used to treat an acute HAE attack.
- Do
not take more than 1 dose of ORLADEYO a day because extra doses can
cause heart rhythm problems.
- It
is not known if ORLADEYO is safe and effective to treat an acute HAE attack.
- It
is not known if ORLADEYO is safe and effective in children under 2 years
of age.
Before you take
ORLADEYO, tell your healthcare provider about all of your medical conditions,
including if you:
- have
liver problems or kidney problems.
.
. .
How should I take
ORLADEYO?
- Take
ORLADEYO exactly as your healthcare provider tells you to take it.
- Take
ORLADEYO with food.
- ORLADEYO
capsules (for adults and children ages 12 years and older): Take 1 capsule, by mouth, 1 time
every day.
- ORLADEYO
oral pellets (ages 2 years to under 12 years): Take 1 packet, by mouth, 1 time
every day.
- Eat
a meal either right before or right after you take your dose.
- Do
not chew or crush the oral pellets because this will affect the film coating
and result in bitter taste.
- Hold
the packet with the
cut line on top.
- Gently
tap the packet to settle the oral pellets.
- Open
the packet along the cut line.
- Take
ORLADEYO oral pellets in 1 of the following ways:
- Pour all the oral pellets in the
packet directly into the mouth and swallow right away with a non-acidic liquid
such as water or milk.
or
- Carefully sprinkle all the oral
pellets in the packet over 1 tablespoon (about 15mL) of soft, non-acidic food and take right away. Food
should be at or below room temperature.
Examples
of soft, non-acidic foods include pudding, mashed potatoes, creamed corn,
pureed peas, pureed bananas, and pureed carrots.
- To
prevent the taste-masking coating from dissolving and resulting in a bitter
taste:
- Take the oral pellets within 10
minutes of being sprinkled over food. Throw the oral pellets away if not taken
within 10 minutes of sprinkling over food.
- Do not sprinkle the oral pellets on
acidic foods such as yogurt and applesauce.
What are the possible
side effects of ORLADEYO?
Taking
more than 1 dose of ORLADEYO a day may cause serious side effects,
including:
- heart rhythm problems. A heart rhythm problem called QTc
interval prolongation can happen in people who take more than 1 dose
of ORLADEYO a day. This condition can cause an abnormal heart beat. Do not take
more than 1 dose of ORLADEYO a day.
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