Approved Drug Label (PDF)
5
Warnings and Precautions
5.7 Hepatotoxicity
New
subsection added
In
ALTA 1L, aspartate aminotransferase (AST) elevations occurred in 72% of
patients and Grade 3 or 4 AST elevations occurred in 4.5% of patients. Alanine
aminotransferase (ALT) elevations occurred in 52% of patients and Grade 3 or 4
ALT elevations occurred in 5.2% of patients. One patient (0.7%) had a serious
adverse reaction of hepatocellular injury.
In
ALTA, AST elevations occurred in 38% of patients in the 90 mg group and 65% of
patients in the 90 to 180 mg group. ALT elevations occurred in 34% of patients
in the 90 mg group and 40% of patients in the 90 to 180 mg group. Grade 3 or 4
AST elevations occurred in 0.9% of patients in the 90 mg group and did not
occur in any patients in the 90 to 180 mg group. Grade 3 or 4 ALT elevations
did not occur in any patients in the 90 mg group and in 2.7% of patients in the
90 to 180 mg group.
Monitor
AST, ALT and total bilirubin during treatment with ALUNBRIG, especially during
first
3
months. Withhold ALUNBRIG for Grade 3 or 4 hepatic enzyme elevation with
bilirubin less than or equal to 2 × ULN. Upon resolution or recovery to Grade 1
or less (less than or equal to 3 × ULN) or to baseline, resume ALUNBRIG at a
next lower dose as described in Table 2. Permanently discontinue ALUNBRIG for
Grade 2 to 4 hepatic enzyme elevation with concurrent total bilirubin elevation
greater than 2 times the ULN in the absence of cholestasis or hemolysis [see Dosage and Administration (2.3),
Adverse Reactions (6.1)].
6
Adverse Reactions
Addition of the
following to the bulleted line listing:
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATION
Additions underlined
…
Hepatotoxicity
Inform patients of the signs and symptoms of
hepatotoxicity, and the need to monitor for aspartate aminotransferase (AST),
alanine animotransferase (ALT) and total bilirubin elevations during treatment.
Advise patients to inform their healthcare provider of any new or worsening
symptoms [see Warnings and Precautions
(5.7)].
…
PATIENT INFORMATION
Additions underlined
…
ALUNBRIG
can cause serious side effects, including:
…
Liver problems
(hepatotoxicity). ALUNBRIG may increase the levels of bilirubin in your
blood and enzymes called aspartate aminotransferase (AST) and alanine
aminotransferase (ALT) in your blood, which may be a sign of liver problems.
Your healthcare provider will do blood tests to check your liver during
treatment with ALUNBRIG. Tell your healthcare provider right away if you get
new or worsening signs or symptoms, including:
yellowing of your
skin or the white part of your eyes
bleed or bruise
more easily than normal
dark or brown (tea
color) urine
itchy skin
nausea or vomiting
decreased appetite
pain on the right
side of your stomach area
feeling tired
…
Approved Drug Label (PDF)
5
Warnings and Precautions
5.8 Photosensitivity
(Newly added
subsection)
In ALTA 1L, photosensitivity occurred in 3.7% of
patients who received ALUNBRIG, with 0.7% Grade 3 to 4.
In ALTA, 0.9% of patients who received ALUNBRIG in
the 90 mg group experienced photosensitivity and 0.9% of patients in the 90
mg?180 mg group. Grade 3 to 4 photosensitivity was not reported in patients in
the 90 mg group or in the 90?180 mg group.
Advise patients to limit sun exposure while taking
brigatinib, and for at least 5 days after discontinuation of treatment. Advise
patients, when outdoors to wear a hat and protective clothing, and use a
broad-spectrum Ultraviolet A (UVA)/ Ultraviolet B (UVB) sunscreen and lip balm
(SPF ?30) to help protect against sunburn. Based on the severity withhold
ALUNBRIG, then resume at the same dose, or reduce the dose, or permanently
discontinue as described in Table 2 [see
Dosage and Administration (2.3), Adverse Reactions (6.1)].
6
Adverse Reactions
(Addition of the
following to the bulleted line listing)
6.1 Clinical Trials Experience
(Additions and/or
revisions underlined)
…
Clinically relevant adverse reactions in patients
who received ALUNBRIG included photosensitivity (3.7%).
…
Clinically relevant adverse reactions in patients
who received ALUNBRIG included photosensitivity (0.9%).
…
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATION
(Additions and/or
revisions underlined)
…
Photosensitivity
Inform
patients of the signs and symptoms of photosensitivity. Advise patients to
limit sun exposure while taking ALUNBRIG and for at least 5 days after the
final dose. Advise patients to wear a hat, protective clothing, and to use a
broad-spectrum Ultraviolet A (UVA)/ Ultraviolet B (UVB) sunscreen and lip balm
(SPF ?30) to protect against sunburn [see
Warnings and Precautions (5.8)].
…
PATIENT INFORMATION
(Additions and/or
revisions underlined)
…
What should I
avoid while taking ALUNBRIG?
Limit your time in the sun during treatment with
ALUNBRIG and for at least 5 days after your final dose. ALUNBRIG may make your
skin sensitive to sunlight. You may burn more easily and get severe sunburns.
When you are in the sun, wear a hat and protective clothing, and use a
broad-spectrum sunscreen and lip balm with a Sun Protection Factor (SPF) of 30
or greater to protect against sunburn.
Avoid
eating grapefruit or drinking grapefruit juice during treatment with ALUNBRIG.
Grapefruit may increase the amount of ALUNBRIG in your blood.
…
Approved Drug Label (PDF)
5
Warnings and Precautions
5.1 Interstitial Lung Disease (ILD)/Pneumonitis
(Additions and/or
revisions underlined)
Severe,
life-threatening, and fatal pulmonary adverse reactions consistent with
interstitial lung disease (ILD)/pneumonitis have occurred with ALUNBRIG.
In
Trial ALTA 1L, ILD/pneumonitis occurred in 5.1% of patients receiving
ALUNBRIG.
ILD/pneumonitis
occurred within 8 days of initiation of ALUNBRIG in 2.9% of patients, with
Grade 3 to 4 reactions occurring in 2.2% of patients.
In
Trial ALTA,
ILD/pneumonitis occurred in 3.7% of patients in the 90 mg group (90 mg once
daily) and 9.1% of patients in the 90 to 180 mg group (180 mg once daily with
7-day lead-in at 90 mg once daily). Adverse reactions consistent with
possible ILD/pneumonitis occurred within 9 days of initiation of
ALUNBRIG (median
onset was 2 days) in 6.4% of patients, with Grade 3 to 4 reactions occurring in
2.7%.
Monitor
for new or worsening respiratory symptoms (e.g., dyspnea, cough, etc.),
particularly during the first week of initiating ALUNBRIG. Withhold ALUNBRIG in
any patient with new or worsening respiratory symptoms, and promptly evaluate for
ILD/pneumonitis or other causes of respiratory symptoms (e.g., pulmonary
embolism, tumor progression, and infectious pneumonia). For Grade 1 or 2
ILD/pneumonitis, either resume ALUNBRIG with dose reduction according to Table 1
after recovery to baseline or permanently discontinue ALUNBRIG. Permanently
discontinue ALUNBRIG for Grade 3 or 4 ILD/pneumonitis or recurrence of Grade
1 or 2 ILD/pneumonitis.
5.2 Hypertension
(Additions and/or
revisions underlined)
In
ALTA 1L, hypertension was reported in 32% of patients receiving ALUNBRIG; Grade
3 hypertension occurred in 13% of patients.
In
ALTA, hypertension was reported in 11% of patients in the 90 mg group who
received ALUNBRIG and 21% of patients in the 90 to 180 mg group. Grade 3
hypertension occurred in 5.9% of patients overall.
Control
blood pressure prior to treatment with ALUNBRIG. Monitor blood pressure after 2
weeks and at least monthly thereafter during treatment with ALUNBRIG. Withhold
ALUNBRIG for Grade 3 hypertension despite optimal antihypertensive therapy.
Upon resolution or improvement to Grade 1, resume ALUNBRIG at the same
dose. Consider permanent discontinuation of treatment with ALUNBRIG for Grade 4
hypertension or recurrence of Grade 3 hypertension.
Use
caution when administering ALUNBRIG in combination with antihypertensive agents
that cause bradycardia.
5.3 Bradycardia
(Additions and/or
revisions underlined)
In
ALTA 1L, heart rates less than 50 beats per minute (bpm) occurred in 8.1% of
patients receiving ALUNBRIG. Grade 3 bradycardia occurred in 1 patient (0.7%).
In
ALTA, heart rates less than 50 beats per minute (bpm) occurred in 5.7% of
patients in the 90 mg group and 7.6% of patients in the 90 to 180 mg group. Grade 2
bradycardia occurred in 1 (0.9%) patient in the 90 mg group.
Monitor
heart rate and blood pressure during treatment with ALUNBRIG. Monitor patients
more frequently if concomitant use of drug known to cause bradycardia cannot be
avoided.
For
symptomatic bradycardia, withhold ALUNBRIG and review concomitant medications
for those known to cause bradycardia. If a concomitant medication known to
cause bradycardia is identified and discontinued or dose adjusted, resume ALUNBRIG
at the same dose following resolution of symptomatic bradycardia; otherwise,
reduce the dose of ALUNBRIG following resolution of symptomatic bradycardia. Discontinue
ALUNBRIG for life-threatening bradycardia if no contributing concomitant medication
is identified.
5.4 Visual Disturbance
(Additions and/or
revisions underlined)
In
ALTA 1L, Grade 1 or 2 adverse reactions leading to visual disturbance including
blurred vision, photophobia, photopsia, and reduced visual acuity were reported
in 7.4% of patients receiving ALUNBRIG.
In
ALTA, adverse reactions leading to visual disturbance including blurred vision,
diplopia, and reduced visual acuity, were reported in 7.3% of patients receiving
ALUNBRIG in the 90 mg group and 10% of patients in the 90 to 180 mg group. Grade 3
macular edema and cataract occurred in 1 patient each in the 90 to 180 mg group.
Advise
patients to report any visual symptoms. Withhold ALUNBRIG and obtain an
ophthalmologic evaluation in patients with new or worsening visual symptoms of Grade
2 or greater severity. Upon recovery of Grade 2 or Grade 3 visual disturbances
to Grade 1 severity or baseline, resume ALUNBRIG at a reduced dose. Permanently
discontinue treatment with ALUNBRIG for Grade 4 visual disturbances.
5.5 Creatine Phosphokinase (CPK) Elevation
(Additions and/or
revisions underlined)
In
ALTA 1L, creatine phosphokinase (CPK) elevation occurred in 81% of
patients who received ALUNBRIG. The incidence of Grade 3 or 4 CPK elevation was
24%. Dose reduction for CPK elevation occurred in 15% of patients.
In
ALTA, CPK
elevation occurred in 27% of patients receiving ALUNBRIG in the 90 mg group and
48% of patients in the 90 mg to 180 mg group. The incidence of Grade 3-4 CPK
elevation was 2.8% in the 90 mg group and 12% in the 90 to 180 mg group.
Dose
reduction for CPK elevation occurred in 1.8% of patients in the 90 mg group and
4.5% in the 90 to 180 mg group.
Advise
patients to report any unexplained muscle pain, tenderness, or weakness.
Monitor CPK levels during ALUNBRIG treatment. Withhold ALUNBRIG for Grade 3 or
4 CPK elevation with Grade 2 or higher muscle pain or weakness. Upon
resolution or recovery to Grade 1 CPK elevation or baseline, resume ALUNBRIG at
the same dose or at a reduced dose as described in Table 2.
5.6 Pancreatic Enzymes Elevation
(Additions and/or
revisions underlined)
In
ALTA 1L, amylase elevation occurred in 52% of patients and Grade 3 or 4 amylase
elevation occurred in 6.8% of patients. Lipase elevations occurred in 59% of
patients and Grade 3 or 4 lipase elevation occurred in 17% of patients.
In
ALTA, amylase elevation occurred in 27% of patients in the 90 mg group and 39%
of patients in the 90 to 180 mg group. Lipase elevations occurred in 21% of
patients in the 90 mg group and 45% of patients in the 90 to 180 mg group. Grade 3
or 4 amylase elevation occurred in 3.7% of patients in the 90 mg group and 2.7%
of patients in the 90 to 180 mg group. Grade 3 or 4 lipase elevation occurred in 4.6%
of patients in the 90 mg group and 5.5% of patients in the 90 to 180 mg group.
Monitor
lipase and amylase during treatment with ALUNBRIG. Withhold ALUNBRIG for Grade
3 or 4 pancreatic enzyme elevation. Upon resolution or recovery to Grade 1 or
baseline, resume ALUNBRIG at the same dose or at a reduced dose as described in
Table 2.
5.7 Hyperglycemia
(Additions and/or
revisions underlined)
In
ALTA 1L, 56% of patients who received ALUNBRIG experienced new or worsening
hyperglycemia. Grade 3 hyperglycemia, based on laboratory assessment of serum fasting
glucose levels, occurred in 7.5% of patients.
In
ALTA, 43% of patients who received ALUNBRIG experienced new or worsening
hyperglycemia. Grade 3 hyperglycemia, based on laboratory assessment of serum fasting
glucose levels, occurred in 3.7% of patients. Two of 20 (10%) patients with
diabetes or glucose intolerance at baseline required initiation of insulin
while receiving ALUNBRIG.
Assess
fasting serum glucose prior to initiation of ALUNBRIG and monitor periodically
thereafter. Initiate or optimize antihyperglycemic medications as needed. If
adequate hyperglycemic control cannot be achieved with optimal medical
management, withhold ALUNBRIG until adequate hyperglycemic control is achieved
and consider reducing the dose of ALUNBRIG as described in Table 1 or
permanently discontinuing ALUNBRIG.
6
Adverse Reactions
6.1 Clinical Trials Experience
(Extensive changes;
please refer to label)
8
Use in Specific Populations
8.5 Geriatric Use
(Additions and/or
revisions underlined)
Of
the 359 patients enrolled in the ALTA 1L ALUNBRIG arm and in ALTA, 26.7% were
65 and older and 7.5% were 75 and older. No overall differences in safety or
effectiveness were observed between patients greater than or equal to 65 years and younger patients.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT INFORMATION
(Additions and/or
revisions underlined)
…
What are the possible
side effects of ALUNBRIG?
ALUNBRIG may cause
serious side effects, including:
- See "What is
the most important information I should know about ALUNBRIG?"
The most common
side effects of ALUNBRIG include:
diarrhea cough high blood pressure
fatigue muscle
pain vomiting
nausea headache difficulty
breathing
ALUNBRIG
may cause fertility problems in males. This may affect your ability to father a
child. Talk to your healthcare provider if you have concerns about fertility.
These
are not all of the possible side effects of ALUNBRIG.
Call
your doctor for medical advice about side effects. You may report side effects to
FDA at 1-800-FDA-1088.
…
Approved Drug Label (PDF)
7
Drug Interactions
7.1 Effect of Other Drugs on ALUNBRIG
(Additions
and/or revisions are underlined)
Strong or Moderate CYP3A Inhibitors
Coadministration of ALUNBRIG with a strong or
moderate CYP3A inhibitor increased brigatinib plasma concentrations, which
may increase the incidence of adverse reactions. Avoid coadministration
of ALUNBRIG with strong or moderate CYP3A inhibitors. If coadministration
of strong or moderate CYP3A inhibitors cannot be avoided, modify
dose as recommended.
Strong or Moderate CYP3A Inducers
Coadministration of ALUNBRIG with a strong or moderate
CYP3A inducer decreased brigatinib plasma concentrations, which may decrease
the efficacy of ALUNBRIG. Avoid coadministration of ALUNBRIG with strong or
moderate CYP3A inducers. If coadministration of moderate CYP3A inducers cannot
be avoided, modify dose as recommended.
7.2 Effect of ALUNBRIG on Other Drugs
(Additions
and/or revisions are underlined)
CYP3A Substrates
Brigatinib may decrease
the concentrations of sensitive CYP3A substrates. Coadministration of
ALUNBRIG with CYP3A substrates, including hormonal contraceptives, can result
in decreased concentrations and loss of efficacy of sensitive CYP3A
substrates.
8
Use in Specific Populations
8.3 Females and Males of Reproductive Potential
(Additions and/or revisions are underlined)
Pregnancy Testing
Verify pregnancy status in females of reproductive potential
prior to initiating ALUNBRIG.
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