Approved Drug Label (PDF)
8
Use in Specific Populations
8.6
Hepatic Impairment
Additions
and/or revisions underlined:
In patients with severe
hepatic impairment (Child-Pugh C), the recommended dosage of LORBRENA is
50 mg orally once daily [see Dosage
and Administration (2.5) and Clinical Pharmacology (12.3)].
No
dose adjustment is recommended for patients with mild (total bilirubin less than or equal to ULN
with AST > ULN or total bilirubin >1 to 1.5 × ULN with any AST) to
moderate (Child-Pugh B) hepatic impairment [see Clinical Pharmacology (12.3)].
8.7
Renal Impairment
Additions
and/or revisions underlined:
In patients with CLcr 15 to <30
mL/min (estimated by Cockcroft-Gault), the recommended dosage of LORBRENA is
75 mg orally once daily [see Dosage
and Administration (2.6) and Clinical Pharmacology (12.3)].
No
dose adjustment is recommended for patients with CLcr 30 to 89 mL/min
(estimated by Cockcroft-Gault) [see
Clinical Pharmacology (12.3)].
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT
COUNSELING INFORMATION
Additions
and/or revisions underlined:
.
. .
Hyperglycemia
Inform
patients of the risks of new or worsening hyperglycemia and of the need
to periodically monitor glucose levels and to promptly report hyperglycemia
to their healthcare provider. Advise patients with newly occurring
hyperglycemia during treatment with LORBRENA that antihyperglycemic medications
may need to be initiated. Inform patients with diabetes mellitus or glucose
intolerance that antihyperglycemic medications may need to be adjusted during
treatment with LORBRENA [see Warnings and
Precautions (5.7)].
PATIENT
INFORMATION
Additions
and/or revisions underlined:
What is the most
important information I should know about LORBRENA? LORBRENA can cause
serious side effects, including:
- Liver
problems due to interactions with other medicines. Liver problems can be severe. It is important to know what
medicines not to take during treatment with LORBRENA. See “Tell your healthcare provider about all
the medicines you take, including.”
- Central
nervous system (CNS) effects. CNS
effects can be severe. Tell
your healthcare provider if you get any new or worsening symptoms of CNS
effects, including:
- problems
with thinking, such as forgetfulness or confusion
.
. .
- Increases
in the cholesterol and triglycerides (lipid) levels in your blood. Most people will get an
increase in the lipid levels in their blood during treatment with LORBRENA.
- If
you get increases in the lipid levels in your blood, your healthcare
provider may start you on a new medicine or increase your dose if
you are already taking a medicine to lower the lipid levels in your blood.
- Your
healthcare provider will do blood tests to check the lipid levels in
your blood before starting treatment, 1 and 2 months after starting
treatment, and during treatment with LORBRENA.
- Heart
problems. LORBRENA
can cause very slow or abnormal heartbeats. Your healthcare provider will
check your heart rhythm (electrocardiogram or EKG) before starting and during
treatment with LORBRENA. In some people, these problems are severe, and you may
need to get a pacemaker. Tell your healthcare provider right away if you
feel dizzy or faint or have abnormal heartbeats.
- Lung
problems. LORBRENA
can cause severe or life-threatening swelling (inflammation) of the
lungs during treatment that can lead to death. Symptoms may be like
those from lung cancer. Tell your healthcare provider right away if you get
any new or worsening symptoms of lung problems, including trouble breathing,
shortness of breath, cough, or fever.
- High
blood pressure (hypertension). Your
healthcare provider will check your blood pressure before starting
treatment, 2 weeks after starting treatment, and then at least every month
during treatment with LORBRENA. Your healthcare provider may start or change
your blood pressure medicine if you get high blood pressure. Tell your
healthcare provider right away if you get signs or symptoms of high blood
pressure, including: headaches, dizziness, blurred vision, chest pain or
shortness of breath.
- High
blood sugar (hyperglycemia). LORBRENA
can cause new or worsening increases in your blood sugar levels. Your
healthcare provider will do blood tests to check your blood sugar levels
before starting and during treatment with LORBRENA. Your healthcare provider
may start or change your blood sugar medicine if you get high blood
sugar. Tell your healthcare provider right away if you get any signs and
symptoms of high blood sugar, including:
.
. .
If
you get serious side effects during treatment, your healthcare provider
may change your dose, temporarily stop, or permanently stop
treatment with LORBRENA.
.
. .
What is LORBRENA?
LORBRENA
is a prescription medicine used to treat adults with non-small cell lung cancer
(NSCLC):
- that is caused by an abnormal
anaplastic lymphoma kinase (ALK) gene, and
- that has spread to other parts of
your body (metastatic).
.
. .
Before taking
LORBRENA, tell your healthcare provider about all of your medical conditions,
including if you:
- have
kidney problems
- have
liver problems
.
. .
Tell your healthcare
provider about all the medicines you take, including prescription medicines,
over-the-counter medicines, vitamins, and herbal supplements. Taking
LORBRENA with certain other medicines may increase your risk of
side effects and may affect the way LORBRENA or the other medicines
work.
.
. .
How should I take
LORBRENA?
.
. .
- If you miss a dose, take it as soon
as you remember. However, if it is within 4 hours of the time to take
your next dose, just take your next dose at your regular time. Do not take 2 doses of LORBRENA at the
same time to make up for the missed dose.
.
. .
The
most common side effects of LORBRENA include:
.
. .
- increased cholesterol and triglyceride
levels in the blood
.
. .
LORBRENA
may cause decreased fertility in males, which may affect your ability to
have children. Talk to your healthcare provider if you have concerns
about fertility.
.
. .
How
should I store LORBRENA?
.
. .
- LORBRENA
comes in a bottle that contains a child resistant cap.
Approved Drug Label (PDF)
Boxed Warning
5.2
Central Nervous System Effects
Additions
and/or revisions underlined:
Overall, CNS effects occurred in 52%
of the 476 patients who received 100 mg LORBRENA once daily in
clinical trials [see Adverse
Reactions (6.1)]. Cognitive effects occurred in 28% of the 476
patients; 2.9% of these events were severe (Grade 3 or 4). Mood effects
occurred in 21% of patients; 1.7% of these events were severe. Speech
effects occurred in 11% of patients; 0.6% of these events were
severe. Psychotic effects occurred in 7% of patients; 0.6% of these events were
severe. Mental status changes occurred in 1.3% of patients; 1.1%
of these events were severe. Seizures occurred in 1.9% of patients,
sometimes in conjunction with other neurologic findings. Sleep effects occurred
in 12% of patients. The median time to first onset of any CNS effect was
1.4 months (1 day to 3.4 years). Overall, 2.1% of patients
required permanent discontinuation of LORBRENA for a CNS effect; 10%
required temporary discontinuation and 8% required dose reduction.
Withhold and resume …
5.3
Hyperlipidemia
Additions
and/or revisions underlined:
Increases in serum cholesterol and
triglycerides can occur in patients receiving LORBRENA [see Adverse Reactions (6.1)]. Grade 3 or 4 elevations in total
cholesterol occurred in 18% and Grade 3 or 4 elevations in triglycerides
occurred in 19% of the 476 patients who received 100 mg
LORBRENA once daily. The median time to onset was 15 days for both
hypercholesterolemia and hypertriglyceridemia. Approximately 4% and 7% of
patients required temporary discontinuation and 1% and 3% of patients
required dose reduction of LORBRENA for elevations in cholesterol and in triglycerides
in Study B7461001 and Study B7461006, respectively. Eighty-three percent
of patients required initiation of lipid-lowering medications, with a median
time to onset of start of such medications of 17 days.
Initiate or increase the dose …
5.4
Atrioventricular Block
Additions
and/or revisions underlined:
PR interval prolongation and
atrioventricular (AV) block can occur in patients receiving LORBRENA [see Adverse Reactions (6.1), Clinical
Pharmacology (12.2)]. In 476 patients who received 100 mg LORBRENA
once daily and who had a baseline electrocardiography (ECG), 1.9% experienced
AV block and 0.2% experienced Grade 3 AV block and underwent pacemaker
placement. Monitor ECG prior to initiating LORBRENA ...
5
Warnings and Precautions
5.5
Interstitial Lung Disease/Pneumonitis
Additions
and/or revisions underlined:
Severe or life-threatening pulmonary
adverse reactions consistent with interstitial lung disease (ILD)/pneumonitis
can occur with LORBRENA. ILD/pneumonitis occurred in 1.9% of patients
who received 100 mg LORBRENA once daily, including Grade 3 or 4
ILD/pneumonitis in 0.6% of patients. Four patients (0.8%)
discontinued LORBRENA for ILD/pneumonitis.
Promptly investigate for ILD/pneumonitis …
The
following two subsections are newly added:
5.6
Hypertension
Hypertension can occur in patients
receiving LORBRENA [see Adverse Reactions
(6.1)]. Hypertension occurred in 13% of patients who received 100 mg
LORBRENA once daily, including Grade 3 or 4 in 6% of patients. The median time
to onset of hypertension was 6.4 months (1 day to 2.8 years), and 2.3% of
patients temporarily discontinued LORBRENA for hypertension.
Control blood pressure prior to initiation
of LORBRENA. Monitor blood pressure after 2 weeks and at least monthly
thereafter during treatment with LORBRENA. Withhold and resume at a reduced
dose or permanently discontinue LORBRENA based on severity [see Dosage and Administration (2.3)].
5.7
Hyperglycemia
Hyperglycemia can occur in patients
receiving LORBRENA [see Adverse Reactions
(6.1)]. Hyperglycemia occurred in 9% of patients who received 100 mg
LORBRENA, including Grade 3 or 4 in 3.2% of patients. The median time to onset
of hyperglycemia was 4.8 months (1 day to 2.9 years), and 0.8% of patients
temporarily discontinued LORBRENA for hyperglycemia.
Assess fasting serum glucose prior to
initiation of LORBRENA and monitor periodically thereafter. Withhold and resume
at a reduced dose or permanently discontinue LORBRENA based on severity [see Dosage and Administration (2.3)].
6
Adverse Reactions
Newly
added to the bulleted line listing:
6.1
Clinical Trials Experience
Newly
added information:
The pooled safety population described in
the Warnings and Precautions section reflects exposure to LORBRENA in 476
patients who received 100 mg LORBRENA once daily in Study B7461001 (N=327) and
Study B7461006 (N=149). Among 476 patients who received LORBRENA, 75% were
exposed for 6 months or longer and 61% were exposed for greater than 1 year. In
this pooled safety population, the most frequent adverse reactions in greater
than or equal to 20% of 476 patients who received LORBRENA were edema (56%),
peripheral neuropathy (44%), weight gain (31%), cognitive effects (28%),
fatigue (27%), dyspnea (27%), arthralgia (24%), diarrhea (23%), mood effects
(21%), and cough (21%). The most frequent Grade 3-4 laboratory abnormalities in
greater than or equal to 20% of 476 patients who received LORBRENA were
hypercholesterolemia (21%) and hypertriglyceridemia (21%).
Extensive
revisions to the following underlined sections, with the addition of Tables 1
and 2; please refer to label for complete information:
Previously Untreated ALK-Positive
Metastatic NSCLC (CROWN Study)
Table 2 Adverse Reactions (greater than or
equal to 10% for all NCI CTCAE Grades or greater than or equal to2% for Grades
3-4) in Patients Treated with LORBRENA in Study B7461006*
Table 3 Laboratory Abnormalities Worsening
from Baseline in >20% of Patients in Study B7461006
Previously
Treated ALK-Positive Metastatic NSCLC
7
Drug Interactions
7.1 Effect of Other Drugs on LORBRENA
Newly added information:
Fluconazole
Concomitant use
of LORBRENA with fluconazole may increase lorlatinib plasma concentrations [see Clinical Pharmacology (12.3)],
which may increase the incidence and severity of adverse reactions of LORBRENA.
Avoid concomitant use of LORBRENA with fluconazole. If concomitant use cannot
be avoided, reduce the LORBRENA dosage [see
Dosage and Administration (2.7)].
8
Use in Specific Populations
8.5 Geriatric Use
Additions and/or revisions underlined:
Of the patients
in Study B7461001 (N=295) and Study B7461006 (N=149) who received 100 mg
LORBRENA orally once daily, 18% and 40% of patients, respectively,
were aged 65 years or older. No clinically important differences in safety or
efficacy were observed between patients aged 65 years or older and younger
patients.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATION
Newly added information:
Hypertension
![]()
Advise patients
of the risks of hypertension and to promptly report signs or symptoms of
hypertension to their healthcare provider. Advise patients with hypertension
that antihypertension medications may need to be initiated or adjusted during
treatment with LORBRENA [see Warnings and
Precautions (5.6)].
Hyperglycemia
![]()
Inform patients
of the risks of new or worsening hyperglycemia and the need to periodically
monitor glucose levels. Advise patients with newly occurring hyperglycemia
during treatment with LORBRENA that antihyperglycemic medications may need to
be initiated. Inform patients with diabetes mellitus or glucose intolerance that
antihyperglycemic medications may need to be adjusted during treatment with
LORBRENA [see Warnings and Precautions
(5.7)].
PATIENT INFORMATION
PATIENT INFORMATION
What
is the most important information I should know about LORBRENA?
LORBRENA
may cause serious side effects, including:
Newly
added information:
High blood
pressure (hypertension). Your healthcare provider should check your blood
pressure before starting treatment, 2 weeks after starting treatment, and then
at least every month during treatment with LORBRENA. Your healthcare provider
may need to start or change your blood pressure medicine if you have high blood
pressure during treatment with LORBRENA. Tell your healthcare provider right
away if you get signs or symptoms of high blood pressure, including: headaches,
dizziness, blurred vision, chest pain or shortness of breath.
High
blood sugar (hyperglycemia). LORBRENA may increase your blood sugar levels.
Your healthcare provider should do blood tests to check your blood sugar levels
before starting and during treatment with LORBRENA. Your healthcare provider
may need to start or change your blood sugar medicine to control your blood
sugar levels. Tell your healthcare provider right away if you get new or
worsening signs and symptoms of high blood sugar, including:
feeling
very thirsty
feeling
sick to your stomach
needing
to urinate more than usual
feeling
weak or tired
feeling
very hungry
feeling
confused
Before taking LORBRENA, tell your healthcare provider
about all of your medical conditions, including if you:
Newly added information:
What
are the possible side effects of LORBRENA?
The
most common side effects of LORBRENA include:
Newly added information:
Approved Drug Label (PDF)
8
Use in Specific Populations
8.7 Renal Impairment
(Additions and/or
revisions underlined)
Reduce
the dose when administering LORBRENA to patients with severe (CLcr 15 to <30
mL/min, estimated by Cockcroft-Gault) renal impairment [see Dosage and Administration (2.6) and Clinical Pharmacology (12.3)].
No
dose adjustment is recommended for patients with mild or moderate (CLcr 30
to 89 mL/min, estimated by Cockcroft-Gault) renal impairment [see Clinical Pharmacology (12.3)].
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT INFORMATION
(Additions and/or
revisions underlined)
…
Before taking
LORBRENA, tell your healthcare provider about all of your medical conditions,
including if you:
- have
high levels of cholesterol or triglycerides in your blood
…
Approved Drug Label (PDF)
5
Warnings and Precautions
5.2 Central Nervous System Effects
(Additions and/or
revisions underlined)
A
broad spectrum of central nervous system (CNS) effects can occur in patients
receiving LORBRENA. These include seizures, psychotic effects and
changes in cognitive function, mood (including suicidal ideation), speech,
mental status, and sleep. Overall, CNS effects occurred in 54% of patients
receiving LORBRENA [see Adverse Reactions
(6.1)]. Cognitive effects occurred in 29% of the 332 patients who received
LORBRENA at any dose in Study B7461001; 2.1% of these events were severe (Grade
3 or 4). Mood effects occurred in 24% of patients; 1.8% of these events were severe.
Speech effects occurred in 14% of patients; 0.3% of these events were severe. Psychotic
effects occurred in 7% of patients; 0.6% of these events were severe.
Mental status changes occurred in 2.1% of patients; 1.8% of these events were
severe. Seizures occurred in 3% of patients, sometimes in conjunction with
other neurologic findings. Sleep effects occurred in 10% of patients. The median
time to first onset of any CNS effect was 1.2 months (1 day to 1.7 years).
Overall, 1.5% of patients required permanent discontinuation of LORBRENA for a
CNS effect; 9% required temporary discontinuation and 8% required dose reduction.
Withhold
and resume at the same dose or at a reduced dose or permanently discontinue
LORBRENA based on severity [see Dosage
and Administration (2.2)].
6
Adverse Reactions
6.1 Clinical Trials Experience
(Additions and/or
revisions underlined)
…
Additional
clinically significant adverse reactions occurring at an incidence between 1%
and 10% were psychotic effects (7%).
…
7
Drug Interactions
7.1 Effect of Other Drugs on LORBRENA
(Additions and/or
revisions underlined)
Strong
CYP3A Inducers
Concomitant
use of LORBRENA with a strong CYP3A inducer decreased lorlatinib plasma
concentrations [see Clinical Pharmacology
(12.3)], which may decrease the efficacy of LORBRENA.
Severe
hepatotoxicity occurred in healthy subjects receiving LORBRENA with rifampin, a
strong CYP3A inducer. In 12 healthy subjects receiving a single 100 mg dose of
LORBRENA with multiple daily doses of rifampin, Grade 3 or 4 increases in ALT
or AST occurred in 83% of subjects and Grade 2 increases in ALT or AST occurred
in 8%. A possible mechanism for hepatotoxicity is through activation of the
pregnane X receptor (PXR) by LORBRENA and rifampin, which are both PXR
agonists.
LORBRENA
is contraindicated in patients taking strong CYP3A inducers [see Contraindication (4)]. Discontinue
strong CYP3A inducers for 3 plasma half-lives of the strong CYP3A inducer prior
to initiating LORBRENA [see Dosage and
Administration (2.3)].
Moderate
CYP3A Inducers
Concomitant
use of LORBRENA with a moderate CYP3A inducer decreased lorlatinib plasma
concentrations, which may decrease the efficacy of LORBRENA [see Clinical Pharmacology (12.3)]. Avoid concomitant
use of moderate CYP3A inducers with LORBRENA. If concomitant use is
unavoidable, increase the LORBRENA dose [see
Dosage and Administration (2.4)].
Strong
CYP3A Inhibitors
Concomitant
use with a strong CYP3A inhibitor increased lorlatinib plasma concentrations [see Clinical Pharmacology (12.3)], which
may increase the incidence and severity of adverse reactions of LORBRENA. Avoid
concomitant use of LORBRENA with a strong CYP3A inhibitor. If concomitant use
cannot be avoided, reduce the LORBRENA dosage [see Dosage and Administration (2.5].
7.2 Effect of LORBRENA on Other Drugs
(Additions and/or
revisions underlined)
Certain
CYP3A Substrates
LORBRENA
is a moderate CYP3A inducer. Concomitant use of LORBRENA decreases the concentration
of CYP3A substrates [see Clinical
Pharmacology (12.3)], which may reduce the efficacy of these substrates.
Avoid
concomitant use of LORBRENA with certain CYP3A substrates, for which
minimal concentration changes may lead to serious therapeutic failures. If
concomitant use is unavoidable, increase the CYP3A substrate dosage in
accordance with approved product labeling.
Certain
P-glycoprotein (P-gp) Substrates
LORBRENA
is a moderate P-gp inducer. Concomitant use of LORBRENA decreases the
concentration of P-gp substrates [see
Clinical Pharmacology (12.3)], which may reduce the efficacy of these
substrates. Avoid concomitant use of LORBRENA with certain P-gp
substrates for which minimal concentration changes may lead to serious
therapeutic failures. If concomitant use is unavoidable, increase the P-gp
substrate dosage in accordance with approved product labeling.
8
Use in Specific Populations
8.6 Hepatic Impairment
(Additions and/or
revisions underlined)
No
dose adjustment is recommended for patients with mild hepatic impairment (total
bilirubin ? upper limit of normal [ULN] with AST > ULN or total bilirubin
>1 to 1.5 × ULN with any AST). The recommended dose of LORBRENA has not been
established for patients with moderate (total bilirubin ? 1.5 to 3.0 × ULN
with any
AST)
or severe (total bilirubin > 3.0 × ULN with any AST) hepatic impairment [see Clinical Pharmacology (12.3)].
8.7 Renal Impairment
(Additions and/or
revisions underlined)
No
dose adjustment is recommended for patients with mild or moderate renal
impairment (creatinine clearance [CLcr] 30 to 89 mL/min estimated by
Cockcroft-Gault). The recommended dose of LORBRENA has not been established for
patients with severe renal impairment (CLcr 15 to 29 mL/min estimated by
Cockcroft-Gault) [see Clinical
Pharmacology (12.3)].
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATION
(Additions and/or
revisions underlined)
…
This
product’s labeling may have been updated. For the most recent
prescribing information, please visit www.LORBRENA.com.
PATIENT INFORMATION
(Extensive
changes; please refer to label)
Approved Drug Label (PDF)
7
Drug Interactions
7.2 Effect of LORBRENA on Other Drugs
Additions and/or
revisions underlined:
CYP3A Substrates
Concomitant use of LORBRENA decreases the
concentration of CYP3A substrates [see
Clinical Pharmacology (12.3)], which may reduce the efficacy of these
substrates. LORBRENA is considered a moderate CYP3A inducer. Avoid
concomitant use of LORBRENA with CYP3A substrates, for which minimal
concentration changes may lead to serious therapeutic failures. If concomitant
use is unavoidable, increase the CYP3A substrate dosage in accordance with
approved product labeling.
Newly added information:
P-glycoprotein (P-gp) Substrates
Concomitant use of LORBRENA decreases the
concentration of P-gp substrates [see
Clinical Pharmacology (12.3)], which may reduce the efficacy of these
substrates. LORBRENA is considered a moderate P-gp inducer. Avoid concomitant
use of LORBRENA with P-gp substrates for which minimal concentration changes
may lead to serious therapeutic failures. If concomitant use is unavoidable,
increase the P-gp substrate dosage in accordance with approved product
labeling.
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