Approved Drug Label (PDF)
5
Warnings and Precautions
5.1 Hepatotoxicity
Additions and revisions underlined:
Severe hepatotoxicity, including drug-induced liver injury, occurred in patients treated
with ALECENSA.
In the pooled safety population [see Adverse Reactions (6.1)] of patients
who received ALECENSA, hepatotoxicity occurred in 41% of patients and
the incidence of Grade > or = 3 hepatotoxicity was 8%. In the ALINA study,
hepatotoxicity occurred in 61% of patients treated with ALECENSA and the
incidence of Grade > or = 3 hepatotoxicity was 4.7%. The majority (72% of 136
patients) of elevated transaminases occurred during the first 3 months of
treatment. Treatment discontinuation due to hepatotoxicity occurred in 3.6%
of patients who received ALECENSA in the pooled safety
population and 1.6% of patients treated in the ALINA study.
In the pooled safety
population, concurrent elevations in ALT or AST greater
than or equal to
3 times the ULN and total
bilirubin greater than or equal
to 2 times the ULN, with normal alkaline
phosphatase, occurred in less
than 1% of patients treated with ALECENSA.
5.2 Interstitial Lung Disease (ILD)/Pneumonitis
Additions and revisions underlined:
ILD/pneumonitis occurred
in patients treated
with ALECENSA.
In the pooled safety population [see Adverse
Reactions (6.1)], ILD/pneumonitis occurred in 1.3% of patients treated with ALECENSA with
0.4% of patients experiencing Grade 3 ILD/pneumonitis.
Five patients (0.9%) in the pooled safety population
discontinued ALECENSA due to ILD/pneumonitis. The median time-to-onset of
Grade 3 or higher
ILD/pneumonitis was 2.1 months (range: 0.6 months to 3.6 months).
5.3 Renal Impairment
Additions and revisions underlined:
Renal impairment, including fatal cases, occurred
in patients treated
with ALECENSA.
In the pooled safety population [see Adverse Reactions (6.1)], renal impairment occurred in
12% of patients treated with ALECENSA, including Grade > or = 3 in 1.7% of
patients, of which 0.4% were fatal events. The median time to Grade
> or = 3 renal impairment was 3.7 months
(range 0.5 to 31.8 months). Dosage modifications
for renal impairment were required in 2.4% of patients.
5.4 Bradycardia
Additions and revisions underlined:
Symptomatic bradycardia occurred in patients
treated with ALECENSA.
In
the pooled safety
population [see Adverse Reactions
(6.1)], bradycardia occurred
in 11% of patients treated with ALECENSA. Twenty percent
of 521 patients treated with ALECENSA, for whom serial electrocardiograms
(ECGs) were available, had post-dose heart rates of less than 50 beats per
minute (bpm).
Monitor heart rate and blood pressure
regularly. For asymptomatic bradycardia dose modification is not
required. For symptomatic bradycardia that is not life-threatening,
withhold ALECENSA until recovery to asymptomatic bradycardia or to a heart rate
> or = 60 bpm and evaluate concomitant medications known to cause
bradycardia, as well as anti-hypertensive medications. If bradycardia is attributable
to a concomitant medication, resume ALECENSA
at a reduced dose (see Table
2) upon recovery to asymptomatic bradycardia or to a
heart rate of > or = 60 bpm, with frequent monitoring as clinically indicated.
Permanently discontinue ALECENSA in cases of life-threatening bradycardia if no contributing concomitant medication is identified [see Dosage and Administration (2.4)]. Permanently discontinue
ALECENSA for recurrence of life-threatening bradycardia.
5.5 Severe Myalgia and Creatine Phosphokinase (CPK) Elevation
Additions and revisions underlined:
Severe myalgia and creatine phosphokinase (CPK) elevation occurred
in patients treated
with ALECENSA.
In the pooled
safety population [see Adverse
Reactions (6.1)], myalgia
(including muscle- and
musculoskeletal- related reactions) occurred in 31% of
patients treated with ALECENSA, including Grade ? 3 in 0.8% of
patients. Dosage modifications for myalgia events were required in 2.1%
of patients.
In the pooled safety population, of the 491
patients with CPK laboratory data available, elevated CPK occurred in 56% of
patients treated with ALECENSA, including 6% Grade ? 3. The median
time to Grade ? 3 CPK elevation was 15
days (interquartile range
- 15 –337 days). Dosage modifications for elevation of CPK occurred in 5% of patients.
In the ALINA study, elevated
CPK occurred in 77% of 128 patients
with CPK laboratory data, including 6% Grade ? 3 elevations.
5.6 Hemolytic Anemia
Additions and revisions underlined:
Hemolytic anemia occurred in patients treated with ALECENSA.
Hemolytic anemia was initially
reported with ALECENSA in the postmarketing setting, including cases
associated with a negative direct
antiglobulin test (DAT)
result. Assessments for the determination of hemolytic anemia
were subsequently collected in the ALINA study, where hemolytic anemia was
observed in 3.1% of patients treated with ALECENSA.
5.7 Embryo-Fetal Toxicity
Additions and revisions underlined:
Based on findings from animal studies and its mechanism
of action, ALECENSA can cause fetal harm when administered to pregnant women. Oral administration of alectinib to pregnant rats and rabbits
during the period of organogenesis resulted in
embryo-fetal toxicity and abortion at maternally toxic doses with exposures
approximately 2.7-fold those observed in humans with alectinib 600 mg twice
daily. Advise pregnant women and females of reproductive potential of
the potential risk to a fetus.
Advise females of reproductive potential
to use effective contraception during
treatment with ALECENSA
and for 5 weeks following the last dose [see Use in Specific Populations (8.1 and
8.3) and Clinical Pharmacology (12.1)].
6
Adverse Reactions
6.1 Clinical Trials Experience
Extensive changes; please refer to label
8
Use in Specific Populations
8.3 Females and Males of Reproductive Potential
Additions and revisions underlined:
ALECENSA can cause fetal harm when administered to a pregnant
woman [see Use in Specific
Populations (8.1)].
Pregnancy Testing
Verify pregnancy status
in females of reproductive potential
prior to initiating ALECENSA [see Use in Specific Populations (8.1)].
Contraception
Females
Advise females of reproductive potential
to use effective contraception during treatment with ALECENSA and for 5 weeks after the last
dose [see Use in Specific Populations
(8.1)].
8.5 Geriatric Use
Newly added information:
Nineteen percent of the 533 patients studied in NP28761,
NP28673, ALEX and ALINA were 65 years of age and older (3.2% were 75 years of
age and older). No overall differences in effectiveness were observed based on age. Exploratory analysis suggests a higher incidence of serious adverse events (38% vs 25%), more frequent adverse events leading to
treatment discontinuations (18% vs 6%) and dose modifications (48% vs 35%) in
patients 65 years or older as compared to those younger than 65 years.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
Patient Information
Additions and revisions underlined:
. . .
Liver problems (hepatotoxicity). Liver problems are common with ALECENSA and can be
severe. Your healthcare provider will do blood tests at least every
2 weeks for the first 3 months, and then 1 time
each month and as needed during treatment with
ALECENSA to check your liver function.
. . .
Kidney problems. ALECENSA may cause severe kidney problems that can lead to death.
. . .
ALECENSA 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:
• to help prevent your lung cancer from coming back after
your tumor has been removed by surgery (adjuvant), or
• as treatment when your lung cancer has spread to other
parts of your body (metastatic).
Your healthcare provider will perform a test to make sure
that ALECENSA is right for you.
. . .
Females who are able to become pregnant:
o Your healthcare provider will do a test to see if you
are pregnant before starting treatment with ALECENSA.
o You should use effective birth control (contraception)
during treatment with ALECENSA and for 5 weeks after the
last dose of ALECENSA.
The most common side effects of ALECENSA include:
. . .
• rash
• cough
Approved Drug Label (PDF)
5
Warnings and Precautions
5.1 Hepatotoxicity
(additions underlined)
Elevations of AST greater than 5 times the upper limit of
normal (ULN) occurred in 4.6% of patients, and elevations of ALT greater
than 5 times the ULN occurred in 5.3% of the 405 patients in Studies
NP28761, NP28673 and ALEX who received ALECENSA at a dose of 600 mg BID. Elevations
of bilirubin greater than 3 times the ULN occurred in 3.7% of patients.
The majority (69% of the patients with hepatic transaminase elevations
and 68% of the patients with bilirubin elevations) of these events occurred
during the first 3 months of treatment. Six patients discontinued
ALECENSA for Grades 3–4 AST and/or ALT elevations, and 4 patients discontinued
ALECENSA for Grade 3 bilirubin elevations. Concurrent elevations in ALT or AST
greater than or equal to 3 times the ULN and total bilirubin greater than or
equal to 2 times the ULN, with normal alkaline phosphatase, occurred in less
than 1% of patients treated with ALECENSA across clinical trials. Three
patients with Grades 3–4 AST/ALT elevations had drug-induced liver injury
(documented by liver biopsy in two cases).
![]()
Monitor
liver function tests including ALT, AST, and total bilirubin every 2 weeks
during the first 3 months of treatment, then once a month and as clinically
indicated, with more frequent testing in patients who develop transaminase and
bilirubin elevations. Based on the severity of the adverse drug reaction,
withhold ALECENSA and resume at a reduced dose or permanently discontinue
ALECENSA as described in Table 2.
5.2 Interstitial Lung Disease (ILD)/Pneumonitis
(additions underlined)
ILD/pneumonitis occurred in three (0.7%)
patients treated with ALECENSA in Studies NP28761, NP28673 and ALEX. One
(0.2%) of these events was severe (Grade 3).
![]()
Promptly
investigate for ILD/pneumonitis in any patient who presents with worsening of
respiratory symptoms indicative of ILD/pneumonitis (e.g., dyspnea, cough, and
fever). Immediately withhold ALECENSA treatment in patients diagnosed with
ILD/pneumonitis and permanently discontinue ALECENSA if no other potential
causes of ILD/pneumonitis have been identified.
5.3 Renal Impairment
(new subsection added)
![]()
Renal
impairment occurred in 8% of patients in Studies NP28761, NP28673, and ALEX.
The incidence of Grade equal to or greater than 3 renal impairment was 1.7%, of
which 0.5% were fatal events. Dose modifications for renal impairment were
required in 3.2% of patients. Median time to Grade equal to or greater than 3
renal impairment was 3.7 months (range 0.5 to 14.7 months).
Permanently discontinue ALECENSA for Grade 4 renal
toxicity. Withhold ALECENSA for Grade 3 renal toxicity until recovery to less
than or equal to 1.5 times ULN, then resume at reduced dose.
5.4 Bradycardia
(additions underlined)
![]()
Symptomatic
bradycardia can occur with ALECENSA. Cases of bradycardia (8.6%) have been
reported in patients treated with ALECENSA in Studies NP28761, NP28673 and
ALEX. Eighteen percent of 365 patients treated with ALECENSA for
whom serial ECGs were available had heart rates of less than 50 beats per
minute (bpm).
Monitor heart rate and blood pressure regularly. Dose
modification is not required in cases of asymptomatic bradycardia. In cases of
symptomatic bradycardia that is not life-threatening, withhold ALECENSA until
recovery to asymptomatic bradycardia or to a heart rate of 60 bpm or above and
evaluate concomitant medications known to cause bradycardia, as well as
anti-hypertensive medications. If attributable to a concomitant medication,
resume ALECENSA at a reduced dose (see Table 1) upon recovery to asymptomatic
bradycardia or to a heart rate of 60 bpm or above, with frequent monitoring as
clinically indicated. Permanently discontinue ALECENSA in case of recurrence.
Permanently discontinue ALECENSA in cases of life- threatening bradycardia if
no contributing concomitant medication is identified.
5.5 Severe Myalgia and Creatine Phosphokinase (CPK) Elevation
(additions
underlined)
![]()
Myalgia
or musculoskeletal pain occurred in 26% of patients in Studies NP28761,
NP28673 and ALEX. The incidence of Grade 3 myalgia/musculoskeletal pain was
0.7%. Dose modifications for myalgia/musculoskeletal pain were required
in 0.5% of patients.
Elevations of CPK occurred in 41% of 347 patients
with CPK laboratory data available in Studies NP28761, NP28673 and ALEX. The
incidence of Grade 3 elevations of CPK was 4.0%. Median time to Grade 3
CPK elevation was 14 days (interquartile range 13-28 days). Dose
modifications for elevation of CPK occurred in 3.2 % of patients.
Advise patients to report any unexplained muscle pain,
tenderness, or weakness. Assess CPK levels every 2 weeks for the first month of
treatment and as clinically indicated in patients reporting symptoms. Based on
the severity of the CPK elevation, withhold ALECENSA, then resume or reduce
dose.
6
Adverse Reactions
6.1 Clinical Trials Experience
(extensive
additions and revisions, please refer to label)
(addition
underlined)
The following adverse reactions are discussed in greater
detail in other sections of the label:
- Hepatotoxicity
- Interstitial Lung
Disease (ILD)/Pneumonitis
- Renal Impairment
- Bradycardia
- Severe Myalgia and
Creatine Phosphokinase (CPK) Elevation
- Embryo-Fetal
Toxicity
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATION
(additions
underlined)
…
Renal Impairment
Inform patients of
the risk of severe and potentially fatal renal impairment. Advise patients to
contact their health care provider for change in urine color, reduced urine
output, or swelling in the legs and feet.
…
PATIENT INFORMATION
(additions
underlined)
What
is the most important information I should know about ALECENSA? ALECENSA may
cause serious side effects, including:
…
Kidney
problems. ALECENSA may cause severe or life-threatening
kidney problems. Tell your healthcare provider right away if you have a change
in the amount or color of your urine, or if you get new or worsening swelling
in your legs or feet.
…
Approved Drug Label (PDF)
5
Warnings and Precautions
5.1 Hepatotoxicity
Elevations of bilirubin greater than 3 times the ULN
occurred in 2.8% of patients in Studies 1 and 2.
The majority (76% of the patients with hepatic
transaminase elevations and 68% of the patients with bilirubin
elevations) of these events occurred during the first 3 months of
treatment… In Studies 1 and 2, two patients
with Grade 3-4 AST/ALT elevations had documented drug induced liver injury by
liver biopsy. Concurrent elevations in ALT or AST greater than or
equal to three times the ULN and total bilirubin greater than or equal to two
times the ULN, with normal alkaline phosphatase, occurred in less than 1% of
patients treated with ALECENSA across clinical trials.
Monitor liver function tests including ALT, AST, and
total bilirubin every 2 weeks during the first 3 months of treatment, then once a month and as clinically
indicated, with more frequent testing in patients who develop transaminase
and bilirubin elevations. (additions
underlined)
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
Patient Information
What
is the most important information I should know about ALECENSA?
ALECENSA
may cause serious side effects, including: (additions underlined)
- Liver problems (hepatotoxicity). ALECENSA may cause liver injury. Your healthcare provider will do blood
tests at least every 2 weeks for the first 3 months and then one time
each month and as needed during treatment with ALECENSA.
What is
ALECENSA?
ALECENSA
is a prescription medicine used to treat people 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,
and …
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