Adverse Reactions 

Adverse Reactions in Clinical Trials of ALECENSA® (alectinib)

Adverse reactions from clinical trial experience1

  • Serious adverse reactions occurred in 19% of patients, and the most frequently reported serious adverse reactions were pulmonary embolism (1.2%), dyspnea (1.2%), and hyperbilirubinemia (1.2%) 
  • Fatal adverse reactions occurred in 2.8% of patients, and included:
    • Hemorrhage (0.8%)
    • Intestinal perforation (0.4%)
    • Dyspnea (0.4%)
    • Pulmonary embolism (0.4%)
    • Endocarditis (0.4%)

ADVERSE REACTIONS in ≥10% (ALL GRADES) OR ≥2% (GRADE 3-4) OF PATIENTS IN STUDIES 1 & 2 1

Adverse Reactions ALECENSA
N=253
All Grades (%) Grades 3-4 (%)a
Fatigueb 41 1.2
Constipation 34 0
Edemac 30 0.8
Myalgiad 29 1.2
Cough 19 0
Rashe 18 0.4
Nausea 18 0
Headache 17 0.8
Diarrhea 16 1.2
Dyspnea 16 3.6f
Back pain 12 0
Vomiting 12 0.4
Increased weight 11 0.4
Vision disorderg 10 0
a Per CTCAE version 4.0.
b Includes fatigue and asthenia.
c Includes edema, peripheral edema, generalized edema, eyelid edema, and periorbital edema.
d Includes myalgia and musculoskeletal pain.
e Includes rash, maculopapular rash, acneiform dermatitis, erythema, generalized rash, papular rash, pruritic rash, and macular rash.
f Includes one Grade 5 event.
g Includes blurred vision, vitreous floaters, visual impairment, reduced visual acuity, asthenopia, and diplopia.

Photosensitivity in clinical trial experience 1

  • Photosensitivity occurred in 9.9% of patients exposed to ALECENSA in Studies 1 and 2
  • Patients were advised to avoid sun exposure and to use broad-spectrum sunscreen
  • The incidence of Grade 2 photosensitivity was 0.4% and the remaining events were Grade 1 in severity

Dose modifications due to adverse reactions in clinical trials1

  • The most frequent adverse reactions that led to permanent discontinuation were hyperbilirubinemia (1.6%), increased ALT levels (1.6%), and increased AST levels (1.2%)
  • The most frequent adverse reactions that led to dose reductions or interruptions were elevations in bilirubin (6%), CPK (4.3%), ALT (4.0%), AST (2.8%), and vomiting (2.8%)
  • The median time to first dose reduction was 48 days

23% of patients initiating treatment at the recommended dose required at least 1 dose reduction1

6% of patients treated with ALECENSA in clinical trials permanently discontinued treatment due to adverse reactions1

LABORATORY ABNORMALITIES OCCURRING IN >20% OF PATIENTS IN STUDIES 1 AND 2 1

Parameter ALECENSA
N=250
All Grades (%) Grades 3-4 (%)h
Chemistry
Increased AST 51 3.6
Increased alkaline phosphatase 47 1.2
Increased CPKi 43 4.6
Hyperbilirubinemia 39 2.4
Hyperglycemiaj 36 2.0
Increased ALT 34 4.8
Hypocalcemia 32 0.4
Hypokalemia 29 4.0
Increased creatininek 28 0
Hypophosphatemia 21 2.8
Hyponatremia 20 2.0
Hematology
Anemia 56 2.0
Lymphopenial 22 4.6
h Per CTCAE version 4.0.
i n=218 for CPK (with baseline values missing for 91 of these patients).
j n=152 for fasting blood glucose (with baseline values missing for 5 of these patients).
k Only patients with creatinine increases based on ULN definition.
l n=217 for lymphocytes (with baseline values missing for 5 of these patients).

ALT=alanine transaminase; AST=aspartate transaminase; CPK=creatine phosphokinase; CTCAE=common terminology criteria for adverse events; ULN=upper limit of normal.

OVERALL EFFICACY AND SAFETY

View the overall efficacy data and safety of ALECENSA.

View Data

CNS EFFICACY AND SAFETY

View the CNS efficacy data and safety of ALECENSA.

View Data

DOSE MODIFICATIONS

Learn how to interrupt, reduce, or discontinue doses of ALECENSA, if necessary.

View Dose Modifications

Important Safety Information & Indication

Indication

ALECENSA is indicated for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive, metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib.

This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

Warnings and Precautions

Hepatotoxicity

  • Elevations of AST >5X the upper limit of normal (ULN) occurred in 3.6% of patients, and elevations of ALT >5X the ULN occurred in 4.8% of patients. Elevations of bilirubin >3X 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. Four patients discontinued ALECENSA for Grade 3-4 AST and/or ALT elevations, and three patients discontinued ALECENSA for Grade 3 bilirubin elevations. 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 ≥3X the ULN and total bilirubin ≥2X the ULN, with normal alkaline phosphatase, occurred in <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. Based on the severity of the adverse drug reaction, withhold ALECENSA and resume at a reduced dose, or permanently discontinue ALECENSA

Interstitial Lung Disease (ILD)/Pneumonitis

  • Severe ILD (Grade 3) occurred in one (0.4%) of 253 patients exposed to ALECENSA in Studies 1 and 2
  • Promptly investigate for ILD/pneumonitis in any patient who presents with worsening of respiratory symptoms indicative of ILD/pneumonitis (eg, 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

Bradycardia

  • Symptomatic bradycardia can occur with ALECENSA. Cases of bradycardia (7.5%) have been reported in patients treated with ALECENSA. Twenty percent of 221 patients treated with ALECENSA for whom serial ECGs were available had heart rates of <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 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 upon recovery to asymptomatic bradycardia or to a heart rate of ≥60 bpm, 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

Severe Myalgia and Creatine Phosphokinase (CPK) Elevation

  • Myalgia or musculoskeletal pain occurred in 29% of patients in Studies 1 and 2. The incidence of Grade 3 myalgia/musculoskeletal pain was 1.2%. Dose modifications for myalgia/musculoskeletal pain were required in 0.8% of patients
  • Elevations of CPK occurred in 43% of 218 patients with CPK laboratory data available in Study 1 and Study 2. The incidence of Grade 3 elevations of CPK was 4.6%. Median time to Grade 3 CPK elevation was 14 days (interquartile range 13-14 days). Dose modifications for elevation of CPK occurred in 5.0% 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

Embryo-Fetal Toxicity

  • Based on findings from animal studies and its mechanism of action, ALECENSA can cause fetal harm when administered to pregnant women. Administration of ALECENSA to pregnant rats and rabbits during the period of organogenesis resulted in embryo-fetal toxicity and abortion at maternally toxic doses with exposures approximately 2.7X those observed in humans with ALECENSA 600 mg twice daily. Advise pregnant women of the potential risk to a fetus
  • Advise females of reproductive potential to use effective contraception during treatment with ALECENSA and for 1 week following the final dose

Most Common Adverse Reactions

  • The most common adverse reactions (incidence ≥20%) were fatigue (41%), constipation (34%), edema (30%), and myalgia (29%). Management of adverse reactions may require temporary interruption, dose reduction, or discontinuation of treatment with ALECENSA

Use in Specific Populations

Pregnancy

  • Based on animal studies and its mechanism of action, ALECENSA can cause fetal harm when administered to a pregnant woman. There are no available data on ALECENSA use in pregnant women
  • In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically-recognized pregnancies is 2% to 4% and 15% to 20%, respectively

Lactation

  • Because of the potential for serious adverse reactions in breast-fed infants from ALECENSA, advise a lactating woman not to breastfeed during treatment with ALECENSA and for 1 week after final dose

Females and Males of Reproductive Potential

  • ALECENSA can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with ALECENSA and for 1 week after the final dose
  • Based on genotoxicity findings, advise males with female partners of reproductive potential to use effective contraception during treatment with ALECENSA and for 3 months following the final dose

Patient Counseling Information

Photosensitivity

  • Inform patients of the signs and symptoms of photosensitivity. Advise patients to avoid prolonged sun exposure while taking ALECENSA and for at least 7 days after discontinuation and to use proper protection from the sun. Advise patients to use a broad spectrum ultraviolet A (UVA)/ultraviolet B (UVB) sunscreen and lip balm (SPF ≥50) to help protect against potential sunburn

You may report side effects to the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Genentech at 1-888-835-2555.

Please see additional Important Safety Information in full Prescribing Information.