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  • CLASSES

    Small Molecule Antineoplastic Anaplastic Lymphoma Kinase (ALK) Inhibitors

    DEA CLASS

    Rx

    DESCRIPTION

    Tyrosine kinase inhibitor that targets ALK and RET
    Used for the treatment of patients with ALK-positive, metastatic NSCLC
    Common adverse effects include fatigue, constipation, edema, myalgia, and anemia; serious adverse reactions include hepatotoxicity, pneumonitis, bradycardia, and elevated creatine phosphokinase (CPK)

    COMMON BRAND NAMES

    Alecensa

    HOW SUPPLIED

    Alecensa Oral Cap: 150mg

    DOSAGE & INDICATIONS

    For the treatment of metastatic, ALK-positive non-small cell lung cancer (NSCLC).
    NOTE: The FDA has designated alectinib as an orphan drug for the treatment of ALK-positive NSCLC.
    NOTE: Patients should be selected based on the presence of ALK positivity in tumor specimens. Information on FDA-approved tests for the detection of ALK rearrangements in NSCLC is available at http://www.fda.gov/CompanionDiagnostics.
    Oral dosage
    Adults

    600 mg orally twice daily, with food, until disease progression or unacceptable toxicity. First-line treatment with alectinib (n = 152) significantly improved progression-free survival (PFS) compared with crizotinib (n = 151) in a multicenter, open-label clinical trial of patients with ALK-positive NSCLC (25.7 months vs. 10.4 months); overall survival data were not mature. The overall response rate was 79% (complete response [CR] 13%) compared with 72% (CR, 6%), respectively; the CNS objective response rate was 81% (CR, 38%) vs. 50% (CR, 5%). Patients with locally advanced or metastatic ALK-positive NSCLC who were treated with alectinib after progression on crizotinib had objective response rates of 38% to 48% in two multicenter, single-arm clinical trials (n = 225).[60434] In a multicenter, randomized, open-label phase 3 study, treatment with alectinib (n = 72) also significantly improved median progression-free survival compared with chemotherapy (n = 35) (9.6 months vs. 1.4 months) in patients with advanced ALK-positive NSCLC who progressed on, or were intolerant to, crizotinib. The CNS objective response rate was also significantly higher with alectinib versus chemotherapy in patients with measurable baseline CNS disease (54.2% vs. 0%).[63745]

    MAXIMUM DOSAGE

    Adults

    600 mg by mouth twice daily.

    Geriatric

    600 mg by mouth twice daily.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Baseline Hepatic Impairment
    Mild to moderate hepatic impairment (Child-Pugh A or B): No dosage adjustment necessary.
    Severe hepatic impairment (Child-Pugh C): Reduce the dose of alectinib to 450 mg PO twice daily.
     
    Treatment-Related Hepatotoxicity
    AST/ALT more than 5 times the upper limit of normal (ULN) AND total bilirubin 2 times ULN or less: Hold alectinib. When AST/ALT recovers to less than or equal to 3 times ULN or baseline, resume alectinib at a reduced dose (1st dose reduction, 450 mg twice daily; 2nd dose reduction, 300 mg twice daily); discontinue alectinib if unable to tolerate a dose of 300 mg twice daily.
    AST/ALT greater than 3 times ULN AND total bilirubin greater than 2 times ULN (in the absence of cholestasis or hemolysis): Permanently discontinue alectinib.
    Total bilirubin greater than 3 times ULN: Hold alectinib. When total bilirubin recovers to less than or equal to 1.5 times ULN or baseline, resume alectinib at a reduced dose (1st dose reduction, 450 mg twice daily; 2nd dose reduction, 300 mg twice daily); discontinue alectinib if unable to tolerate a dose of 300 mg twice daily.

    Renal Impairment

    Baseline Renal Impairment
    A dosage adjustment is not recommended for patients with mild to moderate renal impairment. The safety of alectinib in patients with severe renal impairment (CrCL less than 30 mL/min) or end-stage renal disease has not been studied. Alectinib is not likely to be removed by hemodialysis.
     
    Treatment-Related Nephrotoxicity
    Grade 3 renal impairment: Hold alectinib. When serum creatinine (SCr) recovers to less than or equal to 1.5 times ULN, resume alectinib at a reduced dose (1st dose reduction, 450 mg twice daily; 2nd dose reduction, 300 mg twice daily); discontinue alectinib if unable to tolerate a dose of 300 mg twice daily.
    Grade 4 renal impairment: Permanently discontinue alectinib.

    ADMINISTRATION

    Oral Administration

    Administer alectinib with food.
    Do not open or dissolve the contents of the capsule.
    If a dose is missed, or if vomiting occurs after taking a dose, take the dose at the next scheduled time. Do not repeat doses or make up missed doses.

    STORAGE

    Alecensa:
    - Protect from light
    - Protect from moisture
    - Store below 86 degrees F
    - Store in original container

    CONTRAINDICATIONS / PRECAUTIONS

    Hepatic disease, hepatotoxicity

    Elevated hepatic enzymes and bilirubin have occurred with alectinib therapy. Monitor liver function tests (including ALT, AST, and total bilirubin) every 2 weeks for the first 3 months of treatment, and then once monthly and as clinically indicated during treatment; monitor more frequently in patients who develop transaminase and bilirubin elevations. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary. Most cases of hepatotoxicity (69% of transaminase elevations and 68% of bilirubin elevation) occurred during the first 3 months of treatment. Use alectinib with caution in patients with pre-existing hepatic disease.

    Pneumonitis, pulmonary disease

    Pneumonitis or interstitial lung disease (ILD) has been reported in patients treated with alectinib in clinical trials. Hold alectinib therapy and promptly evaluate any patient with worsening respiratory symptoms (e.g., dyspnea, cough, and fever). Permanently discontinue alectinib if ILD/pneumonitis is diagnosed and no other potential cause is identified. Use alectinib with caution in patients with pre-existing pulmonary disease.

    AV block, cardiac arrhythmias, cardiac disease, hypotension, QT prolongation, sick sinus syndrome, syncope

    Symptomatic bradycardia has been reported in patients treated with alectinib. Monitor heart rate and blood pressure regularly; an interruption of therapy, dose reduction, or discontinuation of therapy may be necessary. Use alectinib with caution in patients with pre-existing cardiac disease, including those with cardiac arrhythmias or conduction disturbances (e.g., sick sinus syndrome, AV block, QT prolongation); hypotension or syncope may also be exacerbated.

    Myopathy, rhabdomyolysis

    Musculoskeletal adverse reactions, including severe myalgia and elevated serum creatine phosphokinase (CPK) levels, have been reported with alectinib therapy. Monitor CPK levels every 2 weeks for the first month of treatment, and then as clinically indicated in patients reporting symptoms; a dose reduction, interruption of therapy, or discontinuation of therapy may be necessary. Patients should be advised to promptly report any unexplained muscle pain, tenderness, or weakness, especially if accompanied by malaise or fever. The median time to grade 3 CPK elevation was 14 days (interquartile range, 13 to 28 days). Use alectinib with caution in patients with a history of myopathy (e.g., rhabdomyolysis).

    Sunlight (UV) exposure

    Alectinib is associated with mild to moderate photosensitivity. Patients should be advised to avoid sunlight (UV) exposure, and to wear protective clothing, use a broad spectrum UVA/UVB sunscreen, and wear protective lip balm (SPF 50 or higher) when outdoors while on treatment and for at least 7 days after the last dose.

    Renal disease, renal impairment

    Renal impairment, including fatalities, has occurred with alectinib treatment; use alectinib with caution in patients with pre-existing renal disease. The median time to grade 3 or higher renal impairment was 3.7 months (range, 0.5 to 14.7 months); an interruption of therapy, dose reduction, or discontinuation of therapy may be necessary.

    Pregnancy

    Although there are no adequate and well-controlled studies in pregnant women, alectinib may cause fetal harm when administered during pregnancy. When administered to pregnant rabbits during organogenesis, abortion or complete embryo-fetal mortality occurred in 3 of 6 rabbits exposed to 2.9-fold the estimated AUC in humans treated with the recommended dose of 600 mg twice daily; the remaining 3 rabbits had few live fetuses, decreased fetal and placental weights, and retroesophageal subclavian artery. In pregnant rats, administration of alectinib during organogenesis at approximately 4.5-fold the AUC in humans at the recommended dose resulted in complete litter loss. Exposures of approximately 2.7-fold the estimated human AUC in humans at the recommended dose resulted in maternal toxicity in addition to decreased fetal weight, dilated ureter, thymic cord, small ventricle, and thin ventricle wall, and reduced number of sacral and caudal vertebrae.

    Contraception requirements, male-mediated teratogenicity, reproductive risk

    Counsel patients about the reproductive risk and contraception requirements during alectinib treatment. Alectinib can cause fetal harm if taken by the mother during pregnancy. Females should avoid pregnancy and use effective contraception during and for at least 1 week after treatment with alectinib. Due to the risk of male-mediated teratogenicity, males with female partners of reproductive potential should also use effective contraception during alectinib therapy and for at least 3 months after the last dose. It would be prudent for females of reproductive potential to undergo pregnancy testing prior to initiation of alectinib. Women who become pregnant while receiving alectinib should be apprised of the potential hazard to the fetus.[60434]

    Breast-feeding

    It is not known whether alectinib is present in human milk. Many drugs are excreted in human milk including antibodies. Due to the potential for serious adverse reactions in nursing infants from alectinib, advise women to discontinue breast-feeding during treatment and for 1 week after the final dose.

    ADVERSE REACTIONS

    Severe

    bradycardia / Rapid / 8.6-18.0
    visual impairment / Early / 4.6-10.0
    anemia / Delayed / 2.0-7.0
    elevated hepatic enzymes / Delayed / 0.7-6.0
    hyponatremia / Delayed / 2.0-6.0
    hyperbilirubinemia / Delayed / 2.4-5.0
    lymphopenia / Delayed / 1.4-4.6
    renal failure (unspecified) / Delayed / 1.7-4.1
    hypokalemia / Delayed / 2.0-4.0
    dyspnea / Early / 0-3.6
    hypophosphatemia / Delayed / 1.4-2.8
    hyperglycemia / Delayed / 2.0-2.2
    hyperkalemia / Delayed / 0-1.4
    pneumonitis / Delayed / 0.7-1.3
    myalgia / Early / 0.7-1.2
    musculoskeletal pain / Early / 0.7-1.2
    diarrhea / Early / 0-1.2
    asthenia / Delayed / 1.2-1.2
    fatigue / Early / 1.2-1.2
    pulmonary embolism / Delayed / 1.2-1.2
    headache / Early / 0.8-0.8
    edema / Delayed / 0.7-0.8
    rash / Early / 0.4-0.7
    nausea / Early / 0-0.7
    dysgeusia / Early / 0-0.7
    hypocalcemia / Delayed / 0-0.4
    vomiting / Early / 0-0.4
    weight gain / Delayed / 0-0.4
    GI perforation / Delayed / 0-0.4
    exfoliative dermatitis / Delayed / Incidence not known
    infection / Delayed / Incidence not known

    Moderate

    constipation / Delayed / 34.0-34.0
    hypoalbuminemia / Delayed / 0-14.0
    neutropenia / Delayed / 0-14.0
    stomatitis / Delayed / 0-3.3
    QT prolongation / Rapid / 0-1.0
    bleeding / Early / 0.8-0.8
    erythema / Early / Incidence not known
    blurred vision / Early / Incidence not known
    peripheral edema / Delayed / Incidence not known

    Mild

    cough / Delayed / 0-19.0
    back pain / Delayed / 12.0-12.0
    photosensitivity / Delayed / 5.3-9.9
    pruritus / Rapid / Incidence not known
    maculopapular rash / Early / Incidence not known
    acneiform rash / Delayed / Incidence not known
    diplopia / Early / Incidence not known

    DRUG INTERACTIONS

    Palifermin: (Moderate) Palifermin should not be administered within 24 hours before, during infusion of, or within 24 hours after administration of antineoplastic agents.
    Penicillamine: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Porfimer: (Major) Avoid coadministration of porfimer with alectinib due to the risk of increased photosensitivity. All patients treated with porfimer will be photosensitive. Concomitant use of other photosensitizing agents like alectinib may increase the risk of a photosensitivity reaction.
    Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy.
    Verteporfin: (Moderate) Use caution if coadministration of verteporfin with alectinib is necessary due to the risk of increased photosensitivity. Verteporfin is a light-activated drug used in photodynamic therapy; all patients treated with verteporfin will be photosensitive. Concomitant use of other photosensitizing agents like alectinib may increase the risk of a photosensitivity reaction.

    PREGNANCY AND LACTATION

    Pregnancy

    Although there are no adequate and well-controlled studies in pregnant women, alectinib may cause fetal harm when administered during pregnancy. When administered to pregnant rabbits during organogenesis, abortion or complete embryo-fetal mortality occurred in 3 of 6 rabbits exposed to 2.9-fold the estimated AUC in humans treated with the recommended dose of 600 mg twice daily; the remaining 3 rabbits had few live fetuses, decreased fetal and placental weights, and retroesophageal subclavian artery. In pregnant rats, administration of alectinib during organogenesis at approximately 4.5-fold the AUC in humans at the recommended dose resulted in complete litter loss. Exposures of approximately 2.7-fold the estimated human AUC in humans at the recommended dose resulted in maternal toxicity in addition to decreased fetal weight, dilated ureter, thymic cord, small ventricle, and thin ventricle wall, and reduced number of sacral and caudal vertebrae.

    It is not known whether alectinib is present in human milk. Many drugs are excreted in human milk including antibodies. Due to the potential for serious adverse reactions in nursing infants from alectinib, advise women to discontinue breast-feeding during treatment and for 1 week after the final dose.

    MECHANISM OF ACTION

    Alectinib is a tyrosine kinase inhibitor that targets anaplastic lymphoma kinase (ALK) and RET. Alectinib, a CNS-active and highly selective ALK inhibitor, inhibited ALK phosphorylation and ALK-mediated activation of the downstream signaling proteins STAT3 and AKT in nonclinical studies. It also decreased tumor cell viability in multiple cell lines harboring ALK fusions, amplifications, or activating mutations. The major active metabolite is M4, which has shown similar in vitro potency and activity. Alectinib and M4 have demonstrated in vitro and in vivo activity against multiple mutant forms of the ALK enzyme, including some mutations in NSCLC tumors in patients who have progressed on crizotonib. Administration of alectinib resulted in antitumor activity and prolonged survival in mouse models implanted with tumors carrying ALK fusions, including mouse models implanted intracranially with ALK-driven tumor cell lines.

    PHARMACOKINETICS

    Alectinib is administered orally. Alectinib and its major metabolite, M4, are greater than 99% bound to plasma proteins, independent of drug concentration. The apparent volume of distribution (Vd) is 4,016 liters for alectinib and 10,093 liters for M4; alectinib concentrations in the cerebrospinal fluid of patients with ALK-positive NSCLC approximate the estimated alectinib free concentrations in the plasma. The apparent clearance (CL/F) is 81.9 L/hour for alectinib and 217 L/hour for M4; the geometric mean elimination half-life is 33 hours for alectinib and 31 hours for M4. Steady-state concentrations are reached by day 7 of administration. The geometric mean accumulation was approximately 6-fold for both alectinib and M4. Ninety-eight percent of radioactivity was excreted in feces after oral administration of a single radiolabeled dose of alectinib under fed conditions; 84% of the dose was unchanged alectinib and 6% was M4. Excretion in the urine was less than 0.5% of the radiolabeled dose.
     
    Affected cytochrome (CYP) 450 isoenzymes and drug transporters: CYP3A4, P-glycoprotein (P-gp), and BCRP
    Alectinib is metabolized by CYP3A4 to its major active metabolite, M4; M4 is subsequently also metabolized by CYP3A4. The mean metabolite/parent exposure ratio is 0.4 at steady state; alectinib and M4 account for 76% of the total radioactivity after a dose. In vitro studies suggest that alectinib is not a substrate of P-gp, but M4 is. Additionally, both alectinib and M4 inhibit P-gp and BCRP in vitro. Pharmacokinetic drug interactions with alectinib requiring dosage adjustments have not been identified. Alectinib and M4 are not substrates of BCRP, OATP1B1, or OATP1B3, and do not inhibit CYP1A2, 2B6, 2C9, 2C19, or 2D6. Alectinib did not inhibit OATP1B1, OATP1B3, OAT1, OAT3, or OCT2 in vitro.

    Oral Route

    The maximal concentration (Cmax) for alectinib at steady-state was 665 ng/mL (CV, 44%) and was 246 ng/mL (CV, 45%) for M4, with a peak to trough concentration ratio of 1.2; the time to maximal concentration (Tmax) was was 4 hours. The geometric mean AUC at steady-state from 0 to 12 hours was 7,430 ng x h/mL (CV, 46%) for alectinib and 2,810 ng x h/mL (CV, 46%) for M4. Alectinib exposure is dose proportional between 460 mg to 900 mg (i.e., 0.75 to 1.5 times the approved recommended dose) under fed conditions. The absolute bioavailability (F) of alectinib was 37% (90% CI, 34% to 40%) under fed conditions; a high fat, high-calorie meal increased the AUC of alectinib plus M4 by 3.1-fold (90% CI, 2.7 to 3.6-fold) after oral administration of a single 600-mg dose.