alectinib

Alectinib is a medication used to treat anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC). Alectinib is a type of targeted therapy that works by selectively inhibiting the activity of ALK protein and “rearranged during transfection” (RET) protein, which cause lung cancers because of fusing with other genes and produce fusion proteins (kinases). Alectinib is used only in the treatment of NSCLCs that are positive for ALK or RET protein, and not for other cancers.

Anaplastic lymphoma kinase is an enzyme coded by the ALK gene, which helps in the development of the fetal gastrointestinal and nervous systems. The ALK gene is normally turned off in the fetal stage, but in some people, it can get turned on later and fuse with another gene, producing a fusion protein that causes non-small cell lung cancer. Alectinib targets the rearranged ALK fusion proteins and decreases tumor cell viability.

Alectinib and its metabolite M4 inhibit the activity of ALK and ALK-mediated activation of downstream signaling proteins STAT3 and AKT that promote cancer cell survival and proliferation. Alectinib is a second-generation tyrosine kinase inhibitor that is typically used to treat metastatic NSCLC in patients who have already been treated with crizotinib, a first-generation tyrosine kinase inhibitor, and have cancer progression.

• Alectinib is toxic to the liver (hepatotoxic) and elevation of liver enzymes ALT and AST, and bilirubin have been reported.
  • Monitor liver function including ALT, AST, and total bilirubin every 2 weeks during the first 3 months of treatment, then once a month and as clinically indicated.
  • Patients who develop AST, ALT and bilirubin elevations require more frequent testing.
  • Based on severity of hepatotoxicity, withhold alectinib and resume at reduced dose, or discontinue permanently.
• Some patients developed interstitial lung disease (ILD)/lung inflammation (pneumonitis) following alectinib treatment. Monitor patients for worsening of respiratory symptoms such as shortness of breath (dyspnea), cough and/or fever. Withhold alectinib in patients diagnosed with ILD/pneumonitis, and permanently discontinue if no other cause is found.
• Alectinib is nephrotoxic and can impair kidney function. Withhold the drug in Grade 3 renal toxicity until recovery, and permanently discontinue in case of Grade 4 toxicity.
• Alectinib can cause symptomatic low heart rate (bradycardia).
  • Monitor the patient’s heart rate and blood pressure regularly.
  • Asymptomatic bradycardia does not require dose modification.
  • In case of non-life-threatening symptomatic bradycardia, withhold alectinib. If bradycardia is attributable to other concurrent medications, resume alectinib at a lower dose after the patient is asymptomatic or heart rate recovers to 60 bpm or higher. Permanently discontinue alectinib if bradycardia recurs.
  • In life-threatening symptomatic bradycardia, permanently discontinue alectinib if there are no other contributing concomitant medications.
• There are reports of muscle pain (myalgia) and musculoskeletal pain, and serum elevation of the muscle protein, creatine phosphokinase (CPK). Monitor the patient’s CPK levels and advise them to immediately report muscle pain, tenderness or weakness. Based on severity of CPK elevation, withhold alectinib, and resume at a reduced dose.
• Alectinib can cause fetal harm. Advise women of pregnancy potential and men with women partners of pregnancy potential to follow effective contraception for the recommended periods. Advise pregnant women of the potential risk to the fetus.
• Rapid destruction of red blood cells (hemolytic anemia) has been reported in some patients. If hemolytic anemia is suspected, withhold alectinib and evaluate the patient. Resume with reduced dose after hemolytic anemia is resolved or permanently discontinue.

Common side effects of alectinib include:

• Low red cell count (anemia)
• Low count of lymphocytes (lymphopenia)
• Low count of neutrophil immune cells (neutropenia)
• High serum bilirubin level (hyperbilirubinemia)
• Increase in alkaline phosphatase (ALK)
• Elevated liver enzymes AST and ALT
• Increase in serum creatinine
• Increased creatine phosphokinase (CPK)
• High blood glucose levels (hyperglycemia)
• Low serum albumin (hypoalbuminemia)
• Electrolyte disturbances including:
  • Low calcium (hypocalcemia)
  • Low sodium (hyponatremia)
  • Low potassium (hypokalemia)
  • High potassium (hyperkalemia)
  • Low phosphorus (hypophosphatemia)
• Increase in gamma glutamyl transferase
• Constipation
• Nausea
• Vomiting
• Diarrhea
• Fatigue
• Weakness (asthenia)
• Swelling from fluid retention (edema) including:
  • Peripheral edema
  • Eyelid edema
  • Face edema
  • Localized edema
  • Generalized edema
• Headache
• Muscle pain (myalgia)
• Musculoskeletal pain
• Back pain
• Skin reactions including:
  • Generalized rash
  • Maculopapular rash
  • Redness (erythema)
  • Rash with skin peeling (exfoliative rash)
  • Itchy rash (pruritic rash)
  • Dermatitis acneiform
• Cough
• Shortness of breath (dyspnea)
• Increase in weight
• Blurred vision
• Double vision (diplopia)
• Visual impairment
• Reduced visual acuity
• Vitreous floaters
• Reduced sense of taste (hypogeusia)
• Taste disorder (dysgeusia)
• Abnormally slow heart rate (bradycardia)
• Kidney injury

Call your doctor immediately if you experience any of the following symptoms or serious side effects while using this drug:

• Serious heart symptoms include fast or pounding heartbeats, fluttering in your chest, shortness of breath, and sudden dizziness;
• Severe headache, confusion, slurred speech, severe weakness, vomiting, loss of coordination, feeling unsteady;
• Severe nervous system reaction with very stiff muscles, high fever, sweating, confusion, fast or uneven heartbeats, tremors, and feeling like you might pass out; or
• Serious eye symptoms include blurred vision, tunnel vision, eye pain or swelling, or seeing halos around lights.

This is not a complete list of all side effects or adverse reactions that may occur from the use of this drug. Call your doctor for medical advice about serious side effects or adverse reactions. You may also report side effects or health problems to the FDA at 1-800-FDA-1088.

Capsule

• 150 mg

Adult:

Non-small Cell Lung Cancer

• Indicated for anaplastic lymphoma kinase (ALK)-positive, metastatic non-small cell lung cancer (NSCLC) as detected by an FDA-approved test
• 600 mg orally twice daily until disease progression or unacceptable toxicity

Dosage Modifications

Dose reduction schedule

• Starting dose: 600 mg orally twice daily
• First dose reduction: 450 mg orally twice daily
• Second dose reduction: 300 mg orally twice daily
• Discontinue if patients are unable to tolerate 300 mg orally twice daily

Nephrotoxicity

• Grade 3: Temporarily withhold until serum creatinine recovers to 1.5 times upper limit of normal (ULN) or below, then resume at reduced dose
• Grade 4: Permanently discontinue

Hepatotoxicity

• ALT or AST elevation above 5 times ULN with total bilirubin (TB) 2 times ULN or below: Temporarily withhold until recovery to baseline or to 3 times ULN or below, then resume at reduced dose
• ALT or AST elevation above 3 times ULN with TB elevation above 2 times ULN in absence of cholestasis or hemolysis: Permanently discontinue
• TB elevation above 3 times ULN: Temporarily withhold until recovery to baseline or to 1.5 times ULN or below, then resume at reduced dose

Interstitial lung disease (ILD)/pneumonitis

• Any grade treatment-related ILD/pneumonitis: Permanently discontinue

Bradycardia

• Symptomatic bradycardia
  • Withhold until recovery to asymptomatic bradycardia or to a heart rate 60 bpm or higher
  • If contributing concomitant medication is identified and discontinued, or its dose is adjusted, resume alectinib at previous dose upon recovery to asymptomatic bradycardia or to a heart rate 60 bpm or higher
  • If no contributing concomitant medication is identified, or if contributing concomitant medications are not discontinued or dose modified, resume alectinib at reduced dose upon recovery to asymptomatic bradycardia or to a heart rate 60 bpm or higher
• Life-threatening bradycardia or urgent intervention indicated
  • Permanently discontinue if no contributing concomitant medication is identified
  • If contributing concomitant medication is identified and discontinued, or its dose is adjusted, resume alectinib at reduced dose upon recovery to asymptomatic bradycardia or to a heart rate 60 bpm or higher, with frequent monitoring as clinically indicated
  • Permanently discontinue in case of recurrence

Elevated creatine phosphokinase (CPK)

• CPK above 5 times ULN: Temporarily withhold until recovery to baseline or to 2.5 times ULN or below, then resume at same dose
• CPK above 10 times ULN or second occurrence of above 5 times ULN: Temporarily withhold until recovery to baseline or to 2.5 times ULN or below, then resume at reduced dose

Renal impairment

• Mild-to-moderate: No dose adjustment required
• Severe (creatinine clearance [CrCl] below 30 mL/minute) or end stage renal disease (ESRD): Not studied

Hepatic impairment

• Mild (TB within ULN and AST above ULN or TB above 1-1.5 times ULN and any AST): No dose adjustment required
• Moderate-to-severe: Not studied

Dosing Considerations

• Patients should be tested and present ALK-positive tumor specimens prior to treatment
• If ALK rearrangements are not detected in a plasma specimen, test tumor tissue if feasible
• Information on FDA-approved tests for the detection of ALK rearrangements in NSCLC is available at http://www.fda.gov/CompanionDiagnostics

Pediatric:

• Safety and efficacy not established

Overdose

• There is no experience with alectinib overdose and no known specific antidote. Overdose may be treated with symptomatic and supportive care.

Inform your doctor of all medications you are currently taking, who can advise you on any possible drug interactions. Never begin taking, suddenly discontinue, or change the dosage of any medication without your doctor’s recommendation.

• Alectinib has no listed severe, serious, moderate, or mild interactions with other drugs.

The drug interactions listed above are not all of the possible interactions or adverse effects. For more information on drug interactions, visit the RxList Drug Interaction Checker.

It is important to always tell your doctor, pharmacist, or health care provider of all prescription and over-the-counter medications you use, as well as the dosage for each, and keep a list of the information. Check with your doctor or health care provider if you have any questions about the medication.

• There are no data available on the use of alectinib in pregnant women, however, animal reproductive studies show alectinib can cause fetal harm if administered during pregnancy.
• Women of pregnancy potential must use effective contraception during treatment with alectinib and for 1 week after the final dose.
• Men with women partners with pregnancy potential should use effective contraception during treatment with alectinib and for 3 months after the final dose.
• There is no information on the presence of alectinib in breastmilk, or its effects on milk production or on the breastfed infant. Do not breastfeed during treatment with alectinib and for 1 week following the final dose, because of the potential for serious adverse effects in the breastfed infant from exposure to alectinib.

• Take alectinib exactly as prescribed, with food.
• Report immediately to your physician if you experience:
  • Worsening of respiratory symptoms including shortness of breath (dyspnea), cough and fever
  • Liver injury symptoms such as dark urine, abdominal pain, nausea and vomiting
  • Unusual muscle pain, tenderness or weakness
  • Symptoms of low blood pressure and heart rate including dizziness, lightheadedness or fainting
  • Kidney symptoms such as reduced urine output, changes in urine color and swelling of legs and feet
• Alectinib can increase skin sensitivity to sunlight. Avoid prolonged sun exposure and use sun protection during treatment with alectinib and for at least a week after discontinuing.
• Store alectinib safely out of reach of children.
• In case of overdose, contact your physician or Poison Control.