lorlatinib

General

Genetic Implications: Genetic Implications

Pronunciation:
lor-la-ti-nib


Trade Name(s)

  • Lorbrena

Ther. Class.

antineoplastics

Pharm. Class.

kinase inhibitors

Indications

Genetic implication Metastatic non-small cell lung cancer (NSCLC) that is positive for anaplastic lymphoma kinase (ALK).

Action

Acts as a tyrosine kinase inhibitor, inhibiting ALK as well as other kinases including ROS1, resulting in decreased growth of certain malignant cell lines.

Therapeutic Effect(s):

Slowed progression of metastatic NSCLC.

Pharmacokinetics

Absorption: 81% absorbed following oral administration.

Distribution: Extensively distributed to tissues.

Metabolism and Excretion: Primarily metabolized in the liver by the CYP3A4 isoenzyme and UGT1A4, with some metabolism by the CYP2C8 and CYP2C19 isoenzymes. 48% excreted in urine (<1% as unchanged drug), 41% in feces (9% as unchanged drug).

Half-life: 24 hr.

TIME/ACTION PROFILE (plasma concentrations)

ROUTEONSETPEAKDURATION
POunknown2 hr24 hr

Contraindication/Precautions

Contraindicated in:

  • Concurrent use of moderate or strong CYP3A inducers
  • OB:   Pregnancy (may cause fetal harm);
  •  Lactation: Lactation.

Use Cautiously in:

  • Hypertension
  • Moderate or severe hepatic impairment
  • Severe renal impairment (dosage ↓ required)
  • Rep:   Women of reproductive potential and men with female partners of reproductive potential
  • Pedi:   Safety and effectiveness not established in children.

Adverse Reactions/Side Effects

CV: hypertension, peripheral edema, atrioventricular block, PR interval prolongation

Derm: rash

EENT: visual changes

Endo: hyperglycemia

F and E: hyperkalemia, hypomagnesemia, hypophosphatemia

GI: constipation, diarrhea, hypoalbuminemia, ↑ amylase, ↑ lipase, ↑ liver enzymes, nausea, vomiting

GU: ↓ fertility (males)

Hemat: anemia, lymphopenia, thrombocytopenia

Metabolic: hypercholesterolemia, hypertriglyceridemia, ↑ weight

MS: arthralgia, myalgia

Neuro: SEIZURES, SUICIDAL THOUGHTS, cognitive changes, dizziness, fatigue, headache, mood disturbances, peripheral neuropathy, speech disorders, sleep disturbances, hallucinations, mental status changes

Resp: INTERSTITIAL LUNG DISEASE/PNEUMONITIS, cough, dyspnea, upper respiratory tract infection

Misc: fever

* CAPITALS indicate life-threatening.
Underline indicate most frequent.

Interactions

Drug-Drug

  •  Moderate CYP3A inducers  and  strong CYP3A inducers, including  rifampin  may ↓ effectiveness and ↑ risk of hepatotoxicity; concurrent use with strong CYP3A inducers contraindicated (discontinue strong CYP3A4 inducer for 3 half-lives [3 days] prior to starting lorlatinib); avoid concurrent use with moderate CYP3A inducers (if concurrent use unavoidable, ↓ lorlatinib dose).
  •  Strong CYP3A inhibitors, including  itraconazole , may ↑ levels and risk of toxicity; avoid concurrent use; if must use strong CYP3A inhibitor, ↓ lorlatinib dose.
  • May ↓ levels and effectiveness of  CYP3A substrates ; avoid concurrent use; if must use CYP3A substrate, ↑ dose of CYP3A substrate.
  • May ↓ levels and effectiveness of  P-glycoprotein substrates, including  fexofenadine ; avoid concurrent use; if must use P-glycoprotein substrate, ↑ dose of P-glycoprotein substrate.

Route/Dosage

PO (Adults): 100 mg once daily until disease progression or unacceptable toxicity.  Concurrent use of strong CYP3A inhibitor– 75 mg once daily until disease progression or unacceptable toxicity; if dose already ↓ to 75 mg once daily due to adverse reactions, then further ↓ to 50 mg once daily.  Concurrent use of moderate CYP3A inducer– 125 mg once daily until disease progression or unacceptable toxicity.

Renal Impairment 
PO (Adults): CCr 15–<30 mL/min– 75 mg once daily until disease progression or unacceptable toxicity.

Availability

Tablets: 25 mg, 100 mg

Assessment

  • Monitor for signs and symptoms of CNS effects (seizures; hallucinations; changes in cognitive function, mood, speech, mental status, and sleep; suicidal ideation) during therapy.  For Grade 1 effects:  continue at same dose or hold dose until recovery to baseline. Resume at same dose or at reduced dose.  For Grade 2 or 3 effects:  hold dose until Grade 0 or 1. Resume lorlatinib at reduced dose.  For Grade 4:  permanently discontinue lorlatinib.
  • Monitor ECG before starting therapy and periodically thereafter. May cause PR interval prolongation and atrioventricular block.  If second-degree AV block occurs,  hold dose until PR interval <200 msec. Resume lorlatinib at reduced dose.  For 1st occurrence of complete AV block,  hold lorlatinib until pacemaker placed or PR interval <200 msec. If a pacemaker is placed, resume lorlatinib at same dose. If no pacemaker is placed, resume at a reduced dose.  If recurrent complete AV block occurs,  place pacemaker or permanently discontinue lorlatinib.
  • Monitor for signs and symptoms of interstitial lung disease (ILD)/pneumonitis (worsening dyspnea, cough, and fever) during therapy.  If ILD/pneumonitis occur at any grade,  immediately hold dose and permanently lorlatinib.
  • Monitor BP before starting therapy, after 2 wks, and at least monthly thereafter.  If Grade 3 (SBP ≥160 mmHg or DBP ≥100 mmHg; medical intervention indicated; more than one antihypertensive drug, or more intensive therapy than previously used indicated) occurs,  hold lorlatinib until ≤Grade 1 (SBP <140 mmHg and DBP <90 mmHg), then resume lorlatinib at same dose. If Grade 3 hypertension recurs, hold lorlatinib until recovery to ≤Grade 1 and resume at a reduced dose. If adequate hypertension control cannot be achieved with optimal medical management, permanently discontinue lorlatinib.  If Grade 4 (life-threatening consequences, urgent intervention indicated) hypertension occurs,  hold lorlatinib until recovery to ≤Grade 1 and resume at a reduced dose or permanently discontinue lorlatinib. If Grade 4 hypertension recurs, permanently discontinue lorlatinib.

Lab Test Considerations:

Verify negative pregnancy test before starting therapy.

  • Genetic implication Selection of patients is 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.
  • Monitor serum cholesterol and triglycerides before starting therapy, 1 and 2 mo after starting, and periodically thereafter. Start or increase dose of lipid-lowering agents in patients with hyperlipidemia.  For Grade 4 hypercholesterolemia or Grade 4 hypertriglyceridemia : hold lorlatinib until recovery of hypercholesterolemia and/or hypertriglyceridemia to ≤Grade 2. Resume at same dose. If severe hypercholesterolemia and/or hypertriglyceridemia recurs, resume lorlatinib at a reduced dose.
  • Monitor fasting serum glucose before starting therapy and periodically thereafter. If Grade 3 hyperglycemia (>250 mg/dL) occurs despite optimal anti-hyperglycemic therapy OR Grade 4 hyperglycemia occurs, hold lorlatinib until hyperglycemia is adequately controlled, then resume at the next lower dose. If adequate hyperglycemic control cannot be achieved with optimal medical management, permanently discontinue lorlatinib.

Implementation

  • Dose reduction schedule: First dose reduction:  75 mg once daily.  Second reduction:  50 mg once daily. Discontinue permanently in patients unable to tolerate 50 mg dose.
  • PO Administer once daily, at the same time each day, without regard to food.  DNC: Swallow tablets whole; do not crush, break, or chew.  Do not ingest if tablet is broken or cracked.

Patient/Family Teaching

  • Instruct patient to take lorlatinib at the same time each day, as directed. If vomiting occurs, omit dose and take next scheduled dose next day. Take missed doses as soon as remembered up to 4 hr from next dose; do not double doses. Advise patient to read  Patient Information  before starting therapy and with each Rx refill in case of changes.
  • Advise patient to notify health care professional if signs and symptoms of CNS effects, hypertension (headaches, dizziness, blurred vision, chest pain, shortness of breath), hyperglycemia (excessive thirst, frequent urination, feeling very hungry, nausea, feeling weak or tired, feeling confused) or heart problems (feeling dizzy or faint or have abnormal heartbeats) occur,
  • Advise patient to notify health care professional immediately if signs and symptoms of lung problems (trouble breathing, shortness of breath, cough, fever) occur.
  • Instruct patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and consult health care professional before taking any new medications.
  • Rep:  May cause fetal harm. Advise females of reproductive potential to use effective non-hormonal contraception during and for at least 6 mo after last dose and to avoid breastfeeding during and for 7 days after last dose. Advise men with female partners of reproductive potential to use effective contraception during and for at least 3 mo after last dose. May transiently impair male fertility.

Evaluation/Desired Outcomes

Slowed progression of metastatic NSCLC.

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