General

High Alert Medication: This medication bears a heightened risk of causing significant patient harm when it is used in error.

Genetic Implications:

Pronunciation:
lor-la-ti-nib

Trade Name(s)

• Lorbrena

Ther. Class.

antineoplastics

Pharm. Class.

kinase inhibitors

Indications

 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)

Contraindication/Precautions

Contraindicated in:

• Concurrent use of moderate or strong CYP3A inducers;
• OB:   Pregnancy;
• Lactation: Lactation.

Use Cautiously in:

• Hypertension
• Moderate or severe hepatic impairment;
• Severe renal impairment (↓ dose);
• 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 (AV) block, PR interval prolongation

Derm: rash

EENT: visual changes

Endo: hyperglycemia

F and E: hyperkalemia, hypomagnesemia, hypophosphatemia

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

GU: ↓ fertility (males)

Hemat: anemia, lymphopenia, thrombocytopenia

Metabolic: hypercholesterolemia, hypertriglyceridemia, weight gain

MS: arthralgia, myalgia

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

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

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 concurrent use unavoidable, ↓ lorlatinib dose.
• May ↓ levels and effectiveness of  CYP3A substrates ; avoid concurrent use; if concurrent use unavoidable, ↑ CYP3A substrate dose.
• May ↓ levels and effectiveness of  P-glycoprotein (P-gp) substrates, including  fexofenadine ; avoid concurrent use; if concurrent use unavoidable, ↑ P-gp substrate dose.

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

Lab Test Considerations:

Verify negative pregnancy test before starting therapy.

•  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 ↑ dose of lipid-lowering agents in patients with hyperlipidemia.  For Grade 4 hypercholesterolemia or Grade 4 hypertriglyceridemia:  hold until recovery of hypercholesterolemia and/or hypertriglyceridemia to ≤Grade 2. Resume at same dose. If severe hypercholesterolemia and/or hypertriglyceridemia recurs, resume at a ↓ dose.
• Monitor fasting serum glucose before starting therapy and periodically thereafter.  If Grade 3 hyperglycemia (>250 mg/dL)  occurs despite optimal antihyperglycemic therapy OR  Grade 4 hyperglycemia  occurs, hold until hyperglycemia is adequately controlled; then resume at ↓ dose. If adequate glycemic control cannot be achieved with optimal medical management, permanently discontinue.

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

• Explain purpose and side effects of medication to patient. Advise patient to read  Patient Information  before starting therapy. Instruct patient to take as directed at the same time each day. 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.
• 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.
• 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.
• Rep:  May cause fetal harm. Advise females of reproductive potential to use effective nonhormonal contraception during and for ≥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 ≥3 mo after last dose. May transiently impair male fertility.

Evaluation/Desired Outcomes

Slowed progression of metastatic NSCLC.