Dosing & Uses
Dosage Forms & Strengths
tablet
- 25mg
- 100mg
Non-small Cell Lung Cancer
Indications
- Indicated for patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) whose disease has progressed on the following
- Crizotinib and at least 1 other ALK inhibitor, OR
- Alectinib or ceritinib as first ALK inhibitor therapy
100 mg PO qDay with or without food
Continue until disease progression or unacceptable toxicity
Dosage Modifications
Dosage modifications for adverse reactions
- First dose reduction: 75 mg qDay
- Second dose reduction: 50 mg qDay
- Unable to tolerate 50 mg qDay: Permanently discontinue
Central nervous system (CNS) effects
- Grade 1: Continue at same dose or withhold dose until recovery to baseline; resume at same or reduced dose
- Grades 2 or 3: Withhold dose until Grade <1; resume at reduced dose
- Grade 4: Permanently discontinue
Grade 4 hypercholesterolemia or hypertriglyceridemia
- Withhold until recovery of hypercholesterolemia and/or hypertriglyceridemia to Grade ≤2; resume at same dose
- If severe hypercholesterolemia and/or hypertriglyceridemia recurs, resume at reduced dose
Atrioventricular (AV) Block
- Second-degree AV block: Withhold until PR interval <200 msec; resume at reduced dose
- First occurrence of complete AV block: Withhold until pacemaker placed or PR interval <200 msec
- If pacemaker is placed, resume at same dose
- If no pacemaker is placed, resume at reduced dose
- Recurrent complete AV block: Place pacemaker or permanently discontinue
Interstitial lung disease (ILD)/pneumonitis
- Any grade treatment-related ILD/pneumonitis: Permanently discontinue
Other adverse reactions
- Grades 1 or 2: Continue at same or reduced dose
- Grades 3 or 4: Withhold until symptoms resolve to Grade ≤2 or baseline; resume at reduced dose
Coadministration with CYP3A inducers
- Moderate CYP3A inducers: Avoid use
Strong CYP3A inducers
- Coadministration with strong CYP3A inducers is contraindicated
- Discontinue strong CYP3A inducers for 3 plasma half-lives before initiating lorlatinib
Coadministration with strong CYP3A inhibitors
- Avoid use with strong CYP3A inhibitors; if coadministration unavoidable, reduce starting lorlatinib dose to 75 mg qDay
- If dosed reduced to 75 mg qDay because of adverse reactions and are initiating a strong CYP3A inhibitor, reduce dose to 50 mg qDay
- If strong CYP3A inhibitor is discontinued, increase dose (after 3 plasma half-lives of the strong CYP3A inhibitor) to dose used before starting the strong inhibitor
Hepatic impairment
- Mild (total bilirubin ≤ULN with AST >ULN or total bilirubin >1-1.5x ULN with any AST): No dose adjustment necessary
- Moderate or severe: Recommended dose not established
Renal impairment
- Mild or moderate (CrCl 30-89 mL/min): No dosage adjustment necessary
- Severe (CrCl <30 mL/min): Recommended dose not established
Dosing Considerations
Approved under accelerated approval based on tumor response rate and duration of response
Continued approval may be contingent upon verification and description of clinical benefit in a confirmatory trial
Safety and efficacy not established
Interactions
Interaction Checker
No Results
Contraindicated
Serious - Use Alternative
Significant - Monitor Closely
Minor
Adverse Effects
All grades of severity listed unless otherwise specified
>10%
Hypercholesterolemia (96%)
Hypertriglyceridemia (90%)
Edema (57%)
Hyperglycemia (52%)
Anemia (52%)
Peripheral neuropathy (47%)
Increased AST (37%)
Hypoalbuminemia (33%)
Increased ALT (28%)
Cognitive effects (27%)
Dyspnea (27%)
Fatigue (26%)
Weight gain (24%)
Increased lipase (24%)
Increased alkaline phosphatase (24%)
Thrombocytopenia (23%)
Arthralgia (23%)
Mood effects (23%)
Diarrhea (22%)
Increased amylase (22%)
Lymphopenia (22%)
Hyperkalemia (21%)
Hypomagnesemia (21%)
Headache (18%)
Cough (18%)
Nausea (18%)
Myalgia (17%)
Dizziness (16%)
Vision disorder (15%)
Constipation (15%)
Rash (14%)
Back pain (13%)
Pain in extremity (13%)
Vomiting (12%)
Speech effects (12%)
Pyrexia (12%)
Upper respiratory tract infection (12%)
Grades 3 or 4
- Hypercholesterolemia (18%)
- Hypertriglyceridemia (18%)
1-10% (All Grades)
Sleep effects (10%)
Hallucinations (7%)
Pneumonia (3.4%)
Dyspnea (2.7%)
Pyrexia (2%)
Mental status changes (1.4%)
Respiratory failure (1.4%)
1-10% (Grades 3 or 4)
Dyspnea (5.4%)
Hyperglycemia (5%)
Hypophosphatemia (4.8%)
Anemia (4.8%)
Increased amylase (3.9%)
Lymphopenia (3.4%)
Peripheral neuropathy (2.7%)
Increased AST/ALT (2.1%)
Cognitive effects (2%)
Mood effects (1.7%)
Vomiting (1%)
Increased alkaline phosphatase (1%)
Hypokalemia (1%)
Hypoalbuminemia (1%)
<1% (Grades 3 or 4)
Vision disorder
Nausea
Diarrhea
Headache
Dizziness
Speech effects
Arthralgia
Myalgia
Back pain
Pain in extremity
Fatigue
Pyrexia
Rash
Thrombocytopenia
Warnings
Contraindications
Coadministration with strong CYP3A inducers
Cautions
Severe hepatotoxicity occurred in healthy subjects receiving lorlatinib with rifampin, a strong CYP3A inducer; consider discontinuing lorlatinib or CYP3A inducer for persistent Grade ≥2 hepatotoxicity (see Contraindications)
CNS effects (eg, seizures, hallucinations, changes in cognitive function, mood [including suicidal ideation]) may occur Increased serum cholesterol and triglycerides may occur; initiate or increase dose of lipid-lowering agents in patients with hyperlipidemia; monitor serum cholesterol and triglycerides
PR interval prolongation and AV block reported; monitor ECG before initiating treatment and periodically thereafter
Severe or life-threatening pulmonary adverse reactions consistent with ILD/pneumonitis can occur
Based on animal studies and its mechanism of action, fetal harm may occur when administered to a pregnant woman (see Pregnancy)
Drug interactions overview
CYP3A4 inducers
- Coadministration with strong CYP3A inducers decrease lorlatinib plasma concentrations
- Effect of moderate CYP3A inducer on lorlatinib plasma concentrations not studied; if coadministration unavoidable, monitor ALT, AST, and bilirubin
CYP3A4 inhibitors
- Coadministration with strong CYP3A inhibitors increased lorlatinib plasma concentrations
CYP3A substrates
- Coadministration with CYP3A substrates decreases concentration of CYP3A substrates, which may reduce the efficacy of these substrates
- Avoid use with CYP3A substrates with narrow therapeutic index; if coadministration unavoidable, increase dose of CYP3A substrate in accordance to prescribing information
Pregnancy
Pregnancy
Based on findings from animal studies and its mechanism of action, embryo-fetal harm may occur when administered to a pregnant woman
No available data on use in pregnant women
Advise pregnant women of the potential risk to fetus
Verify pregnancy status in females of reproductive potential before initiating treatment
Animal data
- Administration of lorlatinib to pregnant rats and rabbits by oral gavage during organogenesis resulted in malformations, increased postimplantation loss, and abortion at maternal exposures that were equal to or less than the human exposure at 100 mg qDay
Contraception
- Female patients of reproductive potential: Use effective nonhormonal contraception during treatment and for at least 6 months after final dose, because lorlatinib can render hormonal contraceptives ineffective
- Males: Based on genotoxicity findings, advise males with female partners of reproductive potential to use effective contraception during treatment and for at least 3 months after final dose
Infertility
- Based on animal studies, male fertility may transiently be impaired
Lactation
No data on presence of lorlatinib or its metabolites in either human or animal milk or its effects on the breastfed infant or on milk production
Because of potential for serious adverse reactions in breastfed infants, instruct women not to breastfeed during treatment and for 7 days after final dose
Pregnancy Categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk. C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done. D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk. X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist. NA: Information not available.Pharmacology
Mechanism of Action
ALK/ROS1 tyrosine kinase inhibitor
ALK and ROS1 kinases promote tumor progression in ALK/ROS1 positive lung cancer; lorlatinib binds to and inhibits both kinases, which leads to a disruption of the ALK- and ROS1-mediated signaling; this disruption can subsequently inhibit tumor cell growth in ALK- and ROS1-overexpressing tumor cells
Absorption
Peak plasma concentration: 577 ng/mL
Peak plasma time: 1.2 hr (single 100-mg dose); 2 hr (100 mg qDay at steady-state)
AUC: 5650 ng·hr/mL
Bioavailability: 81%
Distribution
Vd (steady-state): 305 L
Protein bound: 66%
Metabolism
Metabolized primarily by CYP3A4 and UGT1A4; minor contributions by CYP2C8, CYP2C19, CYP3A5, and UGT1A3
Oxidative cleavage metabolite, M8, is pharmacologically inactive
Elimination
Half-life (single 100-mg dose): 24 hr
Oral clearance: 11 L/hr (single100-mg dose); 18 L/hr (steady-state)
Excretion (single 100-mg dose): Urine (48% [<1% unchanged]); feces (41% [~9% unchanged])
Administration
Oral Administration
Swallow tablets whole
Do not chew, crush, or split tablets
Do not ingest if tablets are broken, cracked, or otherwise not intact
Administer at same time each day
Missed dose
- If a dose is missed, then administer dose unless next dose is due within 4 hr
- Do not take 2 doses at the same time
- Do not take an additional dose if vomiting occurs after administration; continue with next scheduled dose
Storage
Tablets: Store at 20-25°C (68-77°F); excursions permitted between 15-30°C (59-86°F)
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Patient Handout
Formulary
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