lorlatinib (Rx)

Brand and Other Names:Lorbrena
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Dosing & Uses


Dosage Forms & Strengths


  • 25mg
  • 100mg

Non-small Cell Lung Cancer

Indicated for metastatic non-small cell lung cancer (NSCLC) in patients whose tumors are anaplastic lymphoma kinase (ALK)-positive as detected by an FDA-approved test

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 to Grade ≤2; resume at same dose
  • If 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


  • Grade 3
    • Systolic blood pressure [SBP] ≥160 mmHg or diastolic blood pressure [DBP] ≥100 mmHg; medical intervention indicated; more than 1 antihypertensive drug, or more intensive therapy than previously used indicated
    • Withhold until recovery to Grade ≤1 (SBP <140 mmHg and DBP < 90 mmHg), then resume at the same dose
    • If recurs, withhold until recovery to Grade ≤1, and resume at reduced dose
    • If adequate hypertension control cannot be achieved with optimal medical management, permanently discontinue
  • Grade 4
    • Life-threatening consequences, urgent intervention indicated
    • Withhold until recovery to Grade ≤1, and resume at reduced dose or permanently discontinue
    • If recurs, permanently discontinue

Hyperglycemia H4

  • Grade 3 (fasting blood glucose >250 mg/dL) despite optimal anti-hyperglycemic therapy OR Grade 4
  • Withhold until hyperglycemia is adequately controlled, then resume at next lower dosage
  • If adequate hyperglycemic control cannot be achieved with optimal medical management, permanently discontinue

Coadministration with CYP3A inducers

  • Strong CYP3A inducers
    • Contraindicated
    • Discontinue strong CYP3A inducers for 3 plasma half-lives before initiating lorlatinib
  • Moderate CYP3A4 inducers
    • Avoid coadministration
    • If use is unavoidable, increase lorlatinib dose to 125 mg

Coadministration with CYP3A inhibitors

  • Avoid coadministration with strong CYP3A4 inhibitors and fluconazole
  • If use is 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

Renal impairment

  • Mild or moderate (CrCl 30-89 mL/min): No dosage adjustment necessary
  • Severe (CrCl 15 to <30 mL/min): Reduce dose to 75 mg PO qDay
  • End-stage renal disease requiring hemodialysis: Not studied

Hepatic impairment

  • Mild (total bilirubin [TB] <1.5x ULN with any AST): No dose adjustment necessary
  • Moderate or severe (TB ≥1.5x ULN with any AST): Pharmacokinetics unknown

Dosing Considerations

Patient selection

Safety and efficacy not established



Interaction Checker

and lorlatinib

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            Adverse Effects

            All grades of severity listed unless otherwise specified


            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





            Speech effects



            Back pain

            Pain in extremity








            Coadministration with strong CYP3A inducers due to potential for serious hepatotoxicity


            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

            Hypertension reported; median time to onset was 6.4 months (1 day to 2.8 years), and 2.3% of patients temporarily discontinued for hypertension; control blood pressure before initiating; monitor blood pressure after 2 weeks and at least monthly thereafter during treatment

            Hyperglycemia can occur; median time to onset of hyperglycemia was 4.8 months (1 day to 2.9 years), and 0.8% of patients temporarily discontinued for hyperglycemia; assess fasting serum glucose prior to initiating and monitor periodically thereafter

            Fetal harm may occur

            Risk of serious hepatotoxicity with concomitant use of strong CYP3A inducers

            • Serious hepatotoxicity occurred in healthy patients received a single dose of lorlatinib with multiple daily doses of rifampin (a strong CYP3A4 inducer)
            • ALT or AST elevations occurred within 3 days and returned to within normal limits after a median of 15 days; median time to recovery for Grade ≥3 was 18 days and for Grade 2 was 7 days

            CNS effects

            • A broad spectrum of CNS effects may occur
            • These include seizures, psychotic effects and changes in cognitive function, mood (including suicidal ideation), speech, mental status, and sleep
            • Median time to first onset of any CNS effect was 1.4 months (1 day to 3.4 years)

            Drug interactions overview

            • CYP3A4 substrate; moderate CYP3A4 inducer and CYP2B6 inducer
            • Inhibitor of P-gp and organic cation transporter (OCT)1, organic anion transporter (OAT)3, multidrug and toxin extrusion (MATE)1, and intestinal breast cancer resistance protein (BCRP)
            • CYP3A4 inducers
              • Strong and moderate CYP3A inducers decrease lorlatinib plasma concentrations
              • Coadministration with strong CYP3A4 inducers are contraindicated and avoid use with moderate CYP3A4 inducers
            • CYP3A4 inhibitors
              • Avoid coadministration
              • Strong CYP3A inhibitors increased lorlatinib plasma concentrations
            • CYP3A substrates
              • Coadministration with certain 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
            • Fluconazole
              • Avoid coadministration
              • Fluconazole may increase lorlatinib plasma concentrations and risk of adverse reactions



            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


            • 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


            • Based on animal studies, male fertility may transiently be impaired


            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.



            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


            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%


            Vd (steady-state): 305 L

            Protein bound: 66%


            Metabolized primarily by CYP3A4 and UGT1A4; minor contributions by CYP2C8, CYP2C19, CYP3A5, and UGT1A3

            Oxidative cleavage metabolite, M8, is pharmacologically inactive


            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])



            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


            Tablets: Store at 20-25°C (68-77°F); excursions permitted between 15-30°C (59-86°F)





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            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
            4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
            PA Prior Authorization
            Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
            QL Quantity Limits
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            Drugs that have step therapy associated with each prescription. This restriction typically requires that certain criteria be met prior to approval for the prescription.
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