lorlatinib (Rx)

Brand and Other Names:Lorbrena
  • Print

Dosing & Uses

AdultPediatric

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

Next:

Interactions

Interaction Checker

and lorlatinib

No Results

     activity indicator 
    No Interactions Found
    Interactions Found

    Contraindicated

      Serious - Use Alternative

        Significant - Monitor Closely

          Minor

            All Interactions Sort By:
             activity indicator 
            Previous
            Next:

            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

            Previous
            Next:

            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
            Previous
            Next:

            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.

            more...
            Previous
            Next:

            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])

            Previous
            Next:

            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)

            Previous
            Next:

            Images

            Previous
            Next:

            Formulary

            FormularyPatient Discounts

            Adding plans allows you to compare formulary status to other drugs in the same class.

            To view formulary information first create a list of plans. Your list will be saved and can be edited at any time.

            Adding plans allows you to:

            • View the formulary and any restrictions for each plan.
            • Manage and view all your plans together – even plans in different states.
            • Compare formulary status to other drugs in the same class.
            • Access your plan list on any device – mobile or desktop.

            The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

            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
            Drugs that have quantity limits associated with each prescription. This restriction typically limits the quantity of the drug that will be covered.
            ST Step Therapy
            Drugs that have step therapy associated with each prescription. This restriction typically requires that certain criteria be met prior to approval for the prescription.
            OR Other Restrictions
            Drugs that have restrictions other than prior authorization, quantity limits, and step therapy associated with each prescription.
            Additional Offers
            Email to Patient

            From:

            To:

            The recipient will receive more details and instructions to access this offer.

            By clicking send, you acknowledge that you have permission to email the recipient with this information.

            Email Forms to Patient

            From:

            To:

            The recipient will receive more details and instructions to access this offer.

            By clicking send, you acknowledge that you have permission to email the recipient with this information.

            Previous
            Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.