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  • CLASSES

    Small Molecule Antineoplastic Anaplastic Lymphoma Kinase (ALK) Inhibitors
    Small Molecule Antineoplastic Multikinase Inhibitors

    DEA CLASS

    Rx

    DESCRIPTION

    Kinase inhibitor
    Used for certain types of metastatic NSCLC
    Risk of serious hepatotoxicity when administered with CYP3A inducers; contraindicated with strong CYP3A inducers

    COMMON BRAND NAMES

    Lorbrena

    HOW SUPPLIED

    Lorbrena Oral Tab: 25mg, 100mg

    DOSAGE & INDICATIONS

    For the treatment of metastatic, ALK-positive non-small cell lung cancer (NSCLC) with disease progression on either alectinib or ceritinib as the first ALK inhibitor for metastatic disease, or disease progression on crizotinib and at least one other ALK inhibitor for metastatic disease.
    NOTE: Lorlatinib has been designated an orphan drug by the FDA for this indication.
    Oral dosage
    Adults

    100 mg PO once daily until disease progression or unacceptable toxicity. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. The overall response rate of lorlatinib per independent central review was 48% (complete response (CR), 4%) for a median duration of 12.5 months (range, 8.4 to 23.7 months) in a subgroup of patients with metastatic, ALK-positive NSCLC previously treated with one or more ALK inhibitors (n = 215) from a multicenter, nonrandomized, dose-ranging, activity-estimating, multicohort study. An intracranial response occurred in 60% of patients with measurable intracranial lesions (CR, 21%) for a median duration of 19.5 months.[63732]

    MAXIMUM DOSAGE

    Adults

    100 mg PO once daily.

    Geriatric

    100 mg PO once daily.

    Adolescents

    Safety and efficacy not established.

    Children

    Safety and efficacy not established.

    Infants

    Safety and efficacy not established.

    Neonates

    Safety and efficacy not established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Mild hepatic impairment (total bilirubin less than or equal to the upper limit of normal (ULN) with AST greater than ULN, OR total bilirubin up to 1.5 times ULN with any AST): No dosage adjustment necessary.
    Moderate or severe hepatic impairment: The recommended dose of lorlatinib has not been established.

    Renal Impairment

    Mild or moderate renal impairment (CrCL 30 to 89 mL/min): No dosage adjustment necessary.
    Severe renal impairment (CrCL less than 30 mL/min): The recommended dose of lorlatinib has not been established.

    ADMINISTRATION

    Oral Administration

    Lorlatinib may be taken with or without food.
    Have the patient swallow the tablet whole. Do not crush, chew, or split tablets. Do not administer if tablets are broken, cracked, or otherwise not intact.
    Administer lorlatinib at the same time each day. If a dose is missed, it can be given up to 4 hours before the next dose. Do not give 2 doses at the same time to make up for a missed dose.
    Do not give an additional dose if vomiting occurs after lorlatinib administration. Continue with the next scheduled dose.[63732]

    STORAGE

    Lorbrena:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    Hepatotoxicity

    Severe hepatotoxicity occurred in 10 of 12 healthy subjects receiving a single dose of lorlatinib with multiple daily doses of rifampin, a strong CYP3A4 inducer. Grade 4 transaminase elevations occurred in 50% of patients, grade 3 in 33%, and grade 2 in 8% of patients. Elevated transaminases occurred within 3 doses of lorlatinib administration and returned to normal limits after a median of 15 days (range, 7 to 34 days). A possible mechanism for hepatotoxicity is through activation of the pregnane X receptor (PXR) by both lorlatinib and rifampin, which are both PXR agonists. Lorlatinib is contraindicated in patients taking strong CYP3A inducers; these medications should be discontinued for 3 plasma half-lives prior to initiating lorlatinib therapy. Moderate CYP3A inducers should also be avoided; if unavoidable, monitor AST, ALT, and bilirubin 48 hours after initiating lorlatinib and at least 3 times during the first week of therapy. Depending on the relative importance of each drug, discontinue lorlatinib or the CYP3A inducer for persistent grade 2 or higher hepatotoxicity.[63732]

    Neurological disease, neurotoxicity, seizures

    Use lorlatinib with caution in patients with pre-existing neurological disease. A broad spectrum of central nervous system (CNS) effects (e.g., neurotoxicity, seizures, hallucinations, changes in cognitive function, mood, speech, mental status, and sleep) have been reported in patients treated with lorlatinib. The median time to the first onset of any CNS effect was 1.2 months. Monitor for these changes; an interruption of therapy, dose reduction, or discontinuation of therapy may be necessary.[63732]

    Hypercholesterolemia, hypertriglyceridemia

    Use lorlatinib with caution in patients with pre-existing hypercholesterolemia or hypertriglyceridemia. Increases in total cholesterol and serum triglycerides are common with lorlatinib therapy; the median time to onset for each was 15 days. Monitor serum cholesterol and triglycerides at baseline, at 1 and 2 months after starting therapy, and then periodically thereafter. Initiate or increase the dose of lipid-lowering agents in patients with hyperlipidemia. An interruption of therapy or dose reduction may be necessary for elevated cholesterol or triglycerides.

    Cardiac arrhythmias

    Use lorlatinib with caution in patients with pre-existing cardiac arrhythmias. Prolongation of the PR interval and atrioventricular (AV) block can occur in patients receiving lorlatinib. Monitor ECG at baseline and periodically thereafter. An interruption of therapy, pacemaker placement, dose reduction, or discontinuation of therapy may be necessary.

    Pneumonitis, pulmonary disease

    Use lorlatinib with caution in patients with pre-existing pulmonary disease, as severe or life-threatening pulmonary adverse reactions consistent with interstitial lung disease (ILD)/pneumonitis can occur with treatment. Promptly investigate for ILD any patient who presents with worsening respiratory symptoms (e.g., dyspnea, cough, fever). Immediately hold lorlatinib therapy in patients with suspected ILD/pneumonitis; permanently discontinue therapy for treatment-related ILD/pneumonitis of any severity.[63732]

    Pregnancy

    Pregnancy should be avoided by females of reproductive potential during lorlatinib treatment and for at least 6 months after the last dose. Although there are no adequately controlled studies in pregnant animals or humans, lorlatinib can cause fetal harm or death when administered during pregnancy based on its mechanism of action and animal studies. Women who are pregnant or who become pregnant while receiving lorlatinib should be apprised of the potential hazard to the fetus. Administration to rabbits at exposures approximately 3 times the human exposure at the recommended dose or higher resulted in abortion and total loss of pregnancy. At approximately 0.6 times the human exposure at the recommended dose, increased post-implantation occurred as well as malformations such as rotated limbs, malformed kidneys, domed head, high arched palate, and dilation of the cerebral ventricles. In rats, exposures of approximately 5 times the human exposure at the recommended dose during organogenesis increased post-implantation loss, decreased fetal body weight, and increased malformations including gastroschisis, rotated limbs, supernumerary digits, and vessel abnormalities.

    Contraception requirements, infertility, male-mediated teratogenicity, pregnancy testing, reproductive risk

    Counsel patients about the reproductive risk and contraception requirements during lorlatinib treatment. Lorlatinib can be teratogenic if taken by the mother during pregnancy. Females of reproductive potential should avoid pregnancy and use effective non-hormonal contraception during and for at least 6 months after treatment with lorlatinib; lorlatinib can render hormonal contraceptives ineffective. Females of reproductive potential should undergo pregnancy testing prior to initiation of lorlatinib. Due to the risk of male-mediated teratogenicity, males with female partners of reproductive potential should use effective contraception during treatment with lorlatinib and for at least 3 months after the final dose. Women who become pregnant while receiving lorlatinib should be apprised of the potential hazard to the fetus. Although there are no data regarding the effect of lorlatinib on human fertility, transient male infertility has been observed in animal studies.

    Breast-feeding

    Due to the potential for serious adverse reactions in nursing infants from lorlatinib, advise women to discontinue breast-feeding during treatment and for 7 days after the final dose. It is not known whether lorlatinib is present in human milk, although many drugs are excreted in human milk.

    ADVERSE REACTIONS

    Severe

    hypercholesterolemia / Delayed / 17.0-18.0
    hypertriglyceridemia / Delayed / 17.0-18.0
    dyspnea / Early / 5.4-5.4
    hyperglycemia / Delayed / 5.0-5.0
    hypophosphatemia / Delayed / 4.8-4.8
    weight gain / Delayed / 4.4-4.4
    hyperamylasemia / Delayed / 3.9-3.9
    lymphopenia / Delayed / 3.4-3.4
    edema / Delayed / 3.1-3.1
    seizures / Delayed / 3.0-3.0
    peripheral neuropathy / Delayed / 2.7-2.7
    elevated hepatic enzymes / Delayed / 2.1-2.1
    pneumonitis / Delayed / 1.2-1.2
    hypoalbuminemia / Delayed / 1.0-1.0
    AV block / Early / 1.0-1.0
    vomiting / Early / 1.0-1.0
    hyperkalemia / Delayed / 1.0-1.0
    myocardial infarction / Delayed / 0.7-0.7
    dizziness / Early / 0.7-0.7
    headache / Early / 0.7-0.7
    nausea / Early / 0.7-0.7
    diarrhea / Early / 0.7-0.7
    back pain / Delayed / 0.7-0.7
    arthralgia / Delayed / 0.7-0.7
    fever / Early / 0.7-0.7
    hallucinations / Early / 0.6-0.6
    visual impairment / Early / 0.3-0.3
    pulmonary edema / Early / 0.3-0.3
    fatigue / Early / 0.3-0.3
    rash / Early / 0.3-0.3
    thrombocytopenia / Delayed / 0.3-0.3
    anemia / Delayed / 4.8
    hepatotoxicity / Delayed / Incidence not known
    dementia / Delayed / Incidence not known
    suicidal ideation / Delayed / Incidence not known
    thromboembolism / Delayed / Incidence not known

    Moderate

    neurotoxicity / Early / 54.0-54.0
    impaired cognition / Early / 25.0-26.9
    hypomagnesemia / Delayed / 21.0-21.0
    constipation / Delayed / 15.0-15.0
    PR prolongation / Rapid / 14.0-14.0
    formication / Early / Incidence not known
    confusion / Early / Incidence not known
    amnesia / Delayed / Incidence not known
    memory impairment / Delayed / Incidence not known
    depression / Delayed / Incidence not known
    mania / Early / Incidence not known
    euphoria / Early / Incidence not known
    aphasia / Delayed / Incidence not known
    dysarthria / Delayed / Incidence not known
    photopsia / Delayed / Incidence not known
    photophobia / Early / Incidence not known
    blurred vision / Early / Incidence not known
    peripheral edema / Delayed / Incidence not known
    hypertension / Early / Incidence not known

    Mild

    cough / Delayed / 18.0-18.0
    myalgia / Early / 17.0-17.0
    infection / Delayed / 12.0-12.0
    dysesthesia / Delayed / Incidence not known
    paresthesias / Delayed / Incidence not known
    carpal tunnel syndrome / Delayed / Incidence not known
    weakness / Early / Incidence not known
    hypoesthesia / Delayed / Incidence not known
    hyperactivity / Early / Incidence not known
    agitation / Early / Incidence not known
    irritability / Delayed / Incidence not known
    anxiety / Delayed / Incidence not known
    emotional lability / Early / Incidence not known
    abnormal dreams / Early / Incidence not known
    nightmares / Early / Incidence not known
    somnambulism / Early / Incidence not known
    insomnia / Early / Incidence not known
    diplopia / Early / Incidence not known
    musculoskeletal pain / Early / Incidence not known
    asthenia / Delayed / Incidence not known
    maculopapular rash / Early / Incidence not known
    acneiform rash / Delayed / Incidence not known

    DRUG INTERACTIONS

    Abacavir; Dolutegravir; Lamivudine: (Moderate) Monitor for decreased efficacy of dolutegravir if coadministered with lorlatinib. Concurrent use may decrease the plasma concentrations of dolutegravir leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Dolutegravir is a CYP3A4 substrate as well as a substrate of P-glycoprotein (P-gp). Lorlatinib is a moderate CYP3A4 inducer and a P-gp inducer.
    Abemaciclib: (Major) Avoid coadministration of lorlatinib with abemaciclib due to decreased exposure to abemaciclib and its active metabolites, which may lead to reduced efficacy. Abemaciclib is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Coadministration with other moderate CYP3A4 inducers is predicted to decrease the relative potency adjusted unbound AUC of abemaciclib plus its active metabolites (M2, M18, and M20) by 29% to 53%.
    Acetaminophen; Butalbital: (Major) Avoid coadministration of lorlatinib with butalbital due to the risk of severe hepatotoxicity as well as decreased lorlatinib exposure which may reduce its efficacy. If concomitant use is unavoidable, monitor ALT, AST, and bilirubin 48 hours after initiating lorlatinib therapy and at least 3 times during the first week of treatment. If persistent grade 2 or higher hepatotoxicity occurs, discontinue either lorlatinib or butalbital. Lorlatinib is a CYP3A substrate and butalbital is a moderate CYP3A inducer. Coadministration with a strong CYP3A inducer decreased lorlatinib exposure by 85% and caused severe (grade 3 or 4) hepatotoxicity in 83% of patients. The effect of the concomitant use of moderate CYP3A inducers on lorlatinib pharmacokinetics or the risk of hepatotoxicity is unknown.
    Acetaminophen; Butalbital; Caffeine: (Major) Avoid coadministration of lorlatinib with butalbital due to the risk of severe hepatotoxicity as well as decreased lorlatinib exposure which may reduce its efficacy. If concomitant use is unavoidable, monitor ALT, AST, and bilirubin 48 hours after initiating lorlatinib therapy and at least 3 times during the first week of treatment. If persistent grade 2 or higher hepatotoxicity occurs, discontinue either lorlatinib or butalbital. Lorlatinib is a CYP3A substrate and butalbital is a moderate CYP3A inducer. Coadministration with a strong CYP3A inducer decreased lorlatinib exposure by 85% and caused severe (grade 3 or 4) hepatotoxicity in 83% of patients. The effect of the concomitant use of moderate CYP3A inducers on lorlatinib pharmacokinetics or the risk of hepatotoxicity is unknown.
    Acetaminophen; Butalbital; Caffeine; Codeine: (Major) Avoid coadministration of lorlatinib with butalbital due to the risk of severe hepatotoxicity as well as decreased lorlatinib exposure which may reduce its efficacy. If concomitant use is unavoidable, monitor ALT, AST, and bilirubin 48 hours after initiating lorlatinib therapy and at least 3 times during the first week of treatment. If persistent grade 2 or higher hepatotoxicity occurs, discontinue either lorlatinib or butalbital. Lorlatinib is a CYP3A substrate and butalbital is a moderate CYP3A inducer. Coadministration with a strong CYP3A inducer decreased lorlatinib exposure by 85% and caused severe (grade 3 or 4) hepatotoxicity in 83% of patients. The effect of the concomitant use of moderate CYP3A inducers on lorlatinib pharmacokinetics or the risk of hepatotoxicity is unknown. (Moderate) Monitor for reduced efficacy of codeine and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with lorlatinib is necessary; consider increasing the dose of codeine as needed. It is recommended to avoid this combination when codeine is being used for cough. If lorlatinib is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Lorlatinib is a moderate CYP3A4 inducer. Concomitant use with lorlatinib can increase norcodeine levels via increased CYP3A4 metabolism, resulting in decreased metabolism via CYP2D6 resulting in lower morphine levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Monitor for reduced efficacy of dihydrocodeine and signs of opioid withdrawal if coadministration with lorlatinib is necessary; consider increasing the dose of dihydrocodeine as needed. If lorlatinib is discontinued, consider a dose reduction of dihydrocodeine and frequently monitor for signs or respiratory depression and sedation. Lorlatinib is a moderate inducer of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine. Concomitant use of dihydrocodeine with lorlatinib can decrease dihydrocodeine levels, resulting in less metabolism by CYP2D6 and decreased dihydromorphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Acetaminophen; Codeine: (Moderate) Monitor for reduced efficacy of codeine and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with lorlatinib is necessary; consider increasing the dose of codeine as needed. It is recommended to avoid this combination when codeine is being used for cough. If lorlatinib is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Lorlatinib is a moderate CYP3A4 inducer. Concomitant use with lorlatinib can increase norcodeine levels via increased CYP3A4 metabolism, resulting in decreased metabolism via CYP2D6 resulting in lower morphine levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Acetaminophen; Hydrocodone: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with lorlatinib is necessary; consider increasing the dose of hydrocodone as needed. It is recommended to avoid this combination when hydrocodone is being used for cough. If lorlatinib is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Concomitant use can decrease hydrocodone levels.
    Acetaminophen; Oxycodone: (Moderate) Monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with lorlatinib is necessary; consider increasing the dose of oxycodone as needed. If lorlatinib is discontinued, consider a dose reduction of lorlatinib and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease oxycodone concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Acetaminophen; Tramadol: (Moderate) Monitor for reduced efficacy of tramadol and signs of opioid withdrawal if coadministration with lorlatinib is necessary; consider increasing the dose of tramadol as needed. If lorlatinib is discontinued, consider a dose reduction of tramadol and frequently monitor for signs or respiratory depression and sedation. Tramadol is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease tramadol levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Afatinib: (Major) Increase the daily dose of afatinib by 10 mg as tolerated if the concomitant use with lorlatinib is necessary; resume the previous dose of afatinib 2 to 3 days after discontinuation of lorlatinib. Afatinib is a P-glycoprotein (P-gp) substrate and lorlatinib is a P-gp inducer; coadministration may decrease plasma concentrations of afatinib. Pre-treatment with another strong P-gp inducer decreased afatinib exposure by 34%.
    Alfentanil: (Moderate) Consider an increased dose of alfentanil and monitor for evidence of opioid withdrawal if coadministration with lorlatinib is necessary. If lorlatinib is discontinued, consider reducing the alfentanil dosage and monitor for evidence of respiratory depression. Coadministration of a moderate CYP3A4 inducer like lorlatinib with alfentanil, a CYP3A4 substrate, may decrease exposure to alfentanil resulting in decreased efficacy or onset of withdrawal symptoms in a patient who has developed physical dependence to alfentanil. Alfentanil plasma concentrations will increase once the inducer is stopped, which may increase or prolong the therapeutic and adverse effects, including serious respiratory depression.
    Aliskiren; Amlodipine: (Moderate) Monitor blood pressure if coadministration of amlodipine with lorlatinib is necessary. Amlodipine is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Concomitant use may decrease amlodipine plasma concentrations, decreasing efficacy.
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Monitor blood pressure if coadministration of amlodipine with lorlatinib is necessary. Amlodipine is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Concomitant use may decrease amlodipine plasma concentrations, decreasing efficacy.
    Amiodarone: (Moderate) Monitor for decreased efficacy of amiodarone if coadministration with lorlatinib is necessary; concomitant use may decrease amiodarone plasma concentrations. Amiodarone is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer.
    Amlodipine: (Moderate) Monitor blood pressure if coadministration of amlodipine with lorlatinib is necessary. Amlodipine is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Concomitant use may decrease amlodipine plasma concentrations, decreasing efficacy.
    Amlodipine; Atorvastatin: (Moderate) Monitor blood pressure if coadministration of amlodipine with lorlatinib is necessary. Amlodipine is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Concomitant use may decrease amlodipine plasma concentrations, decreasing efficacy.
    Amlodipine; Benazepril: (Moderate) Monitor blood pressure if coadministration of amlodipine with lorlatinib is necessary. Amlodipine is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Concomitant use may decrease amlodipine plasma concentrations, decreasing efficacy.
    Amlodipine; Celecoxib: (Moderate) Monitor blood pressure if coadministration of amlodipine with lorlatinib is necessary. Amlodipine is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Concomitant use may decrease amlodipine plasma concentrations, decreasing efficacy.
    Amlodipine; Hydrochlorothiazide, HCTZ; Olmesartan: (Moderate) Monitor blood pressure if coadministration of amlodipine with lorlatinib is necessary. Amlodipine is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Concomitant use may decrease amlodipine plasma concentrations, decreasing efficacy.
    Amlodipine; Hydrochlorothiazide, HCTZ; Valsartan: (Moderate) Monitor blood pressure if coadministration of amlodipine with lorlatinib is necessary. Amlodipine is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Concomitant use may decrease amlodipine plasma concentrations, decreasing efficacy.
    Amlodipine; Olmesartan: (Moderate) Monitor blood pressure if coadministration of amlodipine with lorlatinib is necessary. Amlodipine is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Concomitant use may decrease amlodipine plasma concentrations, decreasing efficacy.
    Amlodipine; Telmisartan: (Moderate) Monitor blood pressure if coadministration of amlodipine with lorlatinib is necessary. Amlodipine is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Concomitant use may decrease amlodipine plasma concentrations, decreasing efficacy.
    Amlodipine; Valsartan: (Moderate) Monitor blood pressure if coadministration of amlodipine with lorlatinib is necessary. Amlodipine is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Concomitant use may decrease amlodipine plasma concentrations, decreasing efficacy.
    Amobarbital: (Major) Avoid coadministration of lorlatinib with amobarbital due to the risk of severe hepatotoxicity as well as decreased lorlatinib exposure which may reduce its efficacy. If concomitant use is unavoidable, monitor ALT, AST, and bilirubin 48 hours after initiating lorlatinib therapy and at least 3 times during the first week of treatment. If persistent grade 2 or higher hepatotoxicity occurs, discontinue either lorlatinib or amobarbital. Lorlatinib is a CYP3A substrate and amobarbital is a moderate CYP3A inducer. Coadministration with a strong CYP3A inducer decreased lorlatinib exposure by 85% and caused severe (grade 3 or 4) hepatotoxicity in 83% of patients. The effect of the concomitant use of moderate CYP3A inducers on lorlatinib pharmacokinetics or the risk of hepatotoxicity is unknown.
    Amoxicillin; Clarithromycin; Lansoprazole: (Major) Avoid coadministration of lorlatinib with clarithromycin due to increased plasma concentrations of lorlatinib, which may increase the incidence and severity of adverse reactions of lorlatinib; plasma concentrations of clarithromycin may also decrease. If concomitant use is unavoidable, reduce the starting dose of lorlatinib from 100 mg to 75 mg once daily, or from 75 mg to 50 mg once daily. If clarithromycin is discontinued, resume the original dose of lorlatinib after 3 plasma half-lives of clarithromycin. Lorlatinib is a CYP3A4 substrate and moderate CYP3A4 inducer. Clarithromycin is a CYP3A4 substrate and strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased lorlatinib exposure by 42%. Inducers of CYP3A enzymes will decrease plasma concentrations of clarithromycin while increasing those of 14-OH-clarithromycin. Since the microbiological activities of clarithromycin and 14-OH-clarithromycin are different for different bacteria, the intended therapeutic effect could be impaired during concomitant administration of clarithromycin and enzyme inducers.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Avoid coadministration of lorlatinib with clarithromycin due to increased plasma concentrations of lorlatinib, which may increase the incidence and severity of adverse reactions of lorlatinib; plasma concentrations of clarithromycin may also decrease. If concomitant use is unavoidable, reduce the starting dose of lorlatinib from 100 mg to 75 mg once daily, or from 75 mg to 50 mg once daily. If clarithromycin is discontinued, resume the original dose of lorlatinib after 3 plasma half-lives of clarithromycin. Lorlatinib is a CYP3A4 substrate and moderate CYP3A4 inducer. Clarithromycin is a CYP3A4 substrate and strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased lorlatinib exposure by 42%. Inducers of CYP3A enzymes will decrease plasma concentrations of clarithromycin while increasing those of 14-OH-clarithromycin. Since the microbiological activities of clarithromycin and 14-OH-clarithromycin are different for different bacteria, the intended therapeutic effect could be impaired during concomitant administration of clarithromycin and enzyme inducers.
    Apalutamide: (Severe) Coadministration of lorlatinib with apalutamide is contraindicated due to the risk of severe hepatotoxicity as well as decreased lorlatinib exposure which may reduce its efficacy. Discontinue apalutamide for 3 plasma half-lives prior to initiating therapy with lorlatinib. Lorlatinib is a CYP3A substrate and apalutamide is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased lorlatinib exposure by 85% and caused severe (grade 3 or 4) hepatotoxicity in 83% of patients.
    Aspirin, ASA; Butalbital; Caffeine: (Major) Avoid coadministration of lorlatinib with butalbital due to the risk of severe hepatotoxicity as well as decreased lorlatinib exposure which may reduce its efficacy. If concomitant use is unavoidable, monitor ALT, AST, and bilirubin 48 hours after initiating lorlatinib therapy and at least 3 times during the first week of treatment. If persistent grade 2 or higher hepatotoxicity occurs, discontinue either lorlatinib or butalbital. Lorlatinib is a CYP3A substrate and butalbital is a moderate CYP3A inducer. Coadministration with a strong CYP3A inducer decreased lorlatinib exposure by 85% and caused severe (grade 3 or 4) hepatotoxicity in 83% of patients. The effect of the concomitant use of moderate CYP3A inducers on lorlatinib pharmacokinetics or the risk of hepatotoxicity is unknown.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Major) Avoid coadministration of lorlatinib with butalbital due to the risk of severe hepatotoxicity as well as decreased lorlatinib exposure which may reduce its efficacy. If concomitant use is unavoidable, monitor ALT, AST, and bilirubin 48 hours after initiating lorlatinib therapy and at least 3 times during the first week of treatment. If persistent grade 2 or higher hepatotoxicity occurs, discontinue either lorlatinib or butalbital. Lorlatinib is a CYP3A substrate and butalbital is a moderate CYP3A inducer. Coadministration with a strong CYP3A inducer decreased lorlatinib exposure by 85% and caused severe (grade 3 or 4) hepatotoxicity in 83% of patients. The effect of the concomitant use of moderate CYP3A inducers on lorlatinib pharmacokinetics or the risk of hepatotoxicity is unknown. (Moderate) Monitor for reduced efficacy of codeine and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with lorlatinib is necessary; consider increasing the dose of codeine as needed. It is recommended to avoid this combination when codeine is being used for cough. If lorlatinib is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Lorlatinib is a moderate CYP3A4 inducer. Concomitant use with lorlatinib can increase norcodeine levels via increased CYP3A4 metabolism, resulting in decreased metabolism via CYP2D6 resulting in lower morphine levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Moderate) Monitor for reduced efficacy of dihydrocodeine and signs of opioid withdrawal if coadministration with lorlatinib is necessary; consider increasing the dose of dihydrocodeine as needed. If lorlatinib is discontinued, consider a dose reduction of dihydrocodeine and frequently monitor for signs or respiratory depression and sedation. Lorlatinib is a moderate inducer of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine. Concomitant use of dihydrocodeine with lorlatinib can decrease dihydrocodeine levels, resulting in less metabolism by CYP2D6 and decreased dihydromorphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Monitor for reduced efficacy of codeine and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with lorlatinib is necessary; consider increasing the dose of codeine as needed. It is recommended to avoid this combination when codeine is being used for cough. If lorlatinib is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Lorlatinib is a moderate CYP3A4 inducer. Concomitant use with lorlatinib can increase norcodeine levels via increased CYP3A4 metabolism, resulting in decreased metabolism via CYP2D6 resulting in lower morphine levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Aspirin, ASA; Oxycodone: (Moderate) Monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with lorlatinib is necessary; consider increasing the dose of oxycodone as needed. If lorlatinib is discontinued, consider a dose reduction of lorlatinib and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease oxycodone concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Atazanavir: (Major) Avoid coadministration of lorlatinib with atazanavir due to increased plasma concentrations of lorlatinib, which may increase the incidence and severity of adverse reactions of lorlatinib; exposure to atazanavir may also decrease. If concomitant use is unavoidable, reduce the starting dose of lorlatinib from 100 mg to 75 mg once daily, or from 75 mg to 50 mg once daily. If atazanavir is discontinued, resume the original dose of lorlatinib after 3 plasma half-lives of atazanavir. Lorlatinib is a CYP3A4 substrate and a moderate CYP3A4 inducer. Atazanavir is a CYP3A4 substrate and a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased lorlatinib exposure by 42%. Concomitant administration of atazanavir with CYP3A4 inducers may decrease plasma concentrations, reducing efficacy and increasing the potential for viral resistance.
    Atazanavir; Cobicistat: (Major) Avoid coadministration of lorlatinib with atazanavir due to increased plasma concentrations of lorlatinib, which may increase the incidence and severity of adverse reactions of lorlatinib; exposure to atazanavir may also decrease. If concomitant use is unavoidable, reduce the starting dose of lorlatinib from 100 mg to 75 mg once daily, or from 75 mg to 50 mg once daily. If atazanavir is discontinued, resume the original dose of lorlatinib after 3 plasma half-lives of atazanavir. Lorlatinib is a CYP3A4 substrate and a moderate CYP3A4 inducer. Atazanavir is a CYP3A4 substrate and a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased lorlatinib exposure by 42%. Concomitant administration of atazanavir with CYP3A4 inducers may decrease plasma concentrations, reducing efficacy and increasing the potential for viral resistance. (Major) Avoid coadministration of lorlatinib with cobicistat due to increased plasma concentrations of lorlatinib, which may increase the incidence and severity of adverse reactions of lorlatinib; plasma concentrations of cobicistat may also decrease. If concomitant use is unavoidable, reduce the starting dose of lorlatinib from 100 mg to 75 mg once daily, or from 75 mg to 50 mg once daily. If cobicistat is discontinued, resume the original dose of lorlatinib after 3 half-lives of cobicistat. Lorlatinib is a CYP3A4 substrate and a moderate CYP3A4 inducer. Cobicistat is a CYP3A4 substrate and a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased lorlatinib exposure by 42%. Coadministration of cobicistat with moderate CYP3A4 inducers may reduce antiretroviral efficacy and increase the potential development of viral resistance.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Severe) Coadministration of lorlatinib with phenobarbital is contraindicated due to the risk of severe hepatotoxicity as well as decreased lorlatinib exposure which may reduce its efficacy. Discontinue phenobarbital for 3 plasma half-lives prior to initiating therapy with lorlatinib. Lorlatinib is a CYP3A substrate and phenobarbital is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased lorlatinib exposure by 85% and caused severe (grade 3 or 4) hepatotoxicity in 83% of patients.
    Avanafil: (Major) Coadministration of avanafil with lorlatinib is not recommended by the manufacturer of avanafil due to the potential for decreased avanafil efficacy. Avanafil is a CYP3A4 substrate and lorlatinib is a CYP3A4 inducer. Although the potential effect of CYP inducers on the pharmacokinetics of avanafil was not evaluated, plasma concentrations may decrease.
    Avapritinib: (Major) Avoid coadministration of avapritinib with lorlatinib due to the risk of decreased avapritinib efficacy. Avapritinib is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer is predicted to decrease the AUC and Cmax of avapritinib by 62% and 55%, respectively.
    Axitinib: (Major) Avoid coadministration of axitinib with lorlatinib if possible due to the risk of decreased efficacy of axitinib. Selection of a concomitant medication with no or minimal CYP3A4 induction potential is recommended. Axitinib is a CYP3A4/5 substrate and lorlatinib is a moderate CYP3A4 inducer.
    Bedaquiline: (Major) Avoid coadministration of lorlatinib with bedaquiline due to decreased plasma exposure to bedaquiline. Bedaquiline is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer decreased bedaquiline exposure by approximately 20%. The AUC and Cmax of the primary metabolite of bedaquiline (M2) were increased by 70% and 80%, respectively.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Severe) Coadministration of lorlatinib with phenobarbital is contraindicated due to the risk of severe hepatotoxicity as well as decreased lorlatinib exposure which may reduce its efficacy. Discontinue phenobarbital for 3 plasma half-lives prior to initiating therapy with lorlatinib. Lorlatinib is a CYP3A substrate and phenobarbital is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased lorlatinib exposure by 85% and caused severe (grade 3 or 4) hepatotoxicity in 83% of patients.
    Benzhydrocodone; Acetaminophen: (Moderate) Monitor for reduced efficacy of benzhydrocodone and signs of opioid withdrawal if coadministration with lorlatinib is necessary; consider increasing the dose of benzhydrocodone as needed. If lorlatinib is discontinued, consider a dose reduction of benzhydrocodone and frequently monitor for signs of respiratory depression and sedation. Benzhydrocodone is a prodrug for hydrocodone. Hydrocodone is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease hydrocodone concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Betrixaban: (Major) Avoid coadministration of betrixaban and lorlatinib due to the risk of decreased betrixaban exposure and reduced efficacy. Betrixaban is a P-glycoprotein (P-gp) substrate and lorlatinib is a P-gp inducer.
    Bexarotene: (Major) Avoid coadministration of lorlatinib with bexarotene due to the risk of severe hepatotoxicity as well as decreased lorlatinib exposure which may reduce its efficacy. If concomitant use is unavoidable, monitor ALT, AST, and bilirubin 48 hours after initiating lorlatinib therapy and at least 3 times during the first week of treatment. If persistent grade 2 or higher hepatotoxicity occurs, discontinue either lorlatinib or bexarotene. Lorlatinib is a CYP3A substrate and bexarotene is a moderate CYP3A inducer. Coadministration with a strong CYP3A inducer decreased lorlatinib exposure by 85% and caused severe (grade 3 or 4) hepatotoxicity in 83% of patients. The effect of the concomitant use of moderate CYP3A inducers on lorlatinib pharmacokinetics or the risk of hepatotoxicity is unknown.
    Bosentan: (Major) Avoid coadministration of lorlatinib with bosentan due to the risk of severe hepatotoxicity as well as decreased lorlatinib exposure which may reduce its efficacy. If concomitant use is unavoidable, monitor ALT, AST, and bilirubin 48 hours after initiating lorlatinib therapy and at least 3 times during the first week of treatment. If persistent grade 2 or higher hepatotoxicity occurs, discontinue either lorlatinib or bosentan. Lorlatinib is a CYP3A substrate and bosentan is a moderate CYP3A inducer. Coadministration with a strong CYP3A inducer decreased lorlatinib exposure by 85% and caused severe (grade 3 or 4) hepatotoxicity in 83% of patients. The effect of the concomitant use of moderate CYP3A inducers on lorlatinib pharmacokinetics or the risk of hepatotoxicity is unknown.
    Brigatinib: (Major) Avoid coadministration of brigatinib with lorlatinib due to the risk of severe hepatotoxicity as well as decreased exposure to both drugs which may reduce efficacy. If concomitant use is unavoidable, monitor ALT, AST, and bilirubin 48 hours after initiating concomitant therapy and at least 3 times during the first week of treatment. If persistent grade 2 or higher hepatotoxicity occurs, discontinue either lorlatinib or brigatinib. After 7 days of concomitant treatment, increase the dose of brigatinib as tolerated in 30 mg increments to a maximum of twice the original dose. After discontinuation of lorlatinib, resume the brigatinib dose that was tolerated prior to initiation of lorlatinib. Both drugs are CYP3A4 substrates and moderate inducers. Coadministration with a moderate CYP3A inducer is predicted to decrease the AUC of brigatinib by approximately 50%. Coadministration with a strong CYP3A inducer decreased lorlatinib exposure by 85% and caused severe (grade 3 or 4) hepatotoxicity in 83% of patients. The effect of the concomitant use of moderate CYP3A inducers on lorlatinib pharmacokinetics or the risk of hepatotoxicity is unknown.
    Bromocriptine: (Moderate) Caution and close monitoring are advised if bromocriptine and lorlatinib are used together. Concurrent use may decrease the plasma concentrations of bromocriptine resulting in loss of efficacy. Bromocriptine is extensively metabolized by the liver via CYP3A4; lorlatinib is a moderate inducer of CYP3A4.
    Brompheniramine; Guaifenesin; Hydrocodone: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with lorlatinib is necessary; consider increasing the dose of hydrocodone as needed. It is recommended to avoid this combination when hydrocodone is being used for cough. If lorlatinib is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Concomitant use can decrease hydrocodone levels.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with lorlatinib is necessary; consider increasing the dose of hydrocodone as needed. It is recommended to avoid this combination when hydrocodone is being used for cough. If lorlatinib is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Concomitant use can decrease hydrocodone levels.
    Bupivacaine; Lidocaine: (Moderate) Monitor for decreased efficacy of lidocaine if coadministration of systemic lidocaine with lorlatinib is necessary; higher doses of lidocaine may be required. Lidocaine is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer.
    Buprenorphine: (Moderate) Monitor for decreased efficacy of buprenorphine, and potentially the onset of a withdrawal syndrome in patients who have developed physical dependence to buprenorphine, if coadministration with lorlatinib is necessary; consider increasing the dose of buprenorphine until stable drug effects are achieved. If lorlatinib is discontinued, consider a buprenorphine dose reduction and monitor for signs of respiratory depression. Buprenorphine is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer.
    Buprenorphine; Naloxone: (Moderate) Monitor for decreased efficacy of buprenorphine, and potentially the onset of a withdrawal syndrome in patients who have developed physical dependence to buprenorphine, if coadministration with lorlatinib is necessary; consider increasing the dose of buprenorphine until stable drug effects are achieved. If lorlatinib is discontinued, consider a buprenorphine dose reduction and monitor for signs of respiratory depression. Buprenorphine is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer.
    Buspirone: (Moderate) Monitor for decreased efficacy of buspirone if lorlatinib is added to a patient on a stable dosage of buspirone; a dose increase of buspirone may be needed to maintain anxiolytic activity. Buspirone is a sensitive CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer.
    Butabarbital: (Major) Avoid coadministration of lorlatinib with butabarbital due to the risk of severe hepatotoxicity as well as decreased lorlatinib exposure which may reduce its efficacy. If concomitant use is unavoidable, monitor ALT, AST, and bilirubin 48 hours after initiating lorlatinib therapy and at least 3 times during the first week of treatment. If persistent grade 2 or higher hepatotoxicity occurs, discontinue either lorlatinib or butabarbital. Lorlatinib is a CYP3A substrate and butabarbital is a moderate CYP3A inducer. Coadministration with a strong CYP3A inducer decreased lorlatinib exposure by 85% and caused severe (grade 3 or 4) hepatotoxicity in 83% of patients. The effect of the concomitant use of moderate CYP3A inducers on lorlatinib pharmacokinetics or the risk of hepatotoxicity is unknown.
    Capmatinib: (Major) Avoid coadministration of capmatinib and lorlatinib due to the risk of decreased capmatinib exposure, which may reduce its efficacy. Capmatinib is a CYP3A substrate and lorlatinib is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer decreased capmatinib exposure by 44%.
    Carbamazepine: (Severe) Coadministration of lorlatinib with carbamazepine is contraindicated due to the risk of severe hepatotoxicity as well as decreased lorlatinib exposure which may reduce its efficacy. Discontinue carbamazepine for 3 plasma half-lives prior to initiating therapy with lorlatinib. Lorlatinib is a CYP3A substrate and carbamazepine is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased lorlatinib exposure by 85% and caused severe (grade 3 or 4) hepatotoxicity in 83% of patients.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with lorlatinib is necessary; consider increasing the dose of hydrocodone as needed. It is recommended to avoid this combination when hydrocodone is being used for cough. If lorlatinib is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Concomitant use can decrease hydrocodone levels.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with lorlatinib is necessary; consider increasing the dose of hydrocodone as needed. It is recommended to avoid this combination when hydrocodone is being used for cough. If lorlatinib is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Concomitant use can decrease hydrocodone levels.
    Cariprazine: (Major) Coadministration of cariprazine with lorlatinib is not recommended as the net effect of CYP3A4 induction on cariprazine and its metabolites is unclear. Cariprazine is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Coadministration of cariprazine with CYP3A4 inducers has not been evaluated.
    Cenobamate: (Major) Avoid coadministration of lorlatinib with cenobamate due to the risk of severe hepatotoxicity as well as decreased lorlatinib exposure which may reduce its efficacy. If concomitant use is unavoidable, monitor ALT, AST, and bilirubin 48 hours after initiating concomitant therapy and at least 3 times during the first week of treatment. If persistent grade 2 or higher hepatotoxicity occurs, discontinue either lorlatinib or cenobamate. Lorlatinib is a CYP3A substrate and cenobamate is a moderate CYP3A inducer. Coadministration with a strong CYP3A inducer decreased lorlatinib exposure by 85% and caused severe (grade 3 or 4) hepatotoxicity in 83% of patients. The effect of the concomitant use of moderate CYP3A inducers on lorlatinib pharmacokinetics or the risk of hepatotoxicity is unknown.
    Ceritinib: (Major) Avoid coadministration of lorlatinib with ceritinib due to increased plasma concentrations of lorlatinib, which may increase the incidence and severity of adverse reactions. If concomitant use is unavoidable, reduce the starting dose of lorlatinib from 100 mg to 75 mg once daily, or from 75 mg to 50 mg once daily. If ceritinib is discontinued, resume the original dose of lorlatinib after 3 half-lives of ceritinib. Lorlatinib is a CYP3A substrate and ceritinib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A4 inhibitor increased lorlatinib exposure by 42%.
    Chloramphenicol: (Major) Avoid coadministration of lorlatinib with chloramphenicol due to increased plasma concentrations of lorlatinib, which may increase the incidence and severity of adverse reactions. If concomitant use is unavoidable, reduce the starting dose of lorlatinib from 100 mg to 75 mg once daily, or from 75 mg to 50 mg once daily. If chloramphenicol is discontinued, resume the original dose of lorlatinib after 3 half-lives of chloramphenicol. Lorlatinib is a CYP3A substrate and chloramphenicol is a strong CYP3A inhibitor. Coadministration with another strong CYP3A4 inhibitor increased lorlatinib exposure by 42%.
    Chlorpheniramine; Codeine: (Moderate) Monitor for reduced efficacy of codeine and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with lorlatinib is necessary; consider increasing the dose of codeine as needed. It is recommended to avoid this combination when codeine is being used for cough. If lorlatinib is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Lorlatinib is a moderate CYP3A4 inducer. Concomitant use with lorlatinib can increase norcodeine levels via increased CYP3A4 metabolism, resulting in decreased metabolism via CYP2D6 resulting in lower morphine levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) Monitor for reduced efficacy of dihydrocodeine and signs of opioid withdrawal if coadministration with lorlatinib is necessary; consider increasing the dose of dihydrocodeine as needed. If lorlatinib is discontinued, consider a dose reduction of dihydrocodeine and frequently monitor for signs or respiratory depression and sedation. Lorlatinib is a moderate inducer of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine. Concomitant use of dihydrocodeine with lorlatinib can decrease dihydrocodeine levels, resulting in less metabolism by CYP2D6 and decreased dihydromorphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: (Moderate) Monitor for reduced efficacy of dihydrocodeine and signs of opioid withdrawal if coadministration with lorlatinib is necessary; consider increasing the dose of dihydrocodeine as needed. If lorlatinib is discontinued, consider a dose reduction of dihydrocodeine and frequently monitor for signs or respiratory depression and sedation. Lorlatinib is a moderate inducer of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine. Concomitant use of dihydrocodeine with lorlatinib can decrease dihydrocodeine levels, resulting in less metabolism by CYP2D6 and decreased dihydromorphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with lorlatinib is necessary; consider increasing the dose of hydrocodone as needed. It is recommended to avoid this combination when hydrocodone is being used for cough. If lorlatinib is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Concomitant use can decrease hydrocodone levels.
    Chlorpheniramine; Hydrocodone: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with lorlatinib is necessary; consider increasing the dose of hydrocodone as needed. It is recommended to avoid this combination when hydrocodone is being used for cough. If lorlatinib is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Concomitant use can decrease hydrocodone levels.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with lorlatinib is necessary; consider increasing the dose of hydrocodone as needed. It is recommended to avoid this combination when hydrocodone is being used for cough. If lorlatinib is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Concomitant use can decrease hydrocodone levels.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with lorlatinib is necessary; consider increasing the dose of hydrocodone as needed. It is recommended to avoid this combination when hydrocodone is being used for cough. If lorlatinib is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Concomitant use can decrease hydrocodone levels.
    Clarithromycin: (Major) Avoid coadministration of lorlatinib with clarithromycin due to increased plasma concentrations of lorlatinib, which may increase the incidence and severity of adverse reactions of lorlatinib; plasma concentrations of clarithromycin may also decrease. If concomitant use is unavoidable, reduce the starting dose of lorlatinib from 100 mg to 75 mg once daily, or from 75 mg to 50 mg once daily. If clarithromycin is discontinued, resume the original dose of lorlatinib after 3 plasma half-lives of clarithromycin. Lorlatinib is a CYP3A4 substrate and moderate CYP3A4 inducer. Clarithromycin is a CYP3A4 substrate and strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased lorlatinib exposure by 42%. Inducers of CYP3A enzymes will decrease plasma concentrations of clarithromycin while increasing those of 14-OH-clarithromycin. Since the microbiological activities of clarithromycin and 14-OH-clarithromycin are different for different bacteria, the intended therapeutic effect could be impaired during concomitant administration of clarithromycin and enzyme inducers.
    Clozapine: (Moderate) Monitor for loss of clozapine effectiveness if coadministered with lorlatinib. Consideration should be given to increasing the clozapine dose if necessary. When lorlatinib is discontinued, reduce the clozapine dose based on clinical response. Lorlatinib is a moderate inducer of CYP3A4, one of the isoenzymes responsible for the metabolism of clozapine.
    Cobicistat: (Major) Avoid coadministration of lorlatinib with cobicistat due to increased plasma concentrations of lorlatinib, which may increase the incidence and severity of adverse reactions of lorlatinib; plasma concentrations of cobicistat may also decrease. If concomitant use is unavoidable, reduce the starting dose of lorlatinib from 100 mg to 75 mg once daily, or from 75 mg to 50 mg once daily. If cobicistat is discontinued, resume the original dose of lorlatinib after 3 half-lives of cobicistat. Lorlatinib is a CYP3A4 substrate and a moderate CYP3A4 inducer. Cobicistat is a CYP3A4 substrate and a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased lorlatinib exposure by 42%. Coadministration of cobicistat with moderate CYP3A4 inducers may reduce antiretroviral efficacy and increase the potential development of viral resistance.
    Cobimetinib: (Major) Avoid the concurrent use of cobimetinib with lorlatinib due to decreased cobimetinib efficacy. Cobimetinib is a CYP3A substrate, and lorlatinib is a moderate inducer of CYP3A. Based on simulations, cobimetinib exposure would decrease by 73% when coadministered with a moderate CYP3A inducer.
    Codeine: (Moderate) Monitor for reduced efficacy of codeine and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with lorlatinib is necessary; consider increasing the dose of codeine as needed. It is recommended to avoid this combination when codeine is being used for cough. If lorlatinib is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Lorlatinib is a moderate CYP3A4 inducer. Concomitant use with lorlatinib can increase norcodeine levels via increased CYP3A4 metabolism, resulting in decreased metabolism via CYP2D6 resulting in lower morphine levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Codeine; Guaifenesin: (Moderate) Monitor for reduced efficacy of codeine and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with lorlatinib is necessary; consider increasing the dose of codeine as needed. It is recommended to avoid this combination when codeine is being used for cough. If lorlatinib is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Lorlatinib is a moderate CYP3A4 inducer. Concomitant use with lorlatinib can increase norcodeine levels via increased CYP3A4 metabolism, resulting in decreased metabolism via CYP2D6 resulting in lower morphine levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Codeine; Phenylephrine; Promethazine: (Moderate) Monitor for reduced efficacy of codeine and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with lorlatinib is necessary; consider increasing the dose of codeine as needed. It is recommended to avoid this combination when codeine is being used for cough. If lorlatinib is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Lorlatinib is a moderate CYP3A4 inducer. Concomitant use with lorlatinib can increase norcodeine levels via increased CYP3A4 metabolism, resulting in decreased metabolism via CYP2D6 resulting in lower morphine levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Codeine; Promethazine: (Moderate) Monitor for reduced efficacy of codeine and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with lorlatinib is necessary; consider increasing the dose of codeine as needed. It is recommended to avoid this combination when codeine is being used for cough. If lorlatinib is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Lorlatinib is a moderate CYP3A4 inducer. Concomitant use with lorlatinib can increase norcodeine levels via increased CYP3A4 metabolism, resulting in decreased metabolism via CYP2D6 resulting in lower morphine levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Conivaptan: (Major) Avoid coadministration of lorlatinib with conivaptan due to increased plasma concentrations of lorlatinib, which may increase the incidence and severity of adverse reactions. If concomitant use is unavoidable, reduce the starting dose of lorlatinib from 100 mg to 75 mg once daily, or from 75 mg to 50 mg once daily. If conivaptan is discontinued, resume the original dose of lorlatinib after 3 half-lives of conivaptan. Lorlatinib is a CYP3A substrate and conivaptan is a strong CYP3A inhibitor. Coadministration with another strong CYP3A4 inhibitor increased lorlatinib exposure by 42%.
    Conjugated Estrogens: (Major) Women taking both estrogens and lorlatinib should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed lorlatinib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of lorlatinib. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on lorlatinib, with dose adjustments made based on clinical efficacy. Ethinyl estradiol is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Concurrent administration may increase estrogen elimination.
    Conjugated Estrogens; Bazedoxifene: (Major) Women taking both estrogens and lorlatinib should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed lorlatinib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of lorlatinib. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on lorlatinib, with dose adjustments made based on clinical efficacy. Ethinyl estradiol is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Concurrent administration may increase estrogen elimination.
    Conjugated Estrogens; Medroxyprogesterone: (Major) Women taking both estrogens and lorlatinib should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed lorlatinib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of lorlatinib. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on lorlatinib, with dose adjustments made based on clinical efficacy. Ethinyl estradiol is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Concurrent administration may increase estrogen elimination. (Major) Women taking both progestins and lorlatinib should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed lorlatinib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of lorlatinib. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. Progestins are CYP3A4 substrates and lorlatinib is a moderate CYP3A4 inducer.
    Cyclosporine: (Moderate) Closely monitor cyclosporine concentrations and adjust the dose of cyclosporine as appropriate if coadministration with lorlatinib is necessary. The dose of cyclosporine may need to be adjusted. Concurrent use may decrease cyclosporine exposure resulting in decreased efficacy. Cyclosporine is extensively metabolized by CYP3A4 and has a narrow therapeutic index; it is also a substrate of P-glycoprotein (P-gp). Lorlatinib is a weak CYP3A4 inducer and a moderate inducer of P-gp.
    Dabigatran: (Major) Coadministration of dabigatran with lorlatinib should generally be avoided due to the risk of deceased dabigatran exposure which may reduce its efficacy. Dabigatran is a P-glycoprotein (P-gp) substrate and lorlatinib is a P-gp inducer.
    Dabrafenib: (Major) Avoid coadministration of lorlatinib with dabrafenib due to the risk of severe hepatotoxicity as well as decreased lorlatinib exposure which may reduce its efficacy. If concomitant use is unavoidable, monitor ALT, AST, and bilirubin 48 hours after initiating concomitant therapy and at least 3 times during the first week of treatment. If persistent grade 2 or higher hepatotoxicity occurs, discontinue either lorlatinib or dabrafenib. Lorlatinib is a CYP3A substrate and dabrafenib is a moderate CYP3A inducer. Coadministration with a strong CYP3A inducer decreased lorlatinib exposure by 85% and caused severe (grade 3 or 4) hepatotoxicity in 83% of patients. The effect of the concomitant use of moderate CYP3A inducers on lorlatinib pharmacokinetics or the risk of hepatotoxicity is unknown.
    Daclatasvir: (Major) Increase the dose of daclatasvir to 90 mg PO once daily if coadministered with lorlatinib due to decreased daclatasvir exposure resulting in potential loss of virologic control. Daclatasvir is a CYP3A4 substrate; lorlatinib is a moderate CYP3A4 inducer. Coadministration of a moderate CYP3A4 inducer reduced the daclatasvir AUC by 63%.
    Dapsone: (Moderate) Closely monitor for a reduction in dapsone efficacy and signs of hemolytic anemia if coadministration with lorlatinib is necessary. Dapsone is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Coadministration may decrease plasma concentrations of dapsone and increase the formation of dapsone hydroxylamine (a metabolite associated with hemolysis).
    Darifenacin: (Moderate) Monitor for decreased efficacy of darifenacin if coadministration with lorlatinib is necessary. Lorlatinib is a moderate CYP3A4 inducer and darifenacin is a sensitive CYP3A4 substrate; coadministration may result in decreased plasma concentrations of darifenacin.
    Darolutamide: (Major) Avoid coadministration of darolutamide with lorlatinib due to the risk of decreased darolutamide plasma concentrations which may decrease efficacy. Lorlatinib is a P-glycoprotein (P-gp) inducer and a moderate inducer of CYP3A4; darolutamide is a CYP3A4 substrate. Concomitant use with combined P-gp and moderate CYP3A4 inducers is expected to decrease darolutamide exposure by 36% to 58%.
    Darunavir: (Major) Avoid coadministration of lorlatinib with darunavir due to increased plasma concentrations of lorlatinib, which may increase the incidence and severity of adverse reactions. Plasma concentrations of darunavir may also occur, leading to a reduction of antiviral efficacy and the potential development of viral resistance. If concomitant use is unavoidable, reduce the starting dose of lorlatinib from 100 mg to 75 mg once daily, or from 75 mg to 50 mg once daily. If darunavir is discontinued, resume the original dose of lorlatinib after 3 half-lives of darunavir. Lorlatinib is a CYP3A substrate and moderate inducer. Darunavir is a strong CYP3A inhibitor as well as a sensitive CYP3A4 substrate. Coadministration with another strong CYP3A4 inhibitor increased lorlatinib exposure by 42%.
    Darunavir; Cobicistat: (Major) Avoid coadministration of lorlatinib with cobicistat due to increased plasma concentrations of lorlatinib, which may increase the incidence and severity of adverse reactions of lorlatinib; plasma concentrations of cobicistat may also decrease. If concomitant use is unavoidable, reduce the starting dose of lorlatinib from 100 mg to 75 mg once daily, or from 75 mg to 50 mg once daily. If cobicistat is discontinued, resume the original dose of lorlatinib after 3 half-lives of cobicistat. Lorlatinib is a CYP3A4 substrate and a moderate CYP3A4 inducer. Cobicistat is a CYP3A4 substrate and a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased lorlatinib exposure by 42%. Coadministration of cobicistat with moderate CYP3A4 inducers may reduce antiretroviral efficacy and increase the potential development of viral resistance. (Major) Avoid coadministration of lorlatinib with darunavir due to increased plasma concentrations of lorlatinib, which may increase the incidence and severity of adverse reactions. Plasma concentrations of darunavir may also occur, leading to a reduction of antiviral efficacy and the potential development of viral resistance. If concomitant use is unavoidable, reduce the starting dose of lorlatinib from 100 mg to 75 mg once daily, or from 75 mg to 50 mg once daily. If darunavir is discontinued, resume the original dose of lorlatinib after 3 half-lives of darunavir. Lorlatinib is a CYP3A substrate and moderate inducer. Darunavir is a strong CYP3A inhibitor as well as a sensitive CYP3A4 substrate. Coadministration with another strong CYP3A4 inhibitor increased lorlatinib exposure by 42%.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Avoid coadministration of lorlatinib with cobicistat due to increased plasma concentrations of lorlatinib, which may increase the incidence and severity of adverse reactions of lorlatinib; plasma concentrations of cobicistat may also decrease. If concomitant use is unavoidable, reduce the starting dose of lorlatinib from 100 mg to 75 mg once daily, or from 75 mg to 50 mg once daily. If cobicistat is discontinued, resume the original dose of lorlatinib after 3 half-lives of cobicistat. Lorlatinib is a CYP3A4 substrate and a moderate CYP3A4 inducer. Cobicistat is a CYP3A4 substrate and a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased lorlatinib exposure by 42%. Coadministration of cobicistat with moderate CYP3A4 inducers may reduce antiretroviral efficacy and increase the potential development of viral resistance. (Major) Avoid coadministration of lorlatinib with darunavir due to increased plasma concentrations of lorlatinib, which may increase the incidence and severity of adverse reactions. Plasma concentrations of darunavir may also occur, leading to a reduction of antiviral efficacy and the potential development of viral resistance. If concomitant use is unavoidable, reduce the starting dose of lorlatinib from 100 mg to 75 mg once daily, or from 75 mg to 50 mg once daily. If darunavir is discontinued, resume the original dose of lorlatinib after 3 half-lives of darunavir. Lorlatinib is a CYP3A substrate and moderate inducer. Darunavir is a strong CYP3A inhibitor as well as a sensitive CYP3A4 substrate. Coadministration with another strong CYP3A4 inhibitor increased lorlatinib exposure by 42%.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Avoid coadministration of lorlatinib with ritonavir due to increased plasma concentrations of lorlatinib, which may increase the incidence and severity of adverse reactions. Ritonavir plasma concentrations may also decrease, leading to reduced efficacy and increasing the potential for viral resistance. If concomitant use is unavoidable, reduce the starting dose of lorlatinib from 100 mg to 75 mg once daily, or from 75 mg to 50 mg once daily. If ritonavir is discontinued, resume the original dose of lorlatinib after 3 half-lives of ritonavir. Lorlatinib is a CYP3A substrate and moderate inducer. Ritonavir is a CYP3A4 substrate and strong inhibitor. Coadministration with another strong CYP3A4 inhibitor increased lorlatinib exposure by 42%.
    Deflazacort: (Major) Avoid concomitant use of deflazacort and lorlatinib. Concurrent use may significantly decrease concentrations of 21-desDFZ , the active metabolite of deflazacort, resulting in loss of efficacy. Deflazacort is a CYP3A4 substrate; lorlatinib is a moderate CYP3A4 inducer. Administration of deflazacort with multiple doses of another strong CYP3A4 inducer resulted in geometric mean exposures that were approximately 95% lower compared to administration alone.
    Delavirdine: (Major) Avoid coadministration of lorlatinib with delavirdine due to increased plasma concentrations of lorlatinib, which may increase the incidence and severity of adverse reactions. Plasma concentrations of delavirdine may also decrease, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. If concomitant use is unavoidable, reduce the starting dose of lorlatinib from 100 mg to 75 mg once daily, or from 75 mg to 50 mg once daily. If delavirdine is discontinued, resume the original dose of lorlatinib after 3 half-lives of delavirdine. Lorlatinib is a CYP3A substrate and moderate inducer. Delavirdine is a strong CYP3A inhibitor as well as a CYP3A4 substrate. Coadministration with another strong CYP3A4 inhibitor increased lorlatinib exposure by 42%. Coadministration with another moderate CYP3A4 inducer decreased delavirdine exposure by 82%.
    Dexamethasone: (Major) Avoid coadministration of lorlatinib with dexamethasone due to the risk of severe hepatotoxicity as well as decreased lorlatinib exposure which may reduce its efficacy; dexamethasone plasma concentrations may also decrease. If concomitant use is unavoidable, monitor ALT, AST, and bilirubin 48 hours after initiating concomitant therapy and at least 3 times during the first week of treatment. If persistent grade 2 or higher hepatotoxicity occurs, discontinue either lorlatinib or dexamethasone. A dose adjustment of systemic dexamethasone may be necessary if lorlatinib is initiated or withdrawn during therapy. Both drugs are CYP3A substrates and moderate inducers. Coadministration with a strong CYP3A inducer decreased lorlatinib exposure by 85% and caused severe (grade 3 or 4) hepatotoxicity in 83% of patients. The effect of the concomitant use of moderate CYP3A inducers on lorlatinib pharmacokinetics or the risk of hepatotoxicity is unknown.
    Diazepam: (Moderate) Monitor for diazepam withdrawal symptoms or lack of efficacy if coadministration with lorlatinib is necessary. Lorlatinib is a moderate CYP3A4 inducer and diazepam is a primarily metabolized by CYP2C19 at low concentrations, but at higher concentrations CYP3A4 is also involved. Coadministration may result in decreased plasma concentrations of diazepam.
    Dienogest; Estradiol valerate: (Major) Women taking both estrogens and lorlatinib should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed lorlatinib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of lorlatinib. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on lorlatinib, with dose adjustments made based on clinical efficacy. Ethinyl estradiol is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Concurrent administration may increase estrogen elimination. (Major) Women taking both progestins and lorlatinib should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed lorlatinib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of lorlatinib. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. Progestins are CYP3A4 substrates and lorlatinib is a moderate CYP3A4 inducer.
    Diethylstilbestrol, DES: (Major) Women taking both estrogens and lorlatinib should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed lorlatinib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of lorlatinib. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on lorlatinib, with dose adjustments made based on clinical efficacy. Ethinyl estradiol is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Concurrent administration may increase estrogen elimination.
    Digoxin: (Moderate) Increase monitoring of serum digoxin concentrations when starting, adjusting, or discontinuing lorlatinib. Concurrent use may decrease digoxin exposure. Digoxin is a P-glycoprotein (P-gp) substrate with a narrow therapeutic index and lorlatinib is a P-gp inducer.
    Dihydrocodeine; Guaifenesin; Pseudoephedrine: (Moderate) Monitor for reduced efficacy of dihydrocodeine and signs of opioid withdrawal if coadministration with lorlatinib is necessary; consider increasing the dose of dihydrocodeine as needed. If lorlatinib is discontinued, consider a dose reduction of dihydrocodeine and frequently monitor for signs or respiratory depression and sedation. Lorlatinib is a moderate inducer of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine. Concomitant use of dihydrocodeine with lorlatinib can decrease dihydrocodeine levels, resulting in less metabolism by CYP2D6 and decreased dihydromorphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Diltiazem: (Major) Avoid coadministration of diltiazem and lorlatinib if possible due to decreased plasma concentrations of diltiazem; if unavoidable, monitor blood pressure and heart rate and adjust the diltiazem dose based on clinical response. Diltiazem is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer decreased diltiazem exposure by 69% and decreased exposure to desacetyldiltiazem by 75%.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with lorlatinib is necessary; consider increasing the dose of hydrocodone as needed. It is recommended to avoid this combination when hydrocodone is being used for cough. If lorlatinib is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Concomitant use can decrease hydrocodone levels.
    Dolutegravir: (Moderate) Monitor for decreased efficacy of dolutegravir if coadministered with lorlatinib. Concurrent use may decrease the plasma concentrations of dolutegravir leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Dolutegravir is a CYP3A4 substrate as well as a substrate of P-glycoprotein (P-gp). Lorlatinib is a moderate CYP3A4 inducer and a P-gp inducer.
    Dolutegravir; Lamivudine: (Moderate) Monitor for decreased efficacy of dolutegravir if coadministered with lorlatinib. Concurrent use may decrease the plasma concentrations of dolutegravir leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Dolutegravir is a CYP3A4 substrate as well as a substrate of P-glycoprotein (P-gp). Lorlatinib is a moderate CYP3A4 inducer and a P-gp inducer.
    Dolutegravir; Rilpivirine: (Moderate) Close clinical monitoring is advised when administering lorlatinib with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Lorlatinib is a moderate CYP3A4 inducer and rilpivirine is a CYP3A4 substrate. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response. (Moderate) Monitor for decreased efficacy of dolutegravir if coadministered with lorlatinib. Concurrent use may decrease the plasma concentrations of dolutegravir leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Dolutegravir is a CYP3A4 substrate as well as a substrate of P-glycoprotein (P-gp). Lorlatinib is a moderate CYP3A4 inducer and a P-gp inducer.
    Doravirine: (Moderate) Concurrent administration of doravirine and lorlatinib may result in decreased doravirine exposure, resulting in potential loss of virologic control. Doravirine is a CYP3A4 substrate; lorlatinib is a moderate CYP3A4 inducer.
    Doravirine; Lamivudine; Tenofovir disoproxil fumarate: (Moderate) Concurrent administration of doravirine and lorlatinib may result in decreased doravirine exposure, resulting in potential loss of virologic control. Doravirine is a CYP3A4 substrate; lorlatinib is a moderate CYP3A4 inducer.
    Doxorubicin: (Major) Avoid coadministration of doxorubicin with lorlatinib due to decreased doxorubicin plasma concentrations. Doxorubicin is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Inducers of CYP3A4 may decrease the concentration of doxorubicin and compromise the efficacy of chemotherapy.
    Dronabinol: (Moderate) Monitor for decreased efficacy of dronabinol if coadministration with lorlatinib is necessary. Dronabinol is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Formal drug interaction studies have not been conducted; however, inducers of CYP3A4 may decrease dronabinol exposure.
    Drospirenone: (Major) Women taking both progestins and lorlatinib should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed lorlatinib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of lorlatinib. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. Progestins are CYP3A4 substrates and lorlatinib is a moderate CYP3A4 inducer.
    Drospirenone; Estradiol: (Major) Women taking both estrogens and lorlatinib should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed lorlatinib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of lorlatinib. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on lorlatinib, with dose adjustments made based on clinical efficacy. Ethinyl estradiol is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Concurrent administration may increase estrogen elimination. (Major) Women taking both progestins and lorlatinib should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed lorlatinib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of lorlatinib. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. Progestins are CYP3A4 substrates and lorlatinib is a moderate CYP3A4 inducer.
    Drospirenone; Ethinyl Estradiol: (Major) Women taking both estrogens and lorlatinib should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed lorlatinib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of lorlatinib. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on lorlatinib, with dose adjustments made based on clinical efficacy. Ethinyl estradiol is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Concurrent administration may increase estrogen elimination. (Major) Women taking both progestins and lorlatinib should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed lorlatinib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of lorlatinib. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. Progestins are CYP3A4 substrates and lorlatinib is a moderate CYP3A4 inducer.
    Drospirenone; Ethinyl Estradiol; Levomefolate: (Major) Women taking both estrogens and lorlatinib should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed lorlatinib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of lorlatinib. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on lorlatinib, with dose adjustments made based on clinical efficacy. Ethinyl estradiol is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Concurrent administration may increase estrogen elimination. (Major) Women taking both progestins and lorlatinib should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed lorlatinib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of lorlatinib. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. Progestins are CYP3A4 substrates and lorlatinib is a moderate CYP3A4 inducer.
    Edoxaban: (Moderate) Monitor for decreased efficacy of edoxaban if coadministration with lorlatinib is necessary; decreased concentrations of edoxaban may occur with concomitant use. Edoxaban is a P-glycoprotein (P-gp) substrate and lorlatinib is a P-gp inducer.
    Efavirenz: (Major) Avoid coadministration of lorlatinib with efavirenz due to the potential for serious hepatotoxicity; the efficacy of both drugs may also be decreased. Plasma concentrations of efavirenz may also decrease, reducing efficacy and increasing the potential for viral resistance. If concomitant use is unavoidable, monitor AST, ALT, and bilirubin 48 hours after initiating lorlatinib and at least 3 times during the first week after initiating lorlatinib. If persistent grade 2 or higher hepatotoxicity occurs, discontinue either lorlatinib or efavirenz. Both lorlatinib and efavirenz are CYP3A4 substrates and moderate CYP3A4 inducers. Coadministration with a strong CYP3A inducer decreased lorlatinib exposure by 85% and caused severe (grade 3 or 4) hepatotoxicity in 83% of patients. The effect of the concomitant use of moderate CYP3A inducers on lorlatinib pharmacokinetics or the risk of hepatotoxicity is unknown.
    Efavirenz; Emtricitabine; Tenofovir: (Major) Avoid coadministration of lorlatinib with efavirenz due to the potential for serious hepatotoxicity; the efficacy of both drugs may also be decreased. Plasma concentrations of efavirenz may also decrease, reducing efficacy and increasing the potential for viral resistance. If concomitant use is unavoidable, monitor AST, ALT, and bilirubin 48 hours after initiating lorlatinib and at least 3 times during the first week after initiating lorlatinib. If persistent grade 2 or higher hepatotoxicity occurs, discontinue either lorlatinib or efavirenz. Both lorlatinib and efavirenz are CYP3A4 substrates and moderate CYP3A4 inducers. Coadministration with a strong CYP3A inducer decreased lorlatinib exposure by 85% and caused severe (grade 3 or 4) hepatotoxicity in 83% of patients. The effect of the concomitant use of moderate CYP3A inducers on lorlatinib pharmacokinetics or the risk of hepatotoxicity is unknown.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Major) Avoid coadministration of lorlatinib with efavirenz due to the potential for serious hepatotoxicity; the efficacy of both drugs may also be decreased. Plasma concentrations of efavirenz may also decrease, reducing efficacy and increasing the potential for viral resistance. If concomitant use is unavoidable, monitor AST, ALT, and bilirubin 48 hours after initiating lorlatinib and at least 3 times during the first week after initiating lorlatinib. If persistent grade 2 or higher hepatotoxicity occurs, discontinue either lorlatinib or efavirenz. Both lorlatinib and efavirenz are CYP3A4 substrates and moderate CYP3A4 inducers. Coadministration with a strong CYP3A inducer decreased lorlatinib exposure by 85% and caused severe (grade 3 or 4) hepatotoxicity in 83% of patients. The effect of the concomitant use of moderate CYP3A inducers on lorlatinib pharmacokinetics or the risk of hepatotoxicity is unknown.
    Elagolix: (Major) Avoid coadministration of lorlatinib with elagolix due to the risk of severe hepatotoxicity as well as decreased lorlatinib exposure which may reduce its efficacy. If concomitant use is unavoidable, monitor ALT, AST, and bilirubin 48 hours after initiating concomitant therapy and at least 3 times during the first week of treatment. If persistent grade 2 or higher hepatotoxicity occurs, discontinue either lorlatinib or elagolix. Lorlatinib is a CYP3A substrate and elagolix is a moderate CYP3A inducer. Coadministration with a strong CYP3A inducer decreased lorlatinib exposure by 85% and caused severe (grade 3 or 4) hepatotoxicity in 83% of patients. The effect of the concomitant use of moderate CYP3A inducers on lorlatinib pharmacokinetics or the risk of hepatotoxicity is unknown.
    Elagolix; Estradiol; Norethindrone acetate: (Major) Avoid coadministration of lorlatinib with elagolix due to the risk of severe hepatotoxicity as well as decreased lorlatinib exposure which may reduce its efficacy. If concomitant use is unavoidable, monitor ALT, AST, and bilirubin 48 hours after initiating concomitant therapy and at least 3 times during the first week of treatment. If persistent grade 2 or higher hepatotoxicity occurs, discontinue either lorlatinib or elagolix. Lorlatinib is a CYP3A substrate and elagolix is a moderate CYP3A inducer. Coadministration with a strong CYP3A inducer decreased lorlatinib exposure by 85% and caused severe (grade 3 or 4) hepatotoxicity in 83% of patients. The effect of the concomitant use of moderate CYP3A inducers on lorlatinib pharmacokinetics or the risk of hepatotoxicity is unknown. (Major) Women taking both estrogens and lorlatinib should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed lorlatinib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of lorlatinib. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on lorlatinib, with dose adjustments made based on clinical efficacy. Ethinyl estradiol is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Concurrent administration may increase estrogen elimination. (Major) Women taking both progestins and lorlatinib should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed lorlatinib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of lorlatinib. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. Progestins are CYP3A4 substrates and lorlatinib is a moderate CYP3A4 inducer.
    Elbasvir; Grazoprevir: (Major) Coadministration of elbasvir with lorlatinib is not recommended due to decreased exposure of elbasvir, resulting in decreased virologic response. Elbasvir is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. (Major) Coadministration of grazoprevir with lorlatinib is not recommended due to decreased exposure of grazoprevir, resulting in decreased virologic response. Grazoprevir is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer.
    Elvitegravir: (Moderate) Coadministration may result in significant decreases in the plasma concentrations of elvitegravir, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Elvitegravir is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) Avoid coadministration of lorlatinib with cobicistat due to increased plasma concentrations of lorlatinib, which may increase the incidence and severity of adverse reactions of lorlatinib; plasma concentrations of cobicistat may also decrease. If concomitant use is unavoidable, reduce the starting dose of lorlatinib from 100 mg to 75 mg once daily, or from 75 mg to 50 mg once daily. If cobicistat is discontinued, resume the original dose of lorlatinib after 3 half-lives of cobicistat. Lorlatinib is a CYP3A4 substrate and a moderate CYP3A4 inducer. Cobicistat is a CYP3A4 substrate and a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased lorlatinib exposure by 42%. Coadministration of cobicistat with moderate CYP3A4 inducers may reduce antiretroviral efficacy and increase the potential development of viral resistance. (Moderate) Coadministration may result in significant decreases in the plasma concentrations of elvitegravir, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Elvitegravir is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid coadministration of lorlatinib with cobicistat due to increased plasma concentrations of lorlatinib, which may increase the incidence and severity of adverse reactions of lorlatinib; plasma concentrations of cobicistat may also decrease. If concomitant use is unavoidable, reduce the starting dose of lorlatinib from 100 mg to 75 mg once daily, or from 75 mg to 50 mg once daily. If cobicistat is discontinued, resume the original dose of lorlatinib after 3 half-lives of cobicistat. Lorlatinib is a CYP3A4 substrate and a moderate CYP3A4 inducer. Cobicistat is a CYP3A4 substrate and a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased lorlatinib exposure by 42%. Coadministration of cobicistat with moderate CYP3A4 inducers may reduce antiretroviral efficacy and increase the potential development of viral resistance. (Moderate) Coadministration may result in significant decreases in the plasma concentrations of elvitegravir, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Elvitegravir is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer.
    Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Moderate) Close clinical monitoring is advised when administering lorlatinib with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Lorlatinib is a moderate CYP3A4 inducer and rilpivirine is a CYP3A4 substrate. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Moderate) Close clinical monitoring is advised when administering lorlatinib with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Lorlatinib is a moderate CYP3A4 inducer and rilpivirine is a CYP3A4 substrate. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response.
    Encorafenib: (Major) Avoid coadministration of encorafenib and lorlatinib due to decreased encorafenib exposure and potential loss of efficacy. Encorafenib is a CYP3A4 substrate; lorlatinib is a moderate CYP3A4 inducer. Coadministration with CYP3A4 inducers has not been studied with encorafenib; however, in clinical trials, steady-state encorafenib exposures were lower than encorafenib exposures after the first dose, suggesting CYP3A4 auto-induction.
    Entrectinib: (Major) Avoid coadministration of entrectinib with lorlatinib due to decreased entrectinib exposure and risk of decreased efficacy. Entrectinib is a CYP3A4 substrate; lorlatinib is a moderate CYP3A4 inducer. Coadministration of a moderate CYP3A4 inducer is predicted to reduce the entrectinib AUC by 56%.
    Enzalutamide: (Severe) Coadministration of lorlatinib with enzalutamide is contraindicated due to the risk of severe hepatotoxicity as well as decreased lorlatinib exposure which may reduce its efficacy. Discontinue enzalutamide for 3 plasma half-lives prior to initiating therapy with lorlatinib. Lorlatinib is a CYP3A substrate and enzalutamide is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased lorlatinib exposure by 85% and caused severe (grade 3 or 4) hepatotoxicity in 83% of patients.
    Erdafitinib: (Major) If coadministration of erdafitinib and lorlatinib is necessary at the initiation of erdafitinib therapy, administer the dose of erdafitinib as recommended (8 mg once daily with potential to increase the dose to 9 mg on days 14 to 21 based on phosphate levels and tolerability). If lorlatinib must be added to erdafitinib therapy after the initial dose increase period (days 14 to 21), increase the dose of erdafitinib up to 9 mg. If lorlatinib is discontinued, continue erdafitinib at the same dose in the absence of drug-related toxicity. Erdafitinib is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer.
    Erlotinib: (Major) Avoid coadministration of erlotinib with lorlatinib if possible, due to the risk of decreased erlotinib exposure. If coadministration is necessary, consider increasing the erlotinib dose by 50 mg increments at 2-week intervals as tolerated, to a maximum of 450 mg. Erlotinib is a CYP3A4 substrate, and lorlatinib is a moderate CYP3A4 inducer.
    Eslicarbazepine: (Major) Avoid coadministration of lorlatinib with eslicarbazepine due to the risk of severe hepatotoxicity as well as decreased lorlatinib exposure which may reduce its efficacy. If concomitant use is unavoidable, monitor ALT, AST, and bilirubin 48 hours after initiating concomitant therapy and at least 3 times during the first week of treatment. If persistent grade 2 or higher hepatotoxicity occurs, discontinue either lorlatinib or eslicarbazepine. Lorlatinib is a CYP3A substrate and eslicarbazepine is a moderate CYP3A inducer. Coadministration with a strong CYP3A inducer decreased lorlatinib exposure by 85% and caused severe (grade 3 or 4) hepatotoxicity in 83% of patients. The effect of the concomitant use of moderate CYP3A inducers on lorlatinib pharmacokinetics or the risk of hepatotoxicity is unknown.
    Esterified Estrogens: (Major) Women taking both estrogens and lorlatinib should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed lorlatinib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of lorlatinib. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on lorlatinib, with dose adjustments made based on clinical efficacy. Ethinyl estradiol is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Concurrent administration may increase estrogen elimination.
    Esterified Estrogens; Methyltestosterone: (Major) Women taking both estrogens and lorlatinib should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed lorlatinib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of lorlatinib. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on lorlatinib, with dose adjustments made based on clinical efficacy. Ethinyl estradiol is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Concurrent administration may increase estrogen elimination.
    Estradiol Cypionate; Medroxyprogesterone: (Major) Women taking both estrogens and lorlatinib should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed lorlatinib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of lorlatinib. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on lorlatinib, with dose adjustments made based on clinical efficacy. Ethinyl estradiol is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Concurrent administration may increase estrogen elimination. (Major) Women taking both progestins and lorlatinib should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed lorlatinib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of lorlatinib. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. Progestins are CYP3A4 substrates and lorlatinib is a moderate CYP3A4 inducer.
    Estradiol: (Major) Women taking both estrogens and lorlatinib should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed lorlatinib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of lorlatinib. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on lorlatinib, with dose adjustments made based on clinical efficacy. Ethinyl estradiol is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Concurrent administration may increase estrogen elimination.
    Estradiol; Levonorgestrel: (Major) Women taking both estrogens and lorlatinib should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed lorlatinib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of lorlatinib. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on lorlatinib, with dose adjustments made based on clinical efficacy. Ethinyl estradiol is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Concurrent administration may increase estrogen elimination. (Major) Women taking both progestins and lorlatinib should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed lorlatinib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of lorlatinib. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. Progestins are CYP3A4 substrates and lorlatinib is a moderate CYP3A4 inducer.
    Estradiol; Norethindrone: (Major) Women taking both estrogens and lorlatinib should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed lorlatinib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of lorlatinib. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on lorlatinib, with dose adjustments made based on clinical efficacy. Ethinyl estradiol is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Concurrent administration may increase estrogen elimination. (Major) Women taking both progestins and lorlatinib should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed lorlatinib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of lorlatinib. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. Progestins are CYP3A4 substrates and lorlatinib is a moderate CYP3A4 inducer.
    Estradiol; Norgestimate: (Major) Women taking both estrogens and lorlatinib should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed lorlatinib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of lorlatinib. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on lorlatinib, with dose adjustments made based on clinical efficacy. Ethinyl estradiol is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Concurrent administration may increase estrogen elimination. (Major) Women taking both progestins and lorlatinib should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed lorlatinib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of lorlatinib. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. Progestins are CYP3A4 substrates and lorlatinib is a moderate CYP3A4 inducer.
    Estradiol; Progesterone: (Major) Women taking both estrogens and lorlatinib should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed lorlatinib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of lorlatinib. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on lorlatinib, with dose adjustments made based on clinical efficacy. Ethinyl estradiol is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Concurrent administration may increase estrogen elimination. (Major) Women taking both progestins and lorlatinib should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed lorlatinib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of lorlatinib. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. Progestins are CYP3A4 substrates and lorlatinib is a moderate CYP3A4 inducer.
    Estrogens: (Major) Women taking both estrogens and lorlatinib should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed lorlatinib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of lorlatinib. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on lorlatinib, with dose adjustments made based on clinical efficacy. Ethinyl estradiol is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Concurrent administration may increase estrogen elimination.
    Estropipate: (Major) Women taking both estrogens and lorlatinib should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed lorlatinib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of lorlatinib. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on lorlatinib, with dose adjustments made based on clinical efficacy. Ethinyl estradiol is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Concurrent administration may increase estrogen elimination.
    Ethinyl Estradiol: (Major) Women taking both estrogens and lorlatinib should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed lorlatinib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of lorlatinib. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on lorlatinib, with dose adjustments made based on clinical efficacy. Ethinyl estradiol is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Concurrent administration may increase estrogen elimination.
    Ethinyl Estradiol; Desogestrel: (Major) Women taking both estrogens and lorlatinib should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed lorlatinib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of lorlatinib. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on lorlatinib, with dose adjustments made based on clinical efficacy. Ethinyl estradiol is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Concurrent administration may increase estrogen elimination. (Major) Women taking both progestins and lorlatinib should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed lorlatinib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of lorlatinib. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. Progestins are CYP3A4 substrates and lorlatinib is a moderate CYP3A4 inducer.
    Ethinyl Estradiol; Ethynodiol Diacetate: (Major) Women taking both estrogens and lorlatinib should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed lorlatinib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of lorlatinib. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on lorlatinib, with dose adjustments made based on clinical efficacy. Ethinyl estradiol is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Concurrent administration may increase estrogen elimination. (Major) Women taking both progestins and lorlatinib should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed lorlatinib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of lorlatinib. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. Progestins are CYP3A4 substrates and lorlatinib is a moderate CYP3A4 inducer.
    Ethinyl Estradiol; Etonogestrel: (Major) Women taking both estrogens and lorlatinib should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed lorlatinib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of lorlatinib. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on lorlatinib, with dose adjustments made based on clinical efficacy. Ethinyl estradiol is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Concurrent administration may increase estrogen elimination. (Major) Women taking both progestins and lorlatinib should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed lorlatinib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of lorlatinib. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. Progestins are CYP3A4 substrates and lorlatinib is a moderate CYP3A4 inducer.
    Ethinyl Estradiol; Levonorgestrel: (Major) Women taking both estrogens and lorlatinib should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed lorlatinib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of lorlatinib. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on lorlatinib, with dose adjustments made based on clinical efficacy. Ethinyl estradiol is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Concurrent administration may increase estrogen elimination. (Major) Women taking both progestins and lorlatinib should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed lorlatinib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of lorlatinib. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. Progestins are CYP3A4 substrates and lorlatinib is a moderate CYP3A4 inducer.
    Ethinyl Estradiol; Levonorgestrel; Ferrous bisglycinate: (Major) Women taking both estrogens and lorlatinib should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed lorlatinib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of lorlatinib. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on lorlatinib, with dose adjustments made based on clinical efficacy. Ethinyl estradiol is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Concurrent administration may increase estrogen elimination. (Major) Women taking both progestins and lorlatinib should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed lorlatinib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of lorlatinib. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. Progestins are CYP3A4 substrates and lorlatinib is a moderate CYP3A4 inducer.
    Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (Major) Women taking both estrogens and lorlatinib should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed lorlatinib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of lorlatinib. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on lorlatinib, with dose adjustments made based on clinical efficacy. Ethinyl estradiol is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Concurrent administration may increase estrogen elimination. (Major) Women taking both progestins and lorlatinib should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed lorlatinib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of lorlatinib. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. Progestins are CYP3A4 substrates and lorlatinib is a moderate CYP3A4 inducer.
    Ethinyl Estradiol; Norelgestromin: (Major) Women taking both estrogens and lorlatinib should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed lorlatinib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of lorlatinib. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on lorlatinib, with dose adjustments made based on clinical efficacy. Ethinyl estradiol is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Concurrent administration may increase estrogen elimination. (Major) Women taking both progestins and lorlatinib should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed lorlatinib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of lorlatinib. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. Progestins are CYP3A4 substrates and lorlatinib is a moderate CYP3A4 inducer.
    Ethinyl Estradiol; Norethindrone Acetate: (Major) Women taking both estrogens and lorlatinib should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed lorlatinib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of lorlatinib. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on lorlatinib, with dose adjustments made based on clinical efficacy. Ethinyl estradiol is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Concurrent administration may increase estrogen elimination. (Major) Women taking both progestins and lorlatinib should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed lorlatinib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of lorlatinib. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. Progestins are CYP3A4 substrates and lorlatinib is a moderate CYP3A4 inducer.
    Ethinyl Estradiol; Norethindrone Acetate; Ferrous fumarate: (Major) Women taking both estrogens and lorlatinib should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed lorlatinib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of lorlatinib. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on lorlatinib, with dose adjustments made based on clinical efficacy. Ethinyl estradiol is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Concurrent administration may increase estrogen elimination. (Major) Women taking both progestins and lorlatinib should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed lorlatinib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of lorlatinib. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. Progestins are CYP3A4 substrates and lorlatinib is a moderate CYP3A4 inducer.
    Ethinyl Estradiol; Norethindrone: (Major) Women taking both estrogens and lorlatinib should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed lorlatinib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of lorlatinib. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on lorlatinib, with dose adjustments made based on clinical efficacy. Ethinyl estradiol is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Concurrent administration may increase estrogen elimination. (Major) Women taking both progestins and lorlatinib should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed lorlatinib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of lorlatinib. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. Progestins are CYP3A4 substrates and lorlatinib is a moderate CYP3A4 inducer.
    Ethinyl Estradiol; Norethindrone; Ferrous fumarate: (Major) Women taking both estrogens and lorlatinib should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed lorlatinib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of lorlatinib. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on lorlatinib, with dose adjustments made based on clinical efficacy. Ethinyl estradiol is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Concurrent administration may increase estrogen elimination. (Major) Women taking both progestins and lorlatinib should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed lorlatinib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of lorlatinib. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. Progestins are CYP3A4 substrates and lorlatinib is a moderate CYP3A4 inducer.
    Ethinyl Estradiol; Norgestimate: (Major) Women taking both estrogens and lorlatinib should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed lorlatinib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of lorlatinib. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on lorlatinib, with dose adjustments made based on clinical efficacy. Ethinyl estradiol is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Concurrent administration may increase estrogen elimination. (Major) Women taking both progestins and lorlatinib should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed lorlatinib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of lorlatinib. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. Progestins are CYP3A4 substrates and lorlatinib is a moderate CYP3A4 inducer.
    Ethinyl Estradiol; Norgestrel: (Major) Women taking both estrogens and lorlatinib should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed lorlatinib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of lorlatinib. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on lorlatinib, with dose adjustments made based on clinical efficacy. Ethinyl estradiol is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Concurrent administration may increase estrogen elimination. (Major) Women taking both progestins and lorlatinib should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed lorlatinib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of lorlatinib. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. Progestins are CYP3A4 substrates and lorlatinib is a moderate CYP3A4 inducer.
    Etonogestrel: (Major) Women taking both progestins and lorlatinib should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed lorlatinib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of lorlatinib. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. Progestins are CYP3A4 substrates and lorlatinib is a moderate CYP3A4 inducer.
    Etravirine: (Major) Avoid coadministration of lorlatinib with etravirine due to the risk of severe hepatotoxicity as well as decreased lorlatinib exposure which may reduce its efficacy. Plasma concentrations of etravirine may also decrease, leading to reduced efficacy and increasing the potential for viral resistance. If concomitant use is unavoidable, monitor ALT, AST, and bilirubin 48 hours after initiating concomitant therapy and at least 3 times during the first week of treatment. If persistent grade 2 or higher hepatotoxicity occurs, discontinue either lorlatinib or etravirine. Both drugs are CYP3A substrates and moderate inducers. Coadministration with a strong CYP3A inducer decreased lorlatinib exposure by 85% and caused severe (grade 3 or 4) hepatotoxicity in 83% of patients. The effect of the concomitant use of moderate CYP3A inducers on lorlatinib pharmacokinetics or the risk of hepatotoxicity is unknown.
    Fedratinib: (Major) Avoid coadministration of fedratinib with lorlatinib as concurrent use may decrease fedratinib exposure which may result in decreased therapeutic response. Fedratinib is a CYP3A4 substrate; lorlatinib is a moderate CYP3A4 inducer. The coadministration of fedratinib with a moderate CYP3A4 inducer has not been evaluated.
    Fentanyl: (Moderate) Consider an increased dose of fentanyl and monitor for evidence of opioid withdrawal if coadministration with lorlatinib is necessary. If lorlatinib is discontinued, consider reducing the fentanyl dosage and monitor for evidence of respiratory depression. Coadministration of a moderate CYP3A4 inducer like lorlatinib with fentanyl, a CYP3A4 substrate, may decrease exposure to fentanyl resulting in decreased efficacy or onset of withdrawal symptoms in a patient who has developed physical dependence to fentanyl. Fentanyl plasma concentrations will increase once the inducer is stopped, which may increase or prolong the therapeutic and adverse effects, including serious respiratory depression.
    Flibanserin: (Major) Coadministration of flibanserin with lorlatinib is not recommended due to decreased plasma concentrations of flibanserin. Flibanserin is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer decreased flibanserin exposure by approximately 21%.
    Flurazepam: (Moderate) Monitor for withdrawal symptoms or lack of efficacy if coadministration of flurazepam with lorlatinib is necessary. Flurazepam is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Coadministration may decrease plasma concentrations of flurazepam.
    Fosamprenavir: (Major) Avoid coadministration of lorlatinib with fosamprenavir due to increased plasma concentrations of lorlatinib, which may increase the incidence and severity of adverse reactions. Plasma concentrations of fosamprenavir may also decrease, leading to reduced efficacy and increasing the potential for viral resistance. If concomitant use is unavoidable, reduce the starting dose of lorlatinib from 100 mg to 75 mg once daily, or from 75 mg to 50 mg once daily. If fosamprenavir is discontinued, resume the original dose of lorlatinib after 3 half-lives of fosamprenavir. Lorlatinib is a CYP3A substrate and moderate inducer. Fosamprenavir is a CYP3A4 substrate as well as a strong inhibitor. Coadministration with another strong CYP3A4 inhibitor increased lorlatinib exposure by 42%.
    Fosphenytoin: (Severe) Coadministration of lorlatinib with fosphenytoin is contraindicated due to the risk of severe hepatotoxicity as well as decreased lorlatinib exposure which may reduce its efficacy. Discontinue fosphenytoin for 3 plasma half-lives prior to initiating therapy with lorlatinib. Lorlatinib is a CYP3A substrate and fosphenytoin is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased lorlatinib exposure by 85% and caused severe (grade 3 or 4) hepatotoxicity in 83% of patients.
    Glasdegib: (Major) Avoid coadministration of glasdegib and lorlatinib due to the potential for decreased glasdegib exposure and risk of decreased efficacy. If concurrent use cannot be avoided, increase the glasdegib dosage (i.e., from 100 mg PO daily to 200 mg PO daily; or from 50 mg PO daily to 100 mg PO daily). Resume the previous dose of glasdegib after lorlatinib has been discontinued for 7 days. Glasdegib is a CYP3A4 substrate; lorlatinib is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer was predicted to decrease the glasdegib AUC value by 55%.
    Glecaprevir; Pibrentasvir: (Moderate) Caution is advised with coadministration of glecaprevir and lorlatinib as decreased plasma concentrations of glecaprevir may occur resulting in the potential loss of efficacy of glecaprevir. Glecaprevir is a substrate of CYP3A4 and P-glycoprotein (P-gp). Lorlatinib is a moderate CYP3A4 inducer as well as an inducer of P-gp. (Moderate) Caution is advised with coadministration of pibrentasvir and lorlatinib as decreased plasma concentrations of pibrentasvir may occur resulting in the potential loss of efficacy of pibrentasvir. Pibrentasvir is a substrate of P-glycoprotein (P-gp) and lorlatinib is a P-gp inducer.
    Grapefruit juice: (Major) Advise patients to avoid grapefruit and grapefruit juice due to increased lorlatinib exposure resulting in treatment-related adverse events. Lorlatinib is a CYP3A4 substrate; grapefruit is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased capmatinib exposure by 42%.
    Guaifenesin; Hydrocodone: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with lorlatinib is necessary; consider increasing the dose of hydrocodone as needed. It is recommended to avoid this combination when hydrocodone is being used for cough. If lorlatinib is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Concomitant use can decrease hydrocodone levels.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with lorlatinib is necessary; consider increasing the dose of hydrocodone as needed. It is recommended to avoid this combination when hydrocodone is being used for cough. If lorlatinib is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Concomitant use can decrease hydrocodone levels.
    Guanfacine: (Major) A dose increase of extended-release (ER) guanfacine should be considered if coadministration with lorlatinib is necessary. Consider doubling the recommended dose of guanfacine if therapy is added to a patient already taking lorlatinib; increase the dose of guanfacine over 1 to 2 weeks if lorlatinib therapy is added to a patient already taking guanfacine. Specific recommendations for immediate-release (IR) guanfacine are not available. Guanfacine is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer.
    Homatropine; Hydrocodone: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with lorlatinib is necessary; consider increasing the dose of hydrocodone as needed. It is recommended to avoid this combination when hydrocodone is being used for cough. If lorlatinib is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Concomitant use can decrease hydrocodone levels.
    Hydrocodone: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with lorlatinib is necessary; consider increasing the dose of hydrocodone as needed. It is recommended to avoid this combination when hydrocodone is being used for cough. If lorlatinib is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Concomitant use can decrease hydrocodone levels.
    Hydrocodone; Ibuprofen: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with lorlatinib is necessary; consider increasing the dose of hydrocodone as needed. It is recommended to avoid this combination when hydrocodone is being used for cough. If lorlatinib is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Concomitant use can decrease hydrocodone levels.
    Hydrocodone; Phenylephrine: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with lorlatinib is necessary; consider increasing the dose of hydrocodone as needed. It is recommended to avoid this combination when hydrocodone is being used for cough. If lorlatinib is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Concomitant use can decrease hydrocodone levels.
    Hydrocodone; Potassium Guaiacolsulfonate: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with lorlatinib is necessary; consider increasing the dose of hydrocodone as needed. It is recommended to avoid this combination when hydrocodone is being used for cough. If lorlatinib is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Concomitant use can decrease hydrocodone levels.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with lorlatinib is necessary; consider increasing the dose of hydrocodone as needed. It is recommended to avoid this combination when hydrocodone is being used for cough. If lorlatinib is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Concomitant use can decrease hydrocodone levels.
    Hydrocodone; Pseudoephedrine: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with lorlatinib is necessary; consider increasing the dose of hydrocodone as needed. It is recommended to avoid this combination when hydrocodone is being used for cough. If lorlatinib is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Concomitant use can decrease hydrocodone levels.
    Hydroxyprogesterone: (Major) Women taking both progestins and lorlatinib should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed lorlatinib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of lorlatinib. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. Progestins are CYP3A4 substrates and lorlatinib is a moderate CYP3A4 inducer.
    Ibuprofen; Oxycodone: (Moderate) Monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with lorlatinib is necessary; consider increasing the dose of oxycodone as needed. If lorlatinib is discontinued, consider a dose reduction of lorlatinib and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease oxycodone concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Idelalisib: (Major) Avoid coadministration of lorlatinib with idelalisib due to increased plasma concentrations of lorlatinib, which may increase the incidence and severity of adverse reactions. If concomitant use is unavoidable, reduce the starting dose of lorlatinib from 100 mg to 75 mg once daily, or from 75 mg to 50 mg once daily. If idelalisib is discontinued, resume the original dose of lorlatinib after 3 half-lives of idelalisib. Lorlatinib is a CYP3A substrate and idelalisib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A4 inhibitor increased lorlatinib exposure by 42%.
    Ifosfamide: (Moderate) Closely monitor for increased ifosfamide-related toxicities (e.g., neurotoxicity, nephrotoxicity) if coadministration with lorlatinib is necessary; consider adjusting the dose of ifosfamide as clinically appropriate. Ifosfamide is metabolized to its active alkylating metabolites by CYP3A4; lorlatinib is a moderate CYP3A4 inducer. Concomitant use may increase the formation of the neurotoxic/nephrotoxic ifosfamide metabolite, chloroacetaldehyde.
    Indinavir: (Major) Avoid coadministration of lorlatinib with indinavir due to increased plasma concentrations of lorlatinib, which may increase the incidence and severity of adverse reactions. Plasma concentrations of indinavir may also decrease, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. If concomitant use is unavoidable, reduce the starting dose of lorlatinib from 100 mg to 75 mg once daily, or from 75 mg to 50 mg once daily. Although specific indinavir recommendations are unavailable for use with lorlatinib, an increased dose is recommended (i.e., 1,000 mg PO every 8 hours) when coadministered with other moderate CYP3A4 inducers. If indinavir is discontinued, resume the original dose of lorlatinib after 3 half-lives of indinavir. Lorlatinib is a CYP3A substrate and moderate inducer. Indinavir is a CYP3A substrate and strong inhibitor. Coadministration with another strong CYP3A4 inhibitor increased lorlatinib exposure by 42%. Coadministration with another moderate CYP3A4 inducer decreased indinavir exposure by up to 46%.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Severe) Coadministration of lorlatinib with rifampin is contraindicated due to the risk of severe hepatotoxicity as well as decreased lorlatinib exposure which may reduce its efficacy. Discontinue rifampin for 3 plasma half-lives prior to initiating therapy with lorlatinib. Lorlatinib is a CYP3A substrate and rifampin is a strong CYP3A inducer. Coadministration with rifampin decreased lorlatinib exposure by 85%. Additionally, severe hepatotoxicity occurred, with 50% of patients experiencing grade 4 elevations of ALT/AST, 33% with grade 3 AST/ALT elevations, and 8% with grade 2 ALT/AST elevations. Grade 2 to 4 increases in ALT/AST occurred within 3 days of concomitant use and returned to normal limits within 7 to 34 days (median, 15 days).
    Isoniazid, INH; Rifampin: (Severe) Coadministration of lorlatinib with rifampin is contraindicated due to the risk of severe hepatotoxicity as well as decreased lorlatinib exposure which may reduce its efficacy. Discontinue rifampin for 3 plasma half-lives prior to initiating therapy with lorlatinib. Lorlatinib is a CYP3A substrate and rifampin is a strong CYP3A inducer. Coadministration with rifampin decreased lorlatinib exposure by 85%. Additionally, severe hepatotoxicity occurred, with 50% of patients experiencing grade 4 elevations of ALT/AST, 33% with grade 3 AST/ALT elevations, and 8% with grade 2 ALT/AST elevations. Grade 2 to 4 increases in ALT/AST occurred within 3 days of concomitant use and returned to normal limits within 7 to 34 days (median, 15 days).
    Isradipine: (Moderate) Monitor for decreased efficacy of isradipine if coadministration with lorlatinib is necessary. Isradipine is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Coadministration may decrease isradipine plasma concentrations.
    Itraconazole: (Major) Avoid coadministration of lorlatinib with itraconazole if possible due to the increased risk of lorlatinib-related adverse reactions; itraconazole exposure may also decrease. If concomitant use is unavoidable, reduce the starting dose of lorlatinib from 100 mg to 75 mg once daily, or from 75 mg to 50 mg once daily. If itraconazole is discontinued, resume the original dose of lorlatinib after 3 half-lives of itraconazole. Lorlatinib is a CYP3A substrate and moderate inducer. Itraconazole is a CYP3A substrate and strong inhibitor. Coadministration with itraconazole increased lorlatinib exposure by 42%.
    Ivabradine: (Major) Avoid coadministration of ivabradine and lorlatinib due to decreased plasma concentrations of ivabradine. Ivabradine is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer.
    Ketoconazole: (Major) Avoid coadministration of lorlatinib with ketoconazole due to increased plasma concentrations of lorlatinib, which may increase the incidence and severity of adverse reactions of lorlatinib. If concomitant use is unavoidable, decrease the starting dose of lorlatinib from 100 mg PO once daily to 75 mg PO once daily. In patients who have already had a dose reduction to 75 mg PO once daily due to adverse reactions, reduce the dose of lorlatinib to 50 mg PO once daily. If ketoconazole is discontinued, increase the dose of lorlatinib after 3 plasma half-lives of ketoconazole to the dose that was used before starting ketoconazole. Lorlatinib is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the AUC and Cmax of lorlatinib by 42% and 24%, respectively.
    Ledipasvir; Sofosbuvir: (Major) Coadministration of ledipasvir with lorlatinib is not recommended. Taking these drugs together may decrease ledipasvir plasma concentrations, potentially resulting in loss of antiviral efficacy. Ledipasvir is a P-glycoprotein (P-gp) substrate and lorlatinib is a P-gp inducer.
    Lefamulin: (Major) Avoid coadministration of lefamulin with lorlatinib unless the benefits outweigh the risks as concurrent use may decrease lefamulin exposure and efficacy. Lefamulin is a CYP3A4 substrate and P-glycoprotein (P-gp) substrate. Lorlatinib is a moderate CYP3A inducer as well as a P-gp inducer. Coadministration of a combined P-gp and strong CYP3A4 inducer decreased the mean AUC of lefamulin oral tablets by 72% and the mean AUC of lefamulin injection by 28%.
    Lemborexant: (Major) Avoid coadministration of lemborexant and lorlatinib as concurrent use may decrease lemborexant exposure which may reduce efficacy. Lemborexant is a CYP3A4 substrate; lorlatinib is a moderate CYP3A4 inducer.
    Letermovir: (Major) Concurrent administration of letermovir and lorlatinib is not recommended due to the risk of decreased lorlatinib exposure which may reduce its efficacy. Letermovir is a P-glycoprotein (P-gp) substrate and lorlatinib is a P-gp inducer.
    Leuprolide; Norethindrone: (Major) Women taking both progestins and lorlatinib should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed lorlatinib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of lorlatinib. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. Progestins are CYP3A4 substrates and lorlatinib is a moderate CYP3A4 inducer.
    Levonorgestrel: (Major) Women taking both progestins and lorlatinib should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed lorlatinib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of lorlatinib. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. Progestins are CYP3A4 substrates and lorlatinib is a moderate CYP3A4 inducer.
    Lidocaine: (Moderate) Monitor for decreased efficacy of lidocaine if coadministration of systemic lidocaine with lorlatinib is necessary; higher doses of lidocaine may be required. Lidocaine is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer.
    Lidocaine; Prilocaine: (Moderate) Monitor for decreased efficacy of lidocaine if coadministration of systemic lidocaine with lorlatinib is necessary; higher doses of lidocaine may be required. Lidocaine is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer.
    Lopinavir; Ritonavir: (Major) Avoid coadministration of lorlatinib with ritonavir due to increased plasma concentrations of lorlatinib, which may increase the incidence and severity of adverse reactions. Ritonavir plasma concentrations may also decrease, leading to reduced efficacy and increasing the potential for viral resistance. If concomitant use is unavoidable, reduce the starting dose of lorlatinib from 100 mg to 75 mg once daily, or from 75 mg to 50 mg once daily. If ritonavir is discontinued, resume the original dose of lorlatinib after 3 half-lives of ritonavir. Lorlatinib is a CYP3A substrate and moderate inducer. Ritonavir is a CYP3A4 substrate and strong inhibitor. Coadministration with another strong CYP3A4 inhibitor increased lorlatinib exposure by 42%. (Moderate) Concurrent administration of lorlatinib with lopinavir may result in decreased lopinavir plasma concentrations; thereby, reducing efficacy and increasing the potential for viral resistance. Lorlatinib is a moderate CYP3A4 inducer. Lopinavir is a CYP3A4 substrate.
    Lumacaftor; Ivacaftor: (Severe) Coadministration of lorlatinib with lumacaftor; ivacaftor is contraindicated due to the risk severe hepatotoxicity as well as decreased lorlatinib exposure which may reduce its efficacy. Discontinue lumacaftor; ivacaftor for 3 plasma half-lives prior to initiating therapy with lorlatinib. Lorlatinib is a CYP3A substrate and lumacaftor is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased lorlatinib exposure by 85% and caused severe (grade 3 or 4) hepatotoxicity in 83% of patients.
    Lumacaftor; Ivacaftor: (Severe) Coadministration of lorlatinib with lumacaftor; ivacaftor is contraindicated due to the risk severe hepatotoxicity as well as decreased lorlatinib exposure which may reduce its efficacy. Discontinue lumacaftor; ivacaftor for 3 plasma half-lives prior to initiating therapy with lorlatinib. Lorlatinib is a CYP3A substrate and lumacaftor is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased lorlatinib exposure by 85% and caused severe (grade 3 or 4) hepatotoxicity in 83% of patients.
    Lumateperone: (Major) Avoid coadministration of lumateperone and lorlatinib as concurrent use may decrease lumateperone exposure which may reduce efficacy. Lumateperone is a CYP3A4 substrate; lorlatinib is a moderate CYP3A4 inducer.
    Lurasidone: (Moderate) If lurasidone is used with lorlatinib, it may be necessary to increase the lurasidone dose after chronic treatment (7 days or more) with lorlatinib. Concurrent use may lead to a decrease in efficacy of lurasidone. Lorlatinib is a moderate CYP3A4 inducer; lurasidone is a CYP3A4 substrate.
    Lurbinectedin: (Major) Avoid coadministration of lurbinectedin and lorlatinib due to the risk of decreased lurbinectedin exposure which may reduce its efficacy. Lurbinectedin is a CYP3A substrate and lorlatinib is a moderate CYP3A inducer.
    Maraviroc: (Moderate) Monitor for a decrease in the efficacy of maraviroc if coadministration with lorlatinib is necessary. Maraviroc is a CYP3A4 substrate and a P-glycoprotein (P-gp) substrate. Lorlatinib is a moderate CYP3A4 inducer as well as a P-gp inducer.
    Medroxyprogesterone: (Major) Women taking both progestins and lorlatinib should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed lorlatinib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of lorlatinib. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. Progestins are CYP3A4 substrates and lorlatinib is a moderate CYP3A4 inducer.
    Mefloquine: (Moderate) Use mefloquine with caution if coadministration with lorlatinib is necessary as concurrent use may decrease mefloquine exposure and efficacy. Mefloquine is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer.
    Mephobarbital: (Severe) Coadministration of lorlatinib with mephobarbital is contraindicated due to the risk of severe hepatotoxicity as well as decreased lorlatinib exposure which may reduce its efficacy. Discontinue mephobarbital for 3 plasma half-lives prior to initiating therapy with lorlatinib. Lorlatinib is a CYP3A substrate and mephobarbital is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased lorlatinib exposure by 85% and caused severe (grade 3 or 4) hepatotoxicity in 83% of patients.
    Mestranol; Norethindrone: (Major) Women taking both estrogens and lorlatinib should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed lorlatinib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of lorlatinib. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on lorlatinib, with dose adjustments made based on clinical efficacy. Ethinyl estradiol is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Concurrent administration may increase estrogen elimination. (Major) Women taking both progestins and lorlatinib should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed lorlatinib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of lorlatinib. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. Progestins are CYP3A4 substrates and lorlatinib is a moderate CYP3A4 inducer.
    Methadone: (Moderate) Monitor for reduced efficacy of methadone and signs of opioid withdrawal if coadministration with lorlatinib is necessary; these effects may be more pronounced with concomitant use of drugs that can induce multiple CYP enzymes. Consider increasing the dose of methadone as needed. If lorlatinib is discontinued, consider a dose reduction of methadone and frequently monitor for signs or respiratory depression and sedation. Methadone is a substrate of CYP2C9, CYP2C19, and CYP3A4; lorlatinib is a moderate CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease methadone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Methohexital: (Major) Avoid coadministration of lorlatinib with methohexital due to the risk of severe hepatotoxicity as well as decreased lorlatinib exposure which may reduce its efficacy. If concomitant use is unavoidable, monitor ALT, AST, and bilirubin 48 hours after initiating lorlatinib therapy and at least 3 times during the first week of treatment. If persistent grade 2 or higher hepatotoxicity occurs, discontinue either lorlatinib or methohexital. Lorlatinib is a CYP3A substrate and methohexital is a moderate CYP3A inducer. Coadministration with a strong CYP3A inducer decreased lorlatinib exposure by 85% and caused severe (grade 3 or 4) hepatotoxicity in 83% of patients. The effect of the concomitant use of moderate CYP3A inducers on lorlatinib pharmacokinetics or the risk of hepatotoxicity is unknown.
    Midazolam: (Moderate) Monitor for withdrawal symptoms or lack of midazolam efficacy if coadministration with lorlatinib is necessary. Midazolam is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Coadministration with lorlatinib decreased the AUC and Cmax of oral midazolam by 64% and 50%, respectively.
    Mifepristone: (Major) Avoid coadministration of lorlatinib with mifepristone due to increased plasma concentrations of lorlatinib, which may increase the incidence and severity of adverse reactions. If concomitant use is unavoidable, reduce the starting dose of lorlatinib from 100 mg to 75 mg once daily, or from 75 mg to 50 mg once daily. If mifepristone is discontinued, resume the original dose of lorlatinib after 3 half-lives of mifepristone. Lorlatinib is a CYP3A substrate and mifepristone is a strong CYP3A inhibitor. Coadministration with another strong CYP3A4 inhibitor increased lorlatinib exposure by 42%. The clinical significance of this interaction with the short-term use of mifepristone for termination of pregnancy is unknown.
    Mitotane: (Severe) Coadministration of lorlatinib with mitotane is contraindicated due to the risk of severe hepatotoxicity as well as decreased lorlatinib exposure which may reduce its efficacy. Discontinue mitotane for 3 plasma half-lives prior to initiating therapy with lorlatinib. Lorlatinib is a CYP3A substrate and mitotane is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased lorlatinib exposure by 85% and caused severe (grade 3 or 4) hepatotoxicity in 83% of patients.
    Modafinil: (Major) Avoid coadministration of lorlatinib with modafinil due to the risk of severe hepatotoxicity as well as decreased lorlatinib exposure which may reduce its efficacy. If concomitant use is unavoidable, monitor ALT, AST, and bilirubin 48 hours after initiating concomitant therapy and at least 3 times during the first week of treatment. If persistent grade 2 or higher hepatotoxicity occurs, discontinue either lorlatinib or modafinil. Lorlatinib is a CYP3A substrate and modafinil is a moderate CYP3A inducer. Coadministration with a strong CYP3A inducer decreased lorlatinib exposure by 85% and caused severe (grade 3 or 4) hepatotoxicity in 83% of patients. The effect of the concomitant use of moderate CYP3A inducers on lorlatinib pharmacokinetics or the risk of hepatotoxicity is unknown.
    Nafcillin: (Major) Avoid coadministration of lorlatinib with nafcillin due to the risk of severe hepatotoxicity as well as decreased lorlatinib exposure which may reduce its efficacy. If concomitant use is unavoidable, monitor ALT, AST, and bilirubin 48 hours after initiating concomitant therapy and at least 3 times during the first week of treatment. If persistent grade 2 or higher hepatotoxicity occurs, discontinue either lorlatinib or nafcillin. Lorlatinib is a CYP3A substrate and nafcillin is a moderate CYP3A inducer. Coadministration with a strong CYP3A inducer decreased lorlatinib exposure by 85% and caused severe (grade 3 or 4) hepatotoxicity in 83% of patients. The effect of the concomitant use of moderate CYP3A inducers on lorlatinib pharmacokinetics or the risk of hepatotoxicity is unknown.
    Nanoparticle Albumin-Bound Paclitaxel: (Moderate) Monitor for decreased efficacy of nab-paclitaxel if coadministration with loraltinib is necessary due to the risk of decreased plasma concentrations of paclitaxel. Nab-paclitaxel is a CYP3A4 substrate and loraltinib is a moderate CYP3A4 inducer.
    Nefazodone: (Major) Avoid coadministration of lorlatinib with nefazodone due to increased plasma concentrations of lorlatinib, which may increase the incidence and severity of adverse reactions. If concomitant use is unavoidable, reduce the starting dose of lorlatinib from 100 mg to 75 mg once daily, or from 75 mg to 50 mg once daily. If nefazodone is discontinued, resume the original dose of lorlatinib after 3 half-lives of nefazodone. Lorlatinib is a CYP3A substrate and nefazodone is a strong CYP3A inhibitor. Coadministration with another strong CYP3A4 inhibitor increased lorlatinib exposure by 42%.
    Nelfinavir: (Major) Avoid coadministration of lorlatinib with nelfinavir due to increased plasma concentrations of lorlatinib, which may increase the incidence and severity of adverse reactions. Plasma concentrations of nelfinavir may also decrease, leading to reduced efficacy and increasing the potential for viral resistance. If concomitant use is unavoidable, reduce the starting dose of lorlatinib from 100 mg to 75 mg once daily, or from 75 mg to 50 mg once daily. If nelfinavir is discontinued, resume the original dose of lorlatinib after 3 half-lives of nelfinavir. Lorlatinib is a CYP3A substrate and moderate inducer. Nelfinavir is a CYP3A substrate and strong inhibitor. Coadministration with another strong CYP3A4 inhibitor increased lorlatinib exposure by 42%.
    Neratinib: (Major) Avoid concomitant use of lorlatinib with neratinib due to decreased efficacy of neratinib. Neratinib is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Simulations using physiologically based pharmacokinetic (PBPK) models suggest that another moderate CYP3A4 inducer may decrease neratinib exposure by 52%.
    Nevirapine: (Major) Avoid coadministration of lorlatinib with nevirapine due to the risk of severe hepatotoxicity as well as decreased lorlatinib exposure which may reduce its efficacy. If concomitant use is unavoidable, monitor ALT, AST, and bilirubin 48 hours after initiating concomitant therapy and at least 3 times during the first week of treatment. If persistent grade 2 or higher hepatotoxicity occurs, discontinue either lorlatinib or nevirapine. Lorlatinib is a CYP3A substrate and nevirapine is a moderate CYP3A inducer. Coadministration with a strong CYP3A inducer decreased lorlatinib exposure by 85% and caused severe (grade 3 or 4) hepatotoxicity in 83% of patients. The effect of the concomitant use of moderate CYP3A inducers on lorlatinib pharmacokinetics or the risk of hepatotoxicity is unknown.
    Nimodipine: (Moderate) Monitor for decreased efficacy of nimodipine if coadministration with lorlatinib is necessary. Nimodipine is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Concomitant use may decrease plasma concentrations of nimodipine.
    Nisoldipine: (Major) Avoid coadministration of nisoldipine with lorlatinib due to decreased plasma concentrations of nisoldipine. Alternative antihypertensive therapy should be considered. Nisoldipine is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Coadministration with a strong CYP3A4 inducer lowered nisoldipine plasma concentrations to undetectable levels.
    Norethindrone: (Major) Women taking both progestins and lorlatinib should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed lorlatinib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of lorlatinib. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. Progestins are CYP3A4 substrates and lorlatinib is a moderate CYP3A4 inducer.
    Norgestrel: (Major) Women taking both progestins and lorlatinib should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed lorlatinib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of lorlatinib. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. Progestins are CYP3A4 substrates and lorlatinib is a moderate CYP3A4 inducer.
    Olaparib: (Major) Avoid coadministration of olaparib with lorlatinib due to the risk of decreasing the efficacy of olaparib. Olaparib is a CYP3A substrate and lorlatinib is a moderate CYP3A4 inducer; concomitant use may decrease olaparib exposure. Coadministration with a moderate CYP3A inducer is predicted to decrease the olaparib Cmax by 31% and the AUC by 60%.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) Avoid coadministration of lorlatinib with ritonavir due to increased plasma concentrations of lorlatinib, which may increase the incidence and severity of adverse reactions. Ritonavir plasma concentrations may also decrease, leading to reduced efficacy and increasing the potential for viral resistance. If concomitant use is unavoidable, reduce the starting dose of lorlatinib from 100 mg to 75 mg once daily, or from 75 mg to 50 mg once daily. If ritonavir is discontinued, resume the original dose of lorlatinib after 3 half-lives of ritonavir. Lorlatinib is a CYP3A substrate and moderate inducer. Ritonavir is a CYP3A4 substrate and strong inhibitor. Coadministration with another strong CYP3A4 inhibitor increased lorlatinib exposure by 42%.
    Omeprazole; Amoxicillin; Rifabutin: (Major) Avoid coadministration of lorlatinib with rifabutin due to the risk of severe hepatotoxicity as well as decreased lorlatinib exposure which may reduce its efficacy. If concomitant use is unavoidable, monitor ALT, AST, and bilirubin 48 hours after initiating concomitant therapy and at least 3 times during the first week of treatment. If persistent grade 2 or higher hepatotoxicity occurs, discontinue either lorlatinib or rifabutin. Lorlatinib is a CYP3A substrate and rifabutin is a moderate CYP3A inducer. Coadministration with a strong CYP3A inducer decreased lorlatinib exposure by 85% and caused severe (grade 3 or 4) hepatotoxicity in 83% of patients. The effect of the concomitant use of moderate CYP3A inducers on lorlatinib pharmacokinetics or the risk of hepatotoxicity is unknown.
    Oxycodone: (Moderate) Monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with lorlatinib is necessary; consider increasing the dose of oxycodone as needed. If lorlatinib is discontinued, consider a dose reduction of lorlatinib and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease oxycodone concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Paclitaxel: (Moderate) Monitor for decreased efficacy of paclitaxel if coadministration with lorlatinib is necessary. Paclitaxel is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer.
    Pemigatinib: (Major) Avoid coadministration of pemigatinib and lorlatinib due to the risk of decreased pemigatinib exposure which may reduce its efficacy. Pemigatinib is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A4 inducer is predicted to decrease pemigatinib exposure by more than 50%.
    Pentobarbital: (Major) Avoid coadministration of lorlatinib with pentobarbital due to the risk of severe hepatotoxicity as well as decreased lorlatinib exposure which may reduce its efficacy. If concomitant use is unavoidable, monitor ALT, AST, and bilirubin 48 hours after initiating lorlatinib therapy and at least 3 times during the first week of treatment. If persistent grade 2 or higher hepatotoxicity occurs, discontinue either lorlatinib or pentobarbital. Lorlatinib is a CYP3A substrate and pentobarbital is a moderate CYP3A inducer. Coadministration with a strong CYP3A inducer decreased lorlatinib exposure by 85% and caused severe (grade 3 or 4) hepatotoxicity in 83% of patients. The effect of the concomitant use of moderate CYP3A inducers on lorlatinib pharmacokinetics or the risk of hepatotoxicity is unknown.
    Perampanel: (Major) Start perampanel at a higher initial dose of 4 mg once daily at bedtime if perampanel is added to lorlatinib therapy; increase the dose as tolerated in 2 mg increments no more than weekly, based on clinical response. If lorlatinib is added or withdrawn from perampanel therapy, closely monitor patient response; a dosage adjustment may be necessary. Perampanel is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Coadministration may decrease perampanel plasma concentrations.
    Perindopril; Amlodipine: (Moderate) Monitor blood pressure if coadministration of amlodipine with lorlatinib is necessary. Amlodipine is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Concomitant use may decrease amlodipine plasma concentrations, decreasing efficacy.
    Phenobarbital: (Severe) Coadministration of lorlatinib with phenobarbital is contraindicated due to the risk of severe hepatotoxicity as well as decreased lorlatinib exposure which may reduce its efficacy. Discontinue phenobarbital for 3 plasma half-lives prior to initiating therapy with lorlatinib. Lorlatinib is a CYP3A substrate and phenobarbital is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased lorlatinib exposure by 85% and caused severe (grade 3 or 4) hepatotoxicity in 83% of patients.
    Phenytoin: (Severe) Coadministration of lorlatinib with phenytoin is contraindicated due to the risk of severe hepatotoxicity as well as decreased lorlatinib exposure which may reduce its efficacy. Discontinue phenytoin for 3 plasma half-lives prior to initiating therapy with lorlatinib. Lorlatinib is a CYP3A substrate and phenytoin is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased lorlatinib exposure by 85% and caused severe (grade 3 or 4) hepatotoxicity in 83% of patients.
    Pimavanserin: (Major) Because pimavanserin is primarily metabolized by CYP3A4 and CYP3A5, the manufacturer recommends avoiding concomitant use of pimavanserin with moderate CYP3A4 inducers, such as lorlatinib. Moderate inducers of CYP3A4 can reduce pimavanserin exposure, potentially decreasing the effectiveness of pimavanserin.
    Posaconazole: (Major) Avoid coadministration of lorlatinib with posaconazole due to increased plasma concentrations of lorlatinib, which may increase the incidence and severity of adverse reactions; posaconazole exposure may also decrease. If concomitant use is unavoidable, reduce the starting dose of lorlatinib from 100 mg to 75 mg once daily, or from 75 mg to 50 mg once daily. If posaconazole is discontinued, resume the original dose of lorlatinib after 3 half-lives of posaconazole. Lorlatinib is a CYP3A substrate and P-glycoprotein (P-gp) inducer. Posaconazole is a strong CYP3A inhibitor and a P-gp substrate. Coadministration with another strong CYP3A4 inhibitor increased lorlatinib exposure by 42%.
    Praziquantel: (Moderate) Monitor for reduced response to praziquantel if coadministered with lorlatinib. Concomitant use may produce therapeutically ineffective concentrations of praziquantel. In vitro and drug interactions studies suggest that the CYP3A4 isoenzyme is the major enzyme involved in praziquantel metabolism. Lorlatinib is a moderate CYP3A4 inducer.
    Primidone: (Severe) Coadministration of lorlatinib with primidone is contraindicated due to the risk of severe hepatotoxicity as well as decreased lorlatinib exposure which may reduce its efficacy. Discontinue primidone for 3 plasma half-lives prior to initiating therapy with lorlatinib. Lorlatinib is a CYP3A substrate and primidone is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased lorlatinib exposure by 85% and caused severe (grade 3 or 4) hepatotoxicity in 83% of patients.
    Progesterone: (Major) Women taking both progestins and lorlatinib should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed lorlatinib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of lorlatinib. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. Progestins are CYP3A4 substrates and lorlatinib is a moderate CYP3A4 inducer.
    Progestins: (Major) Women taking both progestins and lorlatinib should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed lorlatinib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of lorlatinib. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. Progestins are CYP3A4 substrates and lorlatinib is a moderate CYP3A4 inducer.
    Ranolazine: (Severe) The concomitant use of lorlatinib with ranolazine is contraindicated due to decreased plasma concentrations of ranolazine resulting in decreased efficacy. Lorlatinib is a moderate CYP3A4 inducer and ranolazine is a CYP3A4 substrate.
    Ribociclib: (Major) Avoid coadministration of lorlatinib with ribociclib due to increased plasma concentrations of lorlatinib, which may increase the incidence and severity of adverse reactions. If concomitant use is unavoidable, reduce the starting dose of lorlatinib from 100 mg to 75 mg once daily, or from 75 mg to 50 mg once daily. If ribociclib is discontinued, resume the original dose of lorlatinib after 3 half-lives of ribociclib. Lorlatinib is a CYP3A substrate and ribociclib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A4 inhibitor increased lorlatinib exposure by 42%.
    Ribociclib; Letrozole: (Major) Avoid coadministration of lorlatinib with ribociclib due to increased plasma concentrations of lorlatinib, which may increase the incidence and severity of adverse reactions. If concomitant use is unavoidable, reduce the starting dose of lorlatinib from 100 mg to 75 mg once daily, or from 75 mg to 50 mg once daily. If ribociclib is discontinued, resume the original dose of lorlatinib after 3 half-lives of ribociclib. Lorlatinib is a CYP3A substrate and ribociclib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A4 inhibitor increased lorlatinib exposure by 42%.
    Rifabutin: (Major) Avoid coadministration of lorlatinib with rifabutin due to the risk of severe hepatotoxicity as well as decreased lorlatinib exposure which may reduce its efficacy. If concomitant use is unavoidable, monitor ALT, AST, and bilirubin 48 hours after initiating concomitant therapy and at least 3 times during the first week of treatment. If persistent grade 2 or higher hepatotoxicity occurs, discontinue either lorlatinib or rifabutin. Lorlatinib is a CYP3A substrate and rifabutin is a moderate CYP3A inducer. Coadministration with a strong CYP3A inducer decreased lorlatinib exposure by 85% and caused severe (grade 3 or 4) hepatotoxicity in 83% of patients. The effect of the concomitant use of moderate CYP3A inducers on lorlatinib pharmacokinetics or the risk of hepatotoxicity is unknown.
    Rifampin: (Severe) Coadministration of lorlatinib with rifampin is contraindicated due to the risk of severe hepatotoxicity as well as decreased lorlatinib exposure which may reduce its efficacy. Discontinue rifampin for 3 plasma half-lives prior to initiating therapy with lorlatinib. Lorlatinib is a CYP3A substrate and rifampin is a strong CYP3A inducer. Coadministration with rifampin decreased lorlatinib exposure by 85%. Additionally, severe hepatotoxicity occurred, with 50% of patients experiencing grade 4 elevations of ALT/AST, 33% with grade 3 AST/ALT elevations, and 8% with grade 2 ALT/AST elevations. Grade 2 to 4 increases in ALT/AST occurred within 3 days of concomitant use and returned to normal limits within 7 to 34 days (median, 15 days).
    Rifapentine: (Major) Avoid coadministration of lorlatinib with rifapentine due to the risk of severe hepatotoxicity as well as decreased lorlatinib exposure which may reduce its efficacy. If concomitant use is unavoidable, monitor ALT, AST, and bilirubin 48 hours after initiating concomitant therapy and at least 3 times during the first week of treatment. If persistent grade 2 or higher hepatotoxicity occurs, discontinue either lorlatinib or rifapentine. Lorlatinib is a CYP3A substrate and rifapentine is a moderate CYP3A inducer. Coadministration with a strong CYP3A inducer decreased lorlatinib exposure by 85% and caused severe (grade 3 or 4) hepatotoxicity in 83% of patients. The effect of the concomitant use of moderate CYP3A inducers on lorlatinib pharmacokinetics or the risk of hepatotoxicity is unknown.
    Rifaximin: (Moderate) Avoid coadministration of lorlatinib with rifaximin in patients with hepatic impairment due to the potential for serious hepatotoxicity; the efficacy of lorlatinib may also be decreased. If concomitant use is unavoidable, monitor AST, ALT, and bilirubin 48 hours after initiating lorlatinib and at least 3 times during the first week after initiating lorlatinib. Monitor for changes in clinical response to lorlatinib. Depending upon the relative importance of each drug, discontinue lorlatinib or rifaximin for persistent Grade 2 or higher hepatotoxicity. Lorlatinib is a CYP3A4 substrate. In patients with normal liver function, rifaximin is not expected to induce CYP3A4 at the recommended dosing regimen; it is unknown whether rifaximin may induce CYP3A4 in patients with hepatic impairment who have elevated rifaximin concentrations. Severe hepatotoxicity occurred in healthy subjects receiving a single 100-mg dose of lorlatinib with multiple daily doses of a strong CYP3A4 inducer (n = 12); both drugs were also pregnane X receptor agonists (PXR). The effect of the concomitant use of moderate CYP3A inducers on lorlatinib pharmacokinetics or the risk of hepatotoxicity with the concomitant use of moderate CYP3A inducers is unknown.
    Rilpivirine: (Moderate) Close clinical monitoring is advised when administering lorlatinib with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Lorlatinib is a moderate CYP3A4 inducer and rilpivirine is a CYP3A4 substrate. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response.
    Rimegepant: (Major) Avoid coadministration of rimegepant with lorlatinib; concurrent use may significantly decrease rimegepant exposure which may result in loss of efficacy. Rimegepant is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer.
    Risperidone: (Moderate) Monitor for decreased efficacy of risperidone if coadministration with lorlatinib is necessary. Risperidone is a P-glycoprotein (P-gp) substrate and lorlatinib is a P-gp inducer. Concomitant use may decrease plasma concentrations of risperidone.
    Ritonavir: (Major) Avoid coadministration of lorlatinib with ritonavir due to increased plasma concentrations of lorlatinib, which may increase the incidence and severity of adverse reactions. Ritonavir plasma concentrations may also decrease, leading to reduced efficacy and increasing the potential for viral resistance. If concomitant use is unavoidable, reduce the starting dose of lorlatinib from 100 mg to 75 mg once daily, or from 75 mg to 50 mg once daily. If ritonavir is discontinued, resume the original dose of lorlatinib after 3 half-lives of ritonavir. Lorlatinib is a CYP3A substrate and moderate inducer. Ritonavir is a CYP3A4 substrate and strong inhibitor. Coadministration with another strong CYP3A4 inhibitor increased lorlatinib exposure by 42%.
    Saquinavir: (Major) Avoid coadministration of lorlatinib with saquinavir due to increased plasma concentrations of lorlatinib, which may increase the incidence and severity of adverse reactions. Plasma concentrations of saquinavir may also decrease, leading to reduced efficacy and increasing the potential for viral resistance. If concomitant use is unavoidable, reduce the starting dose of lorlatinib from 100 mg to 75 mg once daily, or from 75 mg to 50 mg once daily. If saquinavir is discontinued, resume the original dose of lorlatinib after 3 half-lives of saquinavir. Lorlatinib is a CYP3A substrate and moderate inducer. Saquinavir is a CYP3A4 substrate and strong inhibitor. Coadministration with another strong CYP3A4 inhibitor increased lorlatinib exposure by 42%.
    Secobarbital: (Major) Avoid coadministration of lorlatinib with secobarbital due to the risk of severe hepatotoxicity as well as decreased lorlatinib exposure which may reduce its efficacy. If concomitant use is unavoidable, monitor ALT, AST, and bilirubin 48 hours after initiating lorlatinib therapy and at least 3 times during the first week of treatment. If persistent grade 2 or higher hepatotoxicity occurs, discontinue either lorlatinib or secobarbital. Lorlatinib is a CYP3A substrate and secobarbital is a moderate CYP3A inducer. Coadministration with a strong CYP3A inducer decreased lorlatinib exposure by 85% and caused severe (grade 3 or 4) hepatotoxicity in 83% of patients. The effect of the concomitant use of moderate CYP3A inducers on lorlatinib pharmacokinetics or the risk of hepatotoxicity is unknown.
    Segesterone Acetate; Ethinyl Estradiol: (Major) Women taking both estrogens and lorlatinib should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed lorlatinib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of lorlatinib. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on lorlatinib, with dose adjustments made based on clinical efficacy. Ethinyl estradiol is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Concurrent administration may increase estrogen elimination. (Major) Women taking both progestins and lorlatinib should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed lorlatinib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of lorlatinib. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. Progestins are CYP3A4 substrates and lorlatinib is a moderate CYP3A4 inducer.
    Selpercatinib: (Major) Avoid coadministration of selpercatinib and lorlatinib due to the risk of decreased selpercatinib exposure which may reduce its efficacy. Selpercatinib is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Coadministration with other moderate CYP3A4 inducers is predicted to decrease selpercatinib exposure by 40% to 70%.
    Selumetinib: (Major) Avoid coadministration of selumetinib and lorlatinib due to the risk of decreased selumetinib exposure which may reduce its efficacy. Selumetinib is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A4 inducer is predicted to decrease selumetinib exposure by 38%.
    Sildenafil: (Moderate) Monitor for decreased efficacy of sildenafil if coadministration with lorlatinib is necessary as concurrent use may decrease sildenafil exposure. Sildenafil is a sensitive CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Population pharmacokinetic analysis indicates an approximately 3-fold increase in sildenafil clearance with concomitant use of weak CYP3A4 inducers.
    Simeprevir: (Major) Coadministration of simeprevir with lorlatinib is not recommended as there is a potential for decreased simeprevir concentrations which may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Simeprevir is metabolized by CYP3A4 and lorlatinib is a moderate CYP3A4 inducer.
    Siponimod: (Moderate) Concomitant use of siponimod and lorlatinib is not recommended for patients with CYP2C9*1/*3 and *2/*3 genotypes due to a significant decrease in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; lorlatinib is a moderate CYP3A4 inducer. Across different CYP2C9 genotypes, a moderate CYP3A4 inducer decreased the exposure of siponimod by up to 52% according to in silico evaluation.
    Sirolimus: (Moderate) Monitor sirolimus whole blood trough concentrations as appropriate if coadministration with lorlatinib is necessary. The dose of sirolimus may need to be increased. Sirolimus is a P-glycoprotein (P-gp) substrate and a CYP3A4 substrate. Lorlatinib is a P-gp inducer and a moderate CYP3A inducer.
    Sofosbuvir; Velpatasvir: (Major) Coadministration of velpatasvir with lorlatinib is not recommended due to the potential for loss of antiviral efficacy. Taking these drugs together may significantly decrease velpatasvir plasma concentrations, potentially resulting in loss of antiviral efficacy. Velpatasvir is a CYP3A4 and P-glycoprotein (P-gp) substrate. Lorlatinib is a moderate CYP3A4 inducer as well as a P-gp inducer.
    Sofosbuvir; Velpatasvir; Voxilaprevir: (Major) Coadministration of velpatasvir with lorlatinib is not recommended due to the potential for loss of antiviral efficacy. Taking these drugs together may significantly decrease velpatasvir plasma concentrations, potentially resulting in loss of antiviral efficacy. Velpatasvir is a CYP3A4 and P-glycoprotein (P-gp) substrate. Lorlatinib is a moderate CYP3A4 inducer as well as a P-gp inducer. (Major) Coadministration of voxilaprevir with lorlatinib is not recommended due to decreased plasma concentrations of voxilaprevir, potentially resulting in loss of antiviral efficacy. Voxilaprevir is a CYP3A4 substrate as well as a P-glycoprotein (P-gp) substrate. Lorlatinib is a moderate CYP3A4 inducer and a P-gp inducer.
    Solifenacin: (Moderate) Monitor for decreased efficacy of solifenacin if coadministration with lorlatinib is necessary. Solifenacin is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Studies have not been conducted to evaluate the effect of CYP3A4 inducers on solifenacin, but inducers of CYP3A4 may decrease solifenacin plasma concentrations.
    Sonidegib: (Major) Avoid the concomitant use of sonidegib and lorlatinib; sonidegib exposure may be significantly decreased and its efficacy reduced. Sonidegib is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A4 inducer for 14 days decreased the geometric mean AUC of sonidegib by 56%; coadministration with a moderate CYP3A4 inducer for 4 months decreased the sonidegib AUC by 69%.
    St. John's Wort, Hypericum perforatum: (Severe) Coadministration of lorlatinib with St. Johns Wort is contraindicated due to the risk of severe hepatotoxicity as well as decreased lorlatinib exposure which may reduce its efficacy. Discontinue St. Johns Wort for 3 plasma half-lives prior to initiating therapy with lorlatinib. Lorlatinib is a CYP3A substrate and St. Johns Wort is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased lorlatinib exposure by 85% and caused severe (grade 3 or 4) hepatotoxicity in 83% of patients.
    Sufentanil: (Moderate) Because the dose of the sufentanil sublingual tablets cannot be titrated, consider an alternate opiate if lorlatinib must be administered. Monitor for reduced efficacy of sufentanil injection and signs of opioid withdrawal if coadministration with lorlatinib is necessary; consider increasing the dose of sufentanil injection as needed. If lorlatinib is discontinued, consider a dose reduction of sufentanil injection and frequently monitor for signs or respiratory depression and sedation. Sufentanil is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease sufentanil concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Sunitinib: (Major) Avoid coadministration of lorlatinib with sunitinib if possible due to decreased exposure to sunitinib which could decrease efficacy. If concomitant use is unavoidable, consider increasing the dose of sunitinib in 12.5 mg increments based on individual safety and tolerability to a maximum of 87.5 mg (GIST and RCC) or 62.5 mg (pNET) daily; monitor carefully for toxicity. The maximum daily dose administered in the pNET study was 50 mg. Sunitinib is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer.
    Tacrolimus: (Moderate) Measure tacrolimus whole blood trough concentrations and adjust the dose as clinically appropriate if coadministration with lorlatinib is necessary. Tacrolimus is a sensitive CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A4 inducer may significantly increase tacrolimus clearance.
    Tazemetostat: (Major) Avoid coadministration of tazemetostat with lorlatinib as concurrent use may decrease tazemetostat exposure, which may reduce its efficacy. Tazemetostat is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer.
    Telithromycin: (Major) Avoid coadministration of lorlatinib with telithromycin due to increased plasma concentrations of lorlatinib, which may increase the incidence and severity of adverse reactions. If concomitant use is unavoidable, reduce the starting dose of lorlatinib from 100 mg to 75 mg once daily, or from 75 mg to 50 mg once daily. If telithromycin is discontinued, resume the original dose of lorlatinib after 3 half-lives of telithromycin. Lorlatinib is a CYP3A substrate and telithromycin is a strong CYP3A inhibitor. Coadministration with another strong CYP3A4 inhibitor increased lorlatinib exposure by 42%.
    Thiopental: (Major) Avoid coadministration of lorlatinib with thiopental due to the risk of severe hepatotoxicity as well as decreased lorlatinib exposure which may reduce its efficacy. If concomitant use is unavoidable, monitor ALT, AST, and bilirubin 48 hours after initiating lorlatinib therapy and at least 3 times during the first week of treatment. If persistent grade 2 or higher hepatotoxicity occurs, discontinue either lorlatinib or thiopental. Lorlatinib is a CYP3A substrate and thiopental is a moderate CYP3A inducer. Coadministration with a strong CYP3A inducer decreased lorlatinib exposure by 85% and caused severe (grade 3 or 4) hepatotoxicity in 83% of patients. The effect of the concomitant use of moderate CYP3A inducers on lorlatinib pharmacokinetics or the risk of hepatotoxicity is unknown.
    Tipranavir: (Major) Avoid coadministration of lorlatinib with tipranavir due to increased plasma concentrations of lorlatinib, which may increase the incidence and severity of adverse reactions. Plasma concentrations of tipranavir may also decrease, leading to reduced efficacy and increasing the potential for viral resistance. If concomitant use is unavoidable, reduce the starting dose of lorlatinib from 100 mg to 75 mg once daily, or from 75 mg to 50 mg once daily. If tipranavir is discontinued, resume the original dose of lorlatinib after 3 half-lives of tipranavir. Lorlatinib is a CYP3A substrate and moderate inducer. Tipranavir is a CYP3A substrate and strong inhibitor. Coadministration with another strong CYP3A4 inhibitor increased lorlatinib exposure by 42%.
    Tramadol: (Moderate) Monitor for reduced efficacy of tramadol and signs of opioid withdrawal if coadministration with lorlatinib is necessary; consider increasing the dose of tramadol as needed. If lorlatinib is discontinued, consider a dose reduction of tramadol and frequently monitor for signs or respiratory depression and sedation. Tramadol is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease tramadol levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Tucatinib: (Major) Avoid coadministration of lorlatinib with tucatinib due to increased plasma concentrations of lorlatinib, which may increase the incidence and severity of adverse reactions. If concomitant use is unavoidable, reduce the starting dose of lorlatinib from 100 mg to 75 mg once daily, or from 75 mg to 50 mg once daily. If tucatinib is discontinued, resume the original dose of lorlatinib after 3 half-lives of tucatinib. Lorlatinib is a CYP3A substrate and tucatinib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A4 inhibitor increased lorlatinib exposure by 42%.
    Ubrogepant: (Major) Increase the initial and second dose of ubrogepant to 100 mg if coadministered with lorlatinib as concurrent use may decrease ubrogepant exposure and reduce its efficacy. Ubrogepant is a CYP3A4 substrate; lorlatinib is a moderate CYP3A4 inducer.
    Ulipristal: (Major) Do not administer ulipristal with lorlatinib due to decreased plasma concentrations of ulipristal. Ulipristal is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Concomitant use may significantly decrease ulipristal exposure.
    Venetoclax: (Major) Avoid coadministration of venetoclax with lorlatinib as concurrent use may decrease venetoclax exposure and lead to reduced efficacy. Venetoclax is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Coadministration with a strong CYP3A4 inducer decreased venetoclax exposure by 71%.
    Voriconazole: (Major) Avoid coadministration of lorlatinib with voriconazole due to increased plasma concentrations of lorlatinib, which may increase the incidence and severity of adverse reactions; plasma concentrations of voriconazole may also be decreased. If concomitant use is unavoidable, reduce the starting dose of lorlatinib from 100 mg to 75 mg once daily, or from 75 mg to 50 mg once daily. If voriconazole is discontinued, resume the original dose of lorlatinib after 3 half-lives of voriconazole. Lorlatinib is a CYP3A substrate and moderate inducer. Voriconazole is a CYP3A substrate and strong inhibitor. Coadministration with another strong CYP3A4 inhibitor increased lorlatinib exposure by 42%.
    Voxelotor: (Major) Avoid coadministration of voxelotor and lorlatinib as concurrent use may decrease voxelotor exposure and lead to reduced efficacy. If coadministration is unavoidable, increase voxelotor dosage to 2,500 mg PO once daily. Voxelotor is a substrate of CYP3A4; lorlatinib is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer is predicted to decrease voxelotor exposure by up to 60%.
    Warfarin: (Moderate) Closely monitor the INR if coadministration of warfarin with lorlatinib is necessary. The more potent warfarin S-enantiomer is metabolized by CYP2C9 while the R-enantiomer is partially metabolized by CYP3A4. Lorlatinib is a moderate CYP3A4 inducer. Inducers of CYP3A4 have the potential to decrease the effect (decrease INR) of warfarin by decreasing warfarin plasma concentrations.
    Zanubrutinib: (Major) Avoid the concomitant use of zanubrutinib and lorlatinib. Coadministration may result in decreased zanubrutinib exposure and reduced efficacy. Zanubrutinib is a CYP3A4 substrate; lorlatinib is a moderate CYP3A4 inducer. The AUC of zanubrutinib is predicted to decrease by 60% when coadministered with another moderate CYP3A4 inducer.

    PREGNANCY AND LACTATION

    Pregnancy

    Pregnancy should be avoided by females of reproductive potential during lorlatinib treatment and for at least 6 months after the last dose. Although there are no adequately controlled studies in pregnant animals or humans, lorlatinib can cause fetal harm or death when administered during pregnancy based on its mechanism of action and animal studies. Women who are pregnant or who become pregnant while receiving lorlatinib should be apprised of the potential hazard to the fetus. Administration to rabbits at exposures approximately 3 times the human exposure at the recommended dose or higher resulted in abortion and total loss of pregnancy. At approximately 0.6 times the human exposure at the recommended dose, increased post-implantation occurred as well as malformations such as rotated limbs, malformed kidneys, domed head, high arched palate, and dilation of the cerebral ventricles. In rats, exposures of approximately 5 times the human exposure at the recommended dose during organogenesis increased post-implantation loss, decreased fetal body weight, and increased malformations including gastroschisis, rotated limbs, supernumerary digits, and vessel abnormalities.

    Due to the potential for serious adverse reactions in nursing infants from lorlatinib, advise women to discontinue breast-feeding during treatment and for 7 days after the final dose. It is not known whether lorlatinib is present in human milk, although many drugs are excreted in human milk.

    MECHANISM OF ACTION

    Lorlatinib is a kinase inhibitor with in vitro activity against anaplastic lymphoma kinase (ALK) and ROS1 as well as TYK1, FER, FPS, TRKA, TRKB, TRKC, FAK, FAK2, and ACK. It demonstrated in vitro activity against multiple mutant forms of the ALK enzyme, including some mutations detected in tumors at the time of disease progression on crizotinib and other ALK inhibitors. Administration of lorlatinib resulted in antitumor activity in mice implanted with tumors harboring EML4 fusions with either ALK variant 1 or ALK mutations, including the G1202R and I1171T mutations detected in tumors at the time of disease progression on ALK inhibitors; it also demonstrated anti-tumor activity and prolonged survival in mice implanted intracranially with EML4-ALK-driven tumor cell lines. The overall antitumor activity of lorlatinib in in vivo models was dose-dependent and correlated with inhibition of ALK phosphorylation.[63732]

    PHARMACOKINETICS

    Lorlatinib is administered orally. It is 66% bound to plasma proteins at a concentration of 2.4 microMolar. The blood-to-plasma ratio was 0.99. The mean (coefficient of variation [CV]) steady-state volume of distribution (Vd) was 305 liters (28%) following a single intravenous dose. The mean plasma half-life of lorlatinib was 24 hours (40%) after a single oral 100-mg dose. The mean oral clearance was 11 liters/hour (35%) following a single dose and increased to 18 liters/hour (39%) at steady-state, indicating autoinduction. After administration of a single oral 100-mg dose of radiolabeled lorlatinib, 48% of radioactivity was recovered in urine (less than 1% as unchanged drug), and 41% in feces (approximately 9% as unchanged drug).[63732]
     
    Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4, UGT1A4, pregnane X receptor (PXR)
    In vitro, lorlatinib is primarily metabolized by CYP3A4 and UGT1A4, with minor contribution from CYP2C8, CYP2C19, CYP3A5, and UGT1A3. In plasma, a benzoic acid metabolite (M8) of lorlatinib resulting from the oxidative cleavage of the amide and aromatic ether bonds of lorlatinib accounted for 21% of the circulating radioactivity in a human mass balance study. The oxidative cleavage metabolite, M8, is pharmacologically inactive. In vitro, lorlatinib is a time-dependent inhibitor as well as an inducer of CYP3A that also activates PXR; the net effect in vivo is CYP3A induction. Lorlatinib also induces CYP2B6 and activates the human constitutive androstane receptor (CAR). Lorlatinib inhibits P-glycoprotein (P-gp), organic cation transporter (OCT)1, organic anion transporter (OAT)3, multidrug and toxin extrusion (MATE)1, and intestinal breast cancer resistance protein (BCRP).[63732]

    Oral Route

    Steady-state lorlatinib maximum plasma concentration (Cmax) increases proportionally and AUC increases slightly less than proportionally over the dose range of 10 mg to 200 mg PO once daily (0.1 to 2 times the recommended dose). At the recommended dose, the mean Cmax was 577 ng/mL (42%) and the AUC was 5,650 ng x h/mL (39%) in patients with cancer. The median time to Cmax (Tmax) was 1.2 hours (range, 0.5 to 4 hours) following a single oral 100-mg dose and 2 hours (range, 0.5 to 23 hours) at steady-state. The mean absolute bioavailability (F) is 81% (90% CI, 75.7% to 86.2%) after oral administration compared to intravenous administration.[63732]
     
    Administration with a high-fat, high-calorie meal (approximately 1,000 calories with 150 calories from protein, 250 calories from carbohydrate, and 500 to 600 calories from fat) had no clinically meaningful effect on lorlatinib pharmacokinetics. Concomitant administration with a proton pump inhibitor did not have a clinically meaningful effect on lorlatinib pharmacokinetics.