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Lorlatinib

Medically reviewed by Drugs.com. Last updated on Nov 3, 2020.

Pronunciation

(lor LA ti nib)

Index Terms

  • PF-06463922

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Lorbrena: 25 mg, 100 mg

Brand Names: U.S.

  • Lorbrena

Pharmacologic Category

  • Antineoplastic Agent, Anaplastic Lymphoma Kinase Inhibitor
  • Antineoplastic Agent, Tyrosine Kinase Inhibitor

Pharmacology

Lorlatinib is a reversible potent third generation tyrosine kinase inhibitor that targets ALK and ROS1; it is highly selective, overcomes known ALK resistance mutations, and penetrates the blood brain barrier (Shaw 2017). Lorlatinib has antitumor 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. Antitumor activity of lorlatinib is dose-dependent and correlates with inhibition of ALK phosphorylation. Lorlatinib also exhibits activity against TYK1, FER, FPS, TRKA, TRKB, TRKC, FAK, FAK2, and ACK.

Absorption

Rapid (Shaw 2017)

Distribution

Vss: 305 L

Metabolism

Primarily via CYP3A4 and UGT1A4, with minor contribution from CYP2C8, CYP2C19, CYP3A5, and UGT1A3

Excretion

Urine: 48% (<1% as unchanged drug); feces: 41% (~9% as unchanged drug)

Time to Peak

1.2 hours (range: 0.5 to 4 hours) following a single dose; 2 hours (range: 0.5 to 23 hours) at steady state

Half-Life Elimination

24 hours

Protein Binding

66%; to plasma proteins

Use: Labeled Indications

Non-small cell lung cancer, metastatic: Treatment of anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) in patients whose disease has progressed on crizotinib and at least 1 other ALK inhibitor for metastatic disease; or progressed on alectinib as the first ALK inhibitor therapy for metastatic disease; or progressed on ceritinib as the first ALK inhibitor therapy for metastatic disease.

Contraindications

Concomitant use of strong CYP3A inducers

Canadian labeling: Additional contraindications (not in US labeling): Hypersensitivity to lorlatinib or any component of the formulation

Dosing: Adult

Non-small cell lung cancer, metastatic (ALK-positive): Oral: 100 mg once daily; continue until disease progression or unacceptable toxicity (Shaw 2017).

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Missed doses: If a dose is missed, administer the missed dose unless it is due within 4 hours. Do not administer 2 doses to make up for a missed dose. If vomiting occurs, do not administer an additional dose; continue with the next scheduled dose.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Adjustment for Toxicity

Recommended dosage reduction levels:

Usual initial dose: 100 mg once daily

First dose reduction level: 75 mg once daily

Second dose reduction level: 50 mg once daily

Discontinue permanently if unable to tolerate 50 mg once daily.

Cardiovascular toxicity (atrioventricular [AV] block):

Second degree AV block: Withhold lorlatinib until PR interval is <200 msec and then resume lorlatinib at a reduced dose.

First occurrence of complete AV block: Withhold lorlatinib until either pacemaker is placed or PR interval is <200 msec. If a pacemaker is placed, resume lorlatinib at the same dose. If no pacemaker is placed, resume lorlatinib at a reduced dose.

Recurrent complete AV block: Place pacemaker or permanently discontinue lorlatinib.

CNS toxicity:

Grade 1: Continue lorlatinib at the same dose or withhold until recovery to baseline. Resume lorlatinib at the same dose or at a reduced dose.

Grade 2 or 3: Withhold dose until resolved to grade 0 or 1, then resume lorlatinib at a reduced dose.

Grade 4: Permanently discontinue lorlatinib.

Hyperlipidemia: Grade 4 hypercholesterolemia or grade 4 hypertriglyceridemia: Withhold lorlatinib until recovery of hypercholesterolemia and/or hypertriglyceridemia to ≤ grade 2 and then resume lorlatinib at the same dose. If severe hypercholesterolemia and/or hypertriglyceridemia recurs, resume lorlatinib at a reduced dose. Hyperlipidemia may require initiation (or increased doses) of lipid-lowering agents.

Pulmonary toxicity: Treatment-related interstitial lung disease (ILD)/pneumonitis, any grade: Permanently discontinue lorlatinib.

Other toxicities:

Grade 1 or 2: Continue lorlatinib at the same dose or at a reduced dose.

Grade 3 or 4: Withhold lorlatinib until symptoms resolve to ≤ grade 2 or baseline, then resume lorlatinib at a reduced dose.

Administration

Oral: Administer with or without food at the same time each day. Swallow intact tablets whole; do not crush or split; do not ingest tablets that are broken, cracked or otherwise not intact.

Storage

Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F).

Drug Interactions

Abametapir: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Abemaciclib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Abemaciclib. Avoid combination

Abiraterone Acetate: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Abiraterone Acetate. Monitor therapy

Acalabrutinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Acalabrutinib. Monitor therapy

Acetaminophen: Lorlatinib may decrease the serum concentration of Acetaminophen. Monitor therapy

Afatinib: P-glycoprotein/ABCB1 Inducers may decrease the serum concentration of Afatinib. Management: Increase the afatinib dose by 10 mg as tolerated in patients requiring chronic coadministration of P-gp inducers with afatinib. Reduce afatinib dose back to the original afatinib dose 2 to 3 days after discontinuation of the P-gp inducer. Consider therapy modification

Alfentanil: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Alfentanil. Management: If concomitant use of alfentanil and moderate CYP3A4 inducers is necessary, consider dosage increase of alfentanil until stable drug effects are achieved. Monitor patients for signs of opioid withdrawal. Consider therapy modification

Aliskiren: P-glycoprotein/ABCB1 Inducers may decrease the serum concentration of Aliskiren. Monitor therapy

Antihepaciviral Combination Products: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Antihepaciviral Combination Products. Avoid combination

Apixaban: Inducers of CYP3A4 (Moderate) and P-glycoprotein may decrease the serum concentration of Apixaban. Monitor therapy

Apremilast: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Apremilast. Monitor therapy

Aprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Aprepitant: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Aprepitant. Monitor therapy

ARIPiprazole: CYP3A4 Inducers (Moderate) may decrease the serum concentration of ARIPiprazole. Monitor therapy

ARIPiprazole Lauroxil: CYP3A4 Inducers (Moderate) may decrease the serum concentration of ARIPiprazole Lauroxil. Monitor therapy

Asunaprevir: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Asunaprevir. Avoid combination

Avanafil: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Avanafil. Avoid combination

Avapritinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Avapritinib. Avoid combination

Axitinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Axitinib. Avoid combination

Bedaquiline: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Bedaquiline. Avoid combination

Benzhydrocodone: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Benzhydrocodone. Specifically, the serum concentrations of hydrocodone may be reduced. Monitor therapy

Betrixaban: P-glycoprotein/ABCB1 Inducers may decrease the serum concentration of Betrixaban. Avoid combination

Bortezomib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Bortezomib. Monitor therapy

Bosutinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Bosutinib. Avoid combination

Brexpiprazole: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Brexpiprazole. Monitor therapy

Brigatinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Brigatinib. Management: Avoid concurrent use of brigatinib with moderate CYP3A4 inducers when possible. If combined, increase the daily dose of brigatinib in 30 mg increments after 7 days of treatment with the current brigatinib dose, up to maximum of twice the dose. Consider therapy modification

BuPROPion: CYP2B6 Inducers (Weak) may decrease the serum concentration of BuPROPion. Monitor therapy

Cabozantinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Cabozantinib. Monitor therapy

Capmatinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Capmatinib. Avoid combination

Celiprolol: P-glycoprotein/ABCB1 Inducers may decrease the serum concentration of Celiprolol. Monitor therapy

Cladribine: P-glycoprotein/ABCB1 Inducers may decrease the serum concentration of Cladribine. Monitor therapy

Clarithromycin: CYP3A4 Inducers (Moderate) may increase serum concentrations of the active metabolite(s) of Clarithromycin. CYP3A4 Inducers (Moderate) may decrease the serum concentration of Clarithromycin. Management: Consider alternative antimicrobial therapy for patients receiving a CYP3A inducer. Drugs that enhance the metabolism of clarithromycin into 14-hydroxyclarithromycin may alter the clinical activity of clarithromycin and impair its efficacy. Consider therapy modification

Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

CloZAPine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of CloZAPine. Monitor therapy

Cobimetinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Cobimetinib. Avoid combination

Codeine: CYP3A4 Inducers (Moderate) may decrease serum concentrations of the active metabolite(s) of Codeine. Monitor therapy

Conivaptan: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Copanlisib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Copanlisib. Monitor therapy

Crizotinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Crizotinib. Monitor therapy

CycloSPORINE (Systemic): CYP3A4 Inducers (Moderate) may decrease the serum concentration of CycloSPORINE (Systemic). Monitor therapy

CYP3A4 Inducers (Moderate): May enhance the hepatotoxic effect of Lorlatinib. CYP3A4 Inducers (Moderate) may decrease the serum concentration of Lorlatinib. Management: Avoid use of lorlatinib with moderate CYP3A4 inducers. If such a combination must be used, monitor AST, ALT, and bilirubin within 48 hours of starting the combination and at least three times within the first week of combined use. Consider therapy modification

CYP3A4 Inducers (Strong): May enhance the hepatotoxic effect of Lorlatinib. CYP3A4 Inducers (Strong) may decrease the serum concentration of Lorlatinib. Avoid combination

CYP3A4 Inhibitors (Moderate): May increase the serum concentration of Lorlatinib. Monitor therapy

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Lorlatinib. Management: Avoid use of lorlatinib with strong CYP3A4 inhibitors. If the combination cannot be avoided, reduce the lorlatinib dose from 100 mg once daily to 75 mg once daily, or from 75 mg once daily to 50 mg once daily. Consider therapy modification

CYP3A4 Substrates (High risk with Inducers): CYP3A4 Inducers (Moderate) may decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Dabigatran Etexilate: P-glycoprotein/ABCB1 Inducers may decrease the serum concentration of Dabigatran Etexilate. Management: Avoid concurrent use of dabigatran with P-glycoprotein inducers whenever possible. Avoid combination

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Seek alternatives to concomitant therapy when possible. If concomitant therapy cannot be avoided, monitor for reduced clinical effects of the CYP3A4 substrate. Consider therapy modification

Daclatasvir: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Daclatasvir. Management: Increase the daclatasvir dose to 90 mg once daily if used with a moderate CYP3A4 inducer. Consider therapy modification

Dapsone (Systemic): CYP3A4 Inducers (Moderate) may decrease the serum concentration of Dapsone (Systemic). Monitor therapy

Darolutamide: Inducers of CYP3A4 (Moderate) and P-glycoprotein may decrease the serum concentration of Darolutamide. Avoid combination

Dasabuvir: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Dasabuvir. Avoid combination

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Deflazacort: CYP3A4 Inducers (Moderate) may decrease serum concentrations of the active metabolite(s) of Deflazacort. Avoid combination

DexAMETHasone (Systemic): CYP3A4 Inducers (Moderate) may decrease the serum concentration of DexAMETHasone (Systemic). Monitor therapy

Digitoxin: P-glycoprotein/ABCB1 Inducers may decrease the serum concentration of Digitoxin. Monitor therapy

Digoxin: P-glycoprotein/ABCB1 Inducers may decrease the serum concentration of Digoxin. Monitor therapy

Doravirine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Doravirine. Monitor therapy

DOXOrubicin (Conventional): P-glycoprotein/ABCB1 Inducers may decrease the serum concentration of DOXOrubicin (Conventional). Avoid combination

Duvelisib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Edoxaban: P-glycoprotein/ABCB1 Inducers may decrease the serum concentration of Edoxaban. Monitor therapy

Elbasvir: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Elbasvir. Avoid combination

Elexacaftor, Tezacaftor, and Ivacaftor: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Elexacaftor, Tezacaftor, and Ivacaftor. Monitor therapy

Encorafenib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Encorafenib. Avoid combination

Entrectinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Entrectinib. Avoid combination

Erdafitinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Erdafitinib. Management: Dose modifications of erdafitinib may be required. See full monograph for details. Consider therapy modification

Estriol (Systemic): CYP3A4 Inducers (Moderate) may decrease the serum concentration of Estriol (Systemic). Monitor therapy

Estriol (Topical): CYP3A4 Inducers (Moderate) may decrease the serum concentration of Estriol (Topical). Monitor therapy

Etoposide: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Etoposide. Monitor therapy

Etoposide Phosphate: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Etoposide Phosphate. Monitor therapy

Everolimus: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Everolimus. Monitor therapy

Fedratinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Fedratinib. Avoid combination

FentaNYL: CYP3A4 Inducers (Moderate) may decrease the serum concentration of FentaNYL. Monitor therapy

Fexofenadine: P-glycoprotein/ABCB1 Inducers may decrease the serum concentration of Fexofenadine. Monitor therapy

Flibanserin: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Flibanserin. Avoid combination

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Fosaprepitant: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Fosaprepitant. Specifically, CYP3A4 Inducers (Moderate) may decrease serum concentrations of the active metabolite aprepitant. Monitor therapy

Fosnetupitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Gilteritinib: Inducers of CYP3A4 (Moderate) and P-glycoprotein may decrease the serum concentration of Gilteritinib. Monitor therapy

Glasdegib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Glasdegib. Management: Avoid use of glasdegib and moderate CYP3A4 inducers whenever possible. If combined, increase glasdegib dose from 100 mg daily to 200 mg daily or from 50 mg daily to 100 mg daily. Resume previous glasdegib dose 7 days after discontinuation of the inducer. Consider therapy modification

Glecaprevir and Pibrentasvir: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Glecaprevir and Pibrentasvir. Monitor therapy

Grazoprevir: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Grazoprevir. Avoid combination

GuanFACINE: CYP3A4 Inducers (Moderate) may decrease the serum concentration of GuanFACINE. Management: Increase extended-release guanfacine dose by up to double when initiating guanfacine in patients taking CYP3A4 inducers or if initiating a CYP3A4 inducer in a patient already taking extended-release guanfacine. Monitor for reduced guanfacine efficacy. Consider therapy modification

HYDROcodone: CYP3A4 Inducers (Moderate) may decrease the serum concentration of HYDROcodone. Monitor therapy

Hydrocortisone (Systemic): CYP3A4 Inducers (Moderate) may decrease the serum concentration of Hydrocortisone (Systemic). Monitor therapy

Ibrutinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Ibrutinib. Monitor therapy

Idelalisib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Ifosfamide: CYP3A4 Inducers (Moderate) may decrease serum concentrations of the active metabolite(s) of Ifosfamide. CYP3A4 Inducers (Moderate) may increase serum concentrations of the active metabolite(s) of Ifosfamide. Monitor therapy

Istradefylline: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Istradefylline. Monitor therapy

Ivacaftor: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Ivacaftor. Monitor therapy

Ivosidenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Lapatinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Lapatinib. Monitor therapy

Larotrectinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Larotrectinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Larotrectinib. Monitor therapy

Ledipasvir: P-glycoprotein/ABCB1 Inducers may decrease the serum concentration of Ledipasvir. Avoid combination

Lefamulin: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Lefamulin. Management: Avoid concomitant use of lefamulin with moderate CYP3A4 inducers unless the benefits outweigh the risks. Consider therapy modification

Lefamulin: P-glycoprotein/ABCB1 Inducers may decrease the serum concentration of Lefamulin. Management: Avoid concomitant use of lefamulin with P-glycoprotein/ABCB1 inducers unless the benefits outweigh the risks. Consider therapy modification

Lefamulin (Intravenous): CYP3A4 Inducers (Moderate) may decrease the serum concentration of Lefamulin (Intravenous). Management: Avoid concomitant use of lefamulin (intravenous) with moderate CYP3A4 inducers unless the benefits outweigh the risks. Consider therapy modification

Lefamulin (Intravenous): P-glycoprotein/ABCB1 Inducers may decrease the serum concentration of Lefamulin (Intravenous). Management: Avoid concomitant use of lefamulin (intravenous) with P-glycoprotein/ABCB1 inducers unless the benefits outweigh the risks. Consider therapy modification

Lemborexant: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Lemborexant. Avoid combination

Lercanidipine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Lercanidipine. Monitor therapy

Letermovir: P-glycoprotein/ABCB1 Inducers may decrease the serum concentration of Letermovir. Avoid combination

LinaGLIPtin: P-glycoprotein/ABCB1 Inducers may decrease the serum concentration of LinaGLIPtin. Management: Strongly consider using an alternative to any P-glycoprotein inducer in patients who are being treated with linagliptin. If this combination is used, monitor patients closely for evidence of reduced linagliptin effectiveness. Consider therapy modification

Lumateperone: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Lumateperone. Avoid combination

Lurasidone: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Lurasidone. Management: Monitor for decreased lurasidone effects if combined with moderate CYP3A4 inducers and consider increasing the lurasidone dose if coadministered with a moderate CYP3A4 inducer for 7 or more days. Consider therapy modification

Lurbinectedin: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Lurbinectedin. Avoid combination

Macitentan: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Macitentan. Monitor therapy

Meperidine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Meperidine. Monitor therapy

MethylPREDNISolone: CYP3A4 Inducers (Moderate) may decrease the serum concentration of MethylPREDNISolone. Monitor therapy

MiFEPRIStone: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Minimize doses of CYP3A4 substrates, and monitor for increased concentrations/toxicity, during and 2 weeks following treatment with mifepristone. Avoid cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus. Consider therapy modification

Mirodenafil: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Mirodenafil. Monitor therapy

Naldemedine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Naldemedine. Monitor therapy

Naloxegol: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Naloxegol. Monitor therapy

Neratinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Neratinib. Avoid combination

Netupitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

NiMODipine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of NiMODipine. Monitor therapy

Nintedanib: Inducers of CYP3A4 (Moderate) and P-glycoprotein may decrease the serum concentration of Nintedanib. Avoid combination

Nisoldipine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Nisoldipine. Avoid combination

Olaparib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Olaparib. Avoid combination

Oliceridine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Oliceridine. Monitor therapy

Palbociclib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Palbociclib. Monitor therapy

Palbociclib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

PAZOPanib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of PAZOPanib. Monitor therapy

Pemigatinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Pemigatinib. Avoid combination

Perampanel: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Perampanel. Management: Increase the perampanel starting dose to 4 mg/day when perampanel is used concurrently with moderate and strong CYP3A4 inducers. Monitor perampanel response closely, particularly with changes to CYP3A4 inducer therapy. Consider therapy modification

Pimavanserin: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Pimavanserin. Avoid combination

Pitolisant: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Pitolisant. Monitor therapy

Pralsetinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Pralsetinib. Monitor therapy

PrednisoLONE (Systemic): CYP3A4 Inducers (Moderate) may decrease the serum concentration of PrednisoLONE (Systemic). Monitor therapy

PredniSONE: CYP3A4 Inducers (Moderate) may decrease the serum concentration of PredniSONE. Monitor therapy

Pretomanid: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Pretomanid. Avoid combination

Propacetamol: Lorlatinib may decrease the serum concentration of Propacetamol. Monitor therapy

Ranolazine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Ranolazine. Avoid combination

Rimegepant: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Rimegepant. Avoid combination

Rivaroxaban: Inducers of CYP3A4 (Moderate) and P-glycoprotein may decrease the serum concentration of Rivaroxaban. Monitor therapy

Rolapitant: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Rolapitant. Monitor therapy

Sarilumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Selpercatinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Selpercatinib. Avoid combination

Selumetinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Selumetinib. Avoid combination

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Simeprevir: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Simeprevir. Avoid combination

Sirolimus: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Sirolimus. Monitor therapy

Sofosbuvir: P-glycoprotein/ABCB1 Inducers may decrease the serum concentration of Sofosbuvir. Avoid combination

Sonidegib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Sonidegib. Avoid combination

Stiripentol: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

SUNItinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of SUNItinib. Monitor therapy

Tacrolimus (Systemic): CYP3A4 Inducers (Moderate) may decrease the serum concentration of Tacrolimus (Systemic). Monitor therapy

Tazemetostat: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Tazemetostat. Avoid combination

Tezacaftor and Ivacaftor: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Tezacaftor and Ivacaftor. Monitor therapy

Ticagrelor: CYP3A4 Inducers (Moderate) may decrease serum concentrations of the active metabolite(s) of Ticagrelor. CYP3A4 Inducers (Moderate) may decrease the serum concentration of Ticagrelor. Monitor therapy

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Tofacitinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Tofacitinib. Monitor therapy

Tolvaptan: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Tolvaptan. Monitor therapy

Toremifene: CYP3A4 Inducers (Moderate) may decrease serum concentrations of the active metabolite(s) of Toremifene. CYP3A4 Inducers (Moderate) may decrease the serum concentration of Toremifene. Monitor therapy

Trabectedin: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Trabectedin. Monitor therapy

Ubrogepant: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Ubrogepant. Management: Use an initial ubrogepant dose of 100 mg and second dose (if needed) of 100 mg when used with a moderate CYP3A4 inducer. Consider therapy modification

Upadacitinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Upadacitinib. Monitor therapy

Valbenazine: CYP3A4 Inducers (Moderate) may decrease serum concentrations of the active metabolite(s) of Valbenazine. CYP3A4 Inducers (Moderate) may decrease the serum concentration of Valbenazine. Monitor therapy

Vandetanib: CYP3A4 Inducers (Moderate) may increase serum concentrations of the active metabolite(s) of Vandetanib. CYP3A4 Inducers (Moderate) may decrease the serum concentration of Vandetanib. Monitor therapy

Velpatasvir: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Velpatasvir. Avoid combination

Vemurafenib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Vemurafenib. Monitor therapy

Venetoclax: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Venetoclax. Avoid combination

Verapamil: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Verapamil. Monitor therapy

Vilazodone: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Vilazodone. Monitor therapy

VinCRIStine (Liposomal): P-glycoprotein/ABCB1 Inducers may decrease the serum concentration of VinCRIStine (Liposomal). Avoid combination

Vitamin K Antagonists (eg, warfarin): CYP2C9 Inducers (Weak) may decrease the serum concentration of Vitamin K Antagonists. Monitor therapy

Vorapaxar: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Vorapaxar. Avoid combination

Vortioxetine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Vortioxetine. Monitor therapy

Voxelotor: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Voxelotor. Management: Avoid concomitant use of voxelotor and moderate CYP3A4 inducers. If concomitant use is unavoidable, increase the voxelotor dose to 2,500 mg once daily. Consider therapy modification

Voxilaprevir: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Voxilaprevir. Avoid combination

Zaleplon: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Zaleplon. Monitor therapy

Zanubrutinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Zanubrutinib. Avoid combination

Zolpidem: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Zolpidem. Monitor therapy

Zopiclone: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Zopiclone. Monitor therapy

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.

>10%:

Cardiovascular: Edema (57%)

Central nervous system: Peripheral neuropathy (47%; grade 3/4: 3%), cognitive dysfunction (27% to 29%), fatigue (26%), mood disorder (23% to 24%), headache (18%), dizziness (16%), speech disturbance (12% to 14%), sleep disorder (10%)

Dermatologic: Skin rash (14%)

Endocrine & metabolic: Hypercholesterolemia (96%), hypertriglyceridemia (90%), hyperglycemia (52%), hypoalbuminemia (33%), weight gain (24%), increased amylase (22%), hyperkalemia (21%), hypomagnesemia (21%), hypophosphatemia (21%)

Gastrointestinal: Increased serum lipase (24%), diarrhea (22%), nausea (18%), constipation (15%), vomiting (12%)

Hematologic & oncologic: Anemia (52%; grade 3/4: 5%), thrombocytopenia (23%; grade 3/4: <1%), lymphocytopenia (22%; grades 3/4: 3%)

Hepatic: Increased serum aspartate aminotransferase (37%), increased serum alanine aminotransferase (28%), increased serum alkaline phosphatase (24%)

Neuromuscular & skeletal: Arthralgia (23%), myalgia (17%), back pain (13%), limb pain (13%)

Ophthalmic: Visual disturbance (15%)

Respiratory: Dyspnea (27%), cough (18%), upper respiratory tract infection (12%)

Miscellaneous: Fever (12%)

1% to 10%:

Cardiovascular: Atrioventricular block (1%)

Central nervous system: Hallucination (7%), seizure (3%), mental status changes (2%)

Respiratory: Pneumonia (3%), interstitial pulmonary disease (≤2%), pneumonitis (≤2%), respiratory failure (1%)

Warnings/Precautions

Concerns related to adverse effects:

• Bone marrow suppression: Anemia (usually mild) commonly occurred with lorlatinib. Mild thrombocytopenia and lymphopenia also occurred.

• Cardiovascular effects: PR interval prolongation and atrioventricular (AV) block may rarely occur in patients receiving lorlatinib, including grade 3 events. Some patients required pacemaker placement. Monitor ECG prior to initiating lorlatinib treatment and periodically thereafter. Withhold treatment and resume at a reduced dose (if no pacemaker placement) or at the same dose in patients who undergo pacemaker placement. Permanently discontinue for recurrence in patients without a pacemaker.

• CNS effects: CNS effects (including seizures, hallucinations, cognitive function, mood [including suicidal ideation], speech, mental status, and sleep changes) may occur in patients receiving lorlatinib. Overall, CNS effects occurred in just over half of patients receiving lorlatinib. Cognitive effects occurred in nearly one-third patients who received lorlatinib (at any dose) in one study; a small percentage of these events were severe (grade 3 or 4). Mood effects occurred in nearly one-fourth of patients; severe events occurred rarely. Speech effects, hallucinations, and mental status changes have also been reported, including rare severe events. Seizures have been observed, sometimes in conjunction with other neurologic findings. Changes in sleep have also been reported. The median time to initial onset of any CNS effect was 1.2 months (range: 1 day to 1.7 years). Depending on the severity, CNS adverse events may require treatment interruption, dose reduction, and/or permanent discontinuation.

• Hepatotoxicity: Severe hepatotoxicity occurred in a majority of healthy subjects who received a lorlatinib dose in combination with multiple daily doses of rifampin (a strong CYP3A inducer). Grade 3 and 4 ALT or AST elevations occurred commonly; grade 2 elevations also were reported. ALT or AST elevations occurred within 3 days and returned to within normal limits after a median of 15 days (range: 7 to 34 days); for subjects with grade 2 ALT or AST elevation, the median time to recovery was 7 days and for subjects with grade 3 or 4 ALT or AST elevations, the median time to recovery was 18 days. Lorlatinib use is contraindicated in patients taking strong CYP3A inducers. Discontinue strong CYP3A inducers for 3 plasma half-lives (of the strong CYP3A inducer) prior to initiating lorlatinib treatment. Avoid concomitant use of lorlatinib with moderate CYP3A inducers; if concomitant use of moderate CYP3A inducers cannot be avoided, monitor AST, ALT, and bilirubin 48 hours after initiating lorlatinib and at least 3 times during the first week after lorlatinib initiation. Depending upon the relative importance of each drug, discontinue lorlatinib or the CYP3A inducer for persistent grade 2 or higher hepatotoxicity.

• Hyperlipidemia: Serum cholesterol and triglycerides increases may occur in patients receiving lorlatinib. Grade 3 or 4 total cholesterol and triglyceride elevations have been reported. The median time to onset (for both hypercholesterolemia and hypertriglyceridemia) was 15 days. A majority of patients with hypercholesterolemia and hypertriglyceridemia required initiation of lipid-lowering medications, usually at ~21 days after lorlatinib initiation. Monitor serum cholesterol and triglycerides prior to initiating lorlatinib, at 1 and 2 months after lorlatinib initiation, and periodically thereafter. Initiate lipid-lowering agents (or increase the dose) in patients with hyperlipidemia. Depending on the severity, hyperlipidemia may require lorlatinib treatment interruption and/or dose reduction.

• Pulmonary toxicity: While rare, severe or life-threatening pulmonary adverse reactions consistent with interstitial lung disease (ILD)/pneumonitis may occur with lorlatinib, including grades 3 and 4 events. Promptly evaluate new or worsening respiratory symptoms indicative of ILD/pneumonitis (eg, dyspnea, cough, fever). Immediately withhold lorlatinib if ILD/pneumonitis is suspected; discontinue permanently for lorlatinib-related ILD/pneumonitis of any severity.

Other warnings/precautions:

• ALK positivity: Lorlatinib is approved for use in patients with metastatic non-small cell lung cancer (NSCLC) who test positive for the abnormal anaplastic lymphoma kinase (ALK) gene. Information on approved tests for detection of ALK gene rearrangements may be found at https://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/InVitroDiagnostics/ucm301431.htm.

Monitoring Parameters

ALK positivity; serum cholesterol and triglycerides (prior to initiating lorlatinib, at 1 and 2 months after lorlatinib initiation, and periodically thereafter); AST, ALT, and bilirubin (48 hours after initiating lorlatinib and at least 3 times during the first week after initiation [if concomitant use of moderate CYP3A inducers cannot be avoided]); pregnancy test (prior to treatment in females of reproductive potential). Monitor ECG (prior to lorlatinib initiation and periodically thereafter). Monitor for signs/symptoms of CNS adverse events and interstitial lung disease/pneumonitis. Monitor adherence.

Reproductive Considerations

Evaluate pregnancy status in females of reproductive potential prior to initiating therapy. Females of reproductive potential should avoid pregnancy and use an effective nonhormonal method of contraception during treatment and for at least 6 months after the final lorlatinib dose. Male patients with female partners of reproductive potential should use effective contraception during treatment and for at least 3 months after the last lorlatinib dose.

Pregnancy Considerations

Based on the mechanism of action and data from animal reproduction studies, lorlatinib may cause fetal harm if administered during pregnancy.

Patient Education

What is this drug used for?

• It is used to treat lung cancer.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Weight gain

• Muscle pain

• Joint pain

• Diarrhea

• Nausea

• Vomiting

• Constipation

• Back pain

• Painful extremities

• Common cold symptoms

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• High blood sugar like confusion, fatigue, increased thirst, increased hunger, passing a lot of urine, flushing, fast breathing, or breath that smells like fruit

• Electrolyte problems like mood changes, confusion, muscle pain or weakness, abnormal heartbeat, seizures, lack of appetite, or severe nausea or vomiting

• Seizures

• Trouble speaking

• Burning or numbness feeling

• Change in balance

• Muscle weakness

• Trouble with memory

• Trouble focusing

• Severe fatigue

• Slow heartbeat

• Abnormal heartbeat

• Dizziness

• Passing out

• Swelling

• Severe loss of strength and energy

• Bruising

• Bleeding

• Chills

• Sore throat

• Anxiety

• Nightmares

• Trouble sleeping

• Vision changes

• Confusion

• Agitation

• Restlessness

• Hallucination

• Severe headache

• Depression like thoughts of suicide, anxiety, emotional instability, or confusion

• Lung problems like shortness of breath or other trouble breathing, cough that is new or worse

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing, swallowing, or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a limited summary of general information about the medicine’s uses from the patient education leaflet and is not intended to be comprehensive. This limited summary does NOT include all information available about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not intended to provide medical advice, diagnosis or treatment and does not replace information you receive from the healthcare provider. For a more detailed summary of information about the risks and benefits of using this medicine, please speak with your healthcare provider and review the entire patient education leaflet.

Frequently asked questions

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.