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Lorlatinib: Drug information

Lorlatinib: Drug information
(For additional information see "Lorlatinib: Patient drug information")

For abbreviations, symbols, and age group definitions used in Lexicomp (show table)
Brand Names: US
  • Lorbrena
Brand Names: Canada
  • Lorbrena
Pharmacologic Category
  • Antineoplastic Agent, Anaplastic Lymphoma Kinase Inhibitor;
  • Antineoplastic Agent, Tyrosine Kinase Inhibitor
Dosing: Adult
Non–small cell lung cancer, metastatic

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

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

Dosing: Kidney Impairment: Adult

Note: Kidney function estimated using the Cockcroft-Gault formula.

CrCl 30 to 89 mL/minute: No dosage adjustment necessary.

CrCl 15 to <30 mL/minute: Reduce dose to 75 mg once daily.

End-stage renal impairment requiring dialysis: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

Dosing: Hepatic Impairment: Adult

Mild impairment (total bilirubin ≤ ULN with AST > ULN or total bilirubin >1 to 1.5 times ULN with any AST): No dosage adjustment necessary.

Moderate impairment (total bilirubin ≥1.5 to 3 times ULN with any AST) or severe impairment (total bilirubin >3 times ULN with any AST): There are no dosage adjustments provided in the manufacturer's labeling (has not been established).

Dosing: Adjustment for Toxicity: Adult
Lorlatinib Dose Reduction Levels for Adverse Reactions

Dose level

Lorlatinib dose

Initial (usual) dose

100 mg once daily

First dose reduction

75 mg once daily

Second dose reduction

50 mg once daily

Subsequent

Permanently discontinue lorlatinib if unable to tolerate 50 mg once daily.

Lorlatinib Recommended Dose Modifications for Adverse Reactions

Adverse reaction

Severity

Lorlatinib dose modification

aControl BP prior to initiating lorlatinib.

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.

Hypertensiona

Grade 3 (systolic BP [SBP] ≥160 mm Hg or diastolic BP [DBP] ≥100 mm Hg; medical intervention indicated; >1 antihypertensive medication, or more intensive therapy than previously used indicated)

Withhold lorlatinib until hypertension has recovered to ≤ grade 1 (SBP <140 mm Hg and DBP <90 mm Hg), then resume lorlatinib at the same dose. If grade 3 hypertension recurs, withhold lorlatinib until recovery to ≤ grade 1, then resume at a reduced dose. If hypertension cannot be adequately controlled with optimal medical management, permanently discontinue lorlatinib.

Grade 4 (life-threatening consequences, urgent intervention indicated)

Withhold lorlatinib until recovery to ≤ grade 1, then resume at a reduced dose or permanently discontinue lorlatinib.

Recurrent grade 4 hypertension

Permanently discontinue lorlatinib.

CNS effects

CNS effects (eg, seizures, psychotic effects, changes in cognitive function, mood [including suicidal ideation], speech, mental status, sleep)

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.

Metabolic effects

Hyperglycemia

Grade 3 (fasting serum glucose >250 mg/dL despite optimal antihyperglycemic therapy or grade 4

Withhold lorlatinib until hyperglycemia is appropriately controlled, then resume at the next lower dose. If hyperglycemia cannot be adequately controlled with optimal medical management, 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 effects

Treatment-related interstitial lung disease (ILD)/pneumonitis

Any grade

Immediately withhold lorlatinib if ILD/pneumonitis is suspected. Permanently discontinue lorlatinib for ILD/pneumonitis of any severity.

Other adverse reactions

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.

Dosing: Older Adult

Refer to adult dosing.

Adverse Reactions

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

>10%:

Cardiovascular: Chest pain (11%), edema (56% to 57%), hypertension (18%)

Dermatologic: Skin rash (11% to 14%)

Endocrine & metabolic: Hypercholesterolemia (91% to 96%), hyperglycemia (48% to 52%), hyperkalemia (21%), hypertriglyceridemia (90% to 95%), hypoalbuminemia (33% to 36%), hypomagnesemia (21%), hypophosphatemia (21%), increased amylase (20% to 22%), increased gamma-glutamyl transferase (52%), weight gain (24% to 38%)

Gastrointestinal: Constipation (15% to 17%), diarrhea (21% to 22%), increased serum lipase (24% to 28%), nausea (15% to 18%), vomiting (12% to 13%)

Hematologic & oncologic: Anemia (48% to 52%; grade 3/4: 2% to 5%), lymphocytopenia (22% to 23%; grades 3/4: 3%), prolonged prothrombin time (25%), thrombocytopenia (23%; grade 3/4: <1%)

Hepatic: Increased serum alanine aminotransferase (28% to 44%), increased serum alkaline phosphatase (23% to 24%), increased serum aspartate aminotransferase (37% to 48%)

Nervous system: Cognitive dysfunction (21% to 27%), dizziness (11% to 16%), fatigue (19% to 26%), headache (17% to 18%), mood disorder (16% to 23%), peripheral neuropathy (34% to 47%; grade 3/4: 2% to 3%), sleep disorder (10% to 11%), speech disturbance (7% to 12%)

Neuromuscular & skeletal: Arthralgia (19% to 23%), back pain (13% to 15%), increased creatine phosphokinase in blood specimen (39%), limb pain (13% to 17%), myalgia (15% to 17%)

Ophthalmic: Visual disturbance (15% to 18%)

Renal: Increased serum creatinine (81%)

Respiratory: Cough (16% to 18%), dyspnea (20% to 27%), upper respiratory tract infection (11% to 12%)

Miscellaneous: Fever (12% to 17%)

1% to 10%:

Nervous system: Mental status changes (1%), psychotic reaction (3% to 7%)

Respiratory: Bronchitis (7%), pneumonia (3% to 7%), respiratory failure (1% to 3%)

Frequency not defined:

Cardiovascular: Atrioventricular block

Nervous system: Seizure

Respiratory: Interstitial pulmonary disease, pneumonitis

Contraindications

Concomitant use of strong CYP3A inducers.

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

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

Warnings/Precautions

Concerns related to adverse effects:

• Cardiovascular effects: PR interval prolongation and atrioventricular block may rarely occur in patients receiving lorlatinib, including grade 3 events. Some patients required pacemaker placement.

• CNS effects: CNS effects (including seizures, psychotic effects/changes and 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 1.4 months (range: 1 day to 3.4 years).

• Hyperglycemia: Hyperglycemia has been reported, including grade 3 or 4 events. The median time to onset of hyperglycemia was 4.8 months (range: 1 day to 2.9 years).

• 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 ~17 days after lorlatinib initiation. Initiate lipid-lowering agents (or increase the dose) in patients with hyperlipidemia.

• Hypertension: Hypertension may occur, including grade 3 and 4 events. The median time to onset of hypertension was 6.4 months (range: 1 day to 2.8 years). Control BP prior to lorlatinib initiation.

• Pulmonary toxicity: Severe or life-threatening pulmonary adverse reactions consistent with interstitial lung disease (ILD)/pneumonitis may rarely occur with lorlatinib, including grades 3 and 4 events. Promptly evaluate new or worsening respiratory symptoms indicative of ILD/pneumonitis (eg, dyspnea, cough, fever).

Other warnings/precautions:

• ALK positivity: Select patients for the treatment of metastatic non-small cell lung cancer based on the presence of ALK positivity in tumor specimens. Information on approved tests for detection of ALK gene rearrangements may be found at https://www.fda.gov/CompanionDiagnostics.

Dosage Forms: US

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

Tablet, Oral:

Lorbrena: 25 mg, 100 mg

Generic Equivalent Available: US

No

Pricing: US

Tablets (Lorbrena Oral)

25 mg (per each): $284.79

100 mg (per each): $854.38

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Dosage Forms: Canada

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

Tablet, Oral:

Lorbrena: 25 mg, 100 mg

Administration: Adult

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

Hazardous Drugs Handling Considerations

This medication is not on the NIOSH (2016) list; however, it may meet the criteria for a hazardous drug. Lorlatinib may cause reproductive toxicity, teratogenicity, genotoxicity, and has a structural/toxicity profile similar to existing hazardous agents.

Use appropriate precautions for receiving, handling, storage, preparation, dispensing, transporting, administration, and disposal. Follow NIOSH and USP 800 recommendations and institution-specific policies/procedures for appropriate containment strategy (NIOSH 2016; USP-NF 2020).

Note: Facilities may perform risk assessment of some hazardous drugs to determine if appropriate for alternative handling and containment strategies (USP-NF 2020). Refer to institution-specific handling policies/procedures.

Use: Labeled Indications

Non-small cell lung cancer, metastatic (ALK-positive): Treatment of metastatic non-small cell lung cancer in adults whose tumors are ALK-positive (as detected by an approved test).

Medication Safety Issues
Sound-alike/look-alike issues:

Lorlatinib may be confused with alectinib, brigatinib, ceritinib, crizotinib, erlotinib, lapatinib, larotrectinib, lenvatinib, loratadine, lorazepam, lornafarnib.

High alert medication:

This medication is in a class the Institute for Safe Medication Practices (ISMP) includes among its lists of drug classes which have a heightened risk of causing significant patient harm when used in error.

Metabolism/Transport Effects

Substrate of CYP3A4 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential; Induces CYP2B6 (weak), CYP2C9 (weak), CYP3A4 (moderate), P-glycoprotein/ABCB1

Drug Interactions

Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.

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

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

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

Acetaminophen: Lorlatinib may decrease the serum concentration of Acetaminophen. Risk C: 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. Risk D: 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. Risk D: Consider therapy modification

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

ALPRAZolam: CYP3A4 Inducers (Moderate) may decrease the serum concentration of ALPRAZolam. Risk C: Monitor therapy

AmLODIPine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of AmLODIPine. Risk C: Monitor therapy

Androgens: Hypertension-Associated Agents may enhance the hypertensive effect of Androgens. Risk C: Monitor therapy

Antidiabetic Agents: Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy

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

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

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

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

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

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

Artemether and Lumefantrine: CYP3A4 Inducers (Moderate) may decrease serum concentrations of the active metabolite(s) of Artemether and Lumefantrine. Specifically, concentrations of dihydroartemisinin (DHA), the active metabolite of artemether may be decreased. CYP3A4 Inducers (Moderate) may decrease the serum concentration of Artemether and Lumefantrine. Risk C: Monitor therapy

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

Atogepant: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Atogepant. Management: For treatment of episodic migraine, the recommended dose of atogepant is 30 mg once daily or 60 mg once daily when combined with CYP3A4 inducers. When used for treatment of chronic migraine, use of atogepant with CYP3A4 inducers should be avoided. Risk D: Consider therapy modification

Atorvastatin: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Atorvastatin. Risk C: Monitor therapy

Avacopan: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Avacopan. Risk X: Avoid combination

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

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

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

Bedaquiline: CYP3A4 Inducers (Moderate) may increase serum concentrations of the active metabolite(s) of Bedaquiline. CYP3A4 Inducers (Moderate) may decrease the serum concentration of Bedaquiline. Risk X: Avoid combination

Belumosudil: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Belumosudil. Risk C: Monitor therapy

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

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

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

Bosutinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Bosutinib. Risk C: Monitor therapy

Brexpiprazole: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Brexpiprazole. Risk C: 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. Risk D: Consider therapy modification

Buprenorphine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Buprenorphine. Risk C: Monitor therapy

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

BusPIRone: CYP3A4 Inducers (Moderate) may decrease the serum concentration of BusPIRone. Risk C: Monitor therapy

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

Cannabis: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Cannabis. More specifically, tetrahydrocannabinol and cannabidiol serum concentrations may be decreased. Risk C: Monitor therapy

Capivasertib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Capivasertib. Risk X: Avoid combination

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

Cariprazine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Cariprazine. Risk X: Avoid combination

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

Cladribine: P-glycoprotein/ABCB1 Inducers may decrease the serum concentration of Cladribine. Risk C: 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 CYP3A4 inducer. Drugs that enhance the metabolism of clarithromycin into 14-hydroxyclarithromycin may alter the clinical activity of clarithromycin and impair its efficacy. Risk D: Consider therapy modification

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

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

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

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

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

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

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

CycloSPORINE (Systemic): CYP3A4 Inducers (Moderate) may decrease the serum concentration of CycloSPORINE (Systemic). Risk C: 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, increase lorlatinib to 125 mg daily. Monitor for reduced lorlatinib efficacy and consider closer monitoring of AST, ALT, and bilirubin. Risk D: Consider therapy modification

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

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. Risk D: Consider therapy modification

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. Risk X: Avoid combination

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. Risk D: Consider therapy modification

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

Daridorexant: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Daridorexant. Risk X: Avoid combination

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

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

Dasatinib: CYP3A4 Inducers (Moderate) may increase the serum concentration of Dasatinib. Risk C: Monitor therapy

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

Delavirdine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Delavirdine. Risk C: Monitor therapy

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

DiazePAM: CYP3A4 Inducers (Moderate) may decrease the serum concentration of DiazePAM. Risk C: Monitor therapy

Dienogest: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Dienogest. Risk C: Monitor therapy

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

DilTIAZem: CYP3A4 Inducers (Moderate) may decrease the serum concentration of DilTIAZem. Risk C: Monitor therapy

Disopyramide: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Disopyramide. Risk C: Monitor therapy

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

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

DOXOrubicin (Conventional): CYP3A4 Inducers (Moderate) may decrease the serum concentration of DOXOrubicin (Conventional). Risk X: Avoid combination

DroNABinol: CYP3A4 Inducers (Moderate) may decrease the serum concentration of DroNABinol. Risk C: Monitor therapy

Dronedarone: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Dronedarone. Risk C: Monitor therapy

Duvelisib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Duvelisib. Management: Avoid if possible. If used, on day 12 of combination increase duvelisib from 25 mg twice daily to 40 mg twice daily or from 15 mg twice daily to 25 mg twice daily. Resume prior duvelisib dose 14 days after stopping moderate CYP3A4 inducer. Risk D: Consider therapy modification

Dydrogesterone: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Dydrogesterone. Risk C: Monitor therapy

Edoxaban: P-glycoprotein/ABCB1 Inducers may decrease the serum concentration of Edoxaban. Management: Avoid coadministration of edoxaban and P-glycoprotein (P-gp) inducers if possible. If concomitant use is required, be aware the edoxaban efficacy may be decreased. Risk D: Consider therapy modification

Elacestrant: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Elacestrant. Risk X: Avoid combination

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

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

Eliglustat: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Eliglustat. Risk C: Monitor therapy

Elvitegravir: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Elvitegravir. Risk C: Monitor therapy

Entrectinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Entrectinib. Risk X: 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. Risk D: Consider therapy modification

Erlotinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Erlotinib. Risk C: Monitor therapy

Estrogen Derivatives: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Estrogen Derivatives. Risk C: Monitor therapy

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

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

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

Exemestane: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Exemestane. Risk C: Monitor therapy

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

Felodipine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Felodipine. Risk C: Monitor therapy

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

Fexinidazole: CYP3A4 Inducers (Moderate) may increase serum concentrations of the active metabolite(s) of Fexinidazole. Risk X: Avoid combination

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

Finerenone: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Finerenone. Risk X: Avoid combination

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

Fluconazole: May increase the serum concentration of Lorlatinib. Management: Avoid use of lorlatinib with fluconazole whenever possible. If the combination cannot be avoided, reduce the lorlatinib dose from 100 mg once daily to 75 mg once daily. Risk D: Consider therapy modification

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

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

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

Fruquintinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Fruquintinib. Management: Avoid this combination when possible. If combined, continue the same fruquintinib dose, but monitor for reduced fruquintinib efficacy. Risk D: Consider therapy modification

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

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

Ganaxolone: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Ganaxolone. Management: Avoid concomitant use of ganaxolone and moderate CYP3A4 inducers whenever possible. If combined, consider increasing the dose of ganaxolone, but do not exceed the maximum recommended daily dose. Risk D: Consider therapy modification

Gefitinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Gefitinib. Risk C: Monitor therapy

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

Gepirone: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Gepirone. Risk C: Monitor therapy

Gilteritinib: Inducers of CYP3A4 (Moderate) and P-glycoprotein may decrease the serum concentration of Gilteritinib. Risk C: 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. Risk D: Consider therapy modification

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

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. Risk D: Consider therapy modification

Hormonal Contraceptives: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Hormonal Contraceptives. Management: Advise patients to use an alternative method of contraception or a back-up method during coadministration, and to continue back-up contraception for 28 days after discontinuing a moderate CYP3A4 inducer to ensure contraceptive reliability. Risk D: Consider therapy modification

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

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

Ibrexafungerp: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Ibrexafungerp. Risk X: Avoid combination

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

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. Risk C: Monitor therapy

Imatinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Imatinib. Risk C: Monitor therapy

Indinavir: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Indinavir. Management: Consider avoiding the combination of indinavir and moderate CYP3A4 inducers whenever possible due to the risk for decreased indinavir concentrations, reduced efficacy, and development of resistance. If combined, monitor for indinavir treatment failure. Risk D: Consider therapy modification

Infigratinib: CYP3A4 Inducers (Moderate) may decrease serum concentrations of the active metabolite(s) of Infigratinib. CYP3A4 Inducers (Moderate) may decrease the serum concentration of Infigratinib. Risk X: Avoid combination

Irinotecan Products: CYP3A4 Inducers (Moderate) may decrease serum concentrations of the active metabolite(s) of Irinotecan Products. Specifically, concentrations of SN-38 may be reduced. Risk C: Monitor therapy

Isavuconazonium Sulfate: CYP3A4 Inducers (Moderate) may decrease serum concentrations of the active metabolite(s) of Isavuconazonium Sulfate. Specifically, CYP3A4 Inducers (Moderate) may decrease isavuconazole serum concentrations. Risk C: Monitor therapy

Isradipine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Isradipine. Risk C: Monitor therapy

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

Ivabradine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Ivabradine. Risk X: Avoid combination

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

Ixabepilone: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Ixabepilone. Risk C: Monitor therapy

Ixazomib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Ixazomib. Risk C: Monitor therapy

Ketamine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Ketamine. Risk C: Monitor therapy

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

Larotrectinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Larotrectinib. Management: Double the larotrectinib dose if used together with a moderate CYP3A4 inducer. Following discontinuation of the moderate CYP3A4 inducer, resume the previous dose of larotrectinib after a period of 3 to 5 times the inducer's half-life. Risk D: Consider therapy modification

Ledipasvir: P-glycoprotein/ABCB1 Inducers may decrease the serum concentration of Ledipasvir. Risk X: 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. Risk D: 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. Risk D: 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. Risk D: 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. Risk D: Consider therapy modification

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

Lenacapavir: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Lenacapavir. Risk X: Avoid combination

Leniolisib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Leniolisib. Risk X: Avoid combination

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

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

Levamlodipine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Levamlodipine. Risk C: Monitor therapy

Levomethadone: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Levomethadone. Risk C: Monitor therapy

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. Risk D: Consider therapy modification

Lonafarnib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Lonafarnib. Risk X: Avoid combination

Lovastatin: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Lovastatin. Risk C: Monitor therapy

Lumateperone: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Lumateperone. Risk X: 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. Risk D: Consider therapy modification

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

Maraviroc: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Maraviroc. Management: Increase maraviroc adult dose to 600 mg twice/day, but only if not receiving a strong CYP3A4 inhibitor. Not recommended for pediatric patients not also receiving a strong CYP3A4 inhibitor. Contraindicated in patients with CrCl less than 30 mL/min. Risk D: Consider therapy modification

Maribavir: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Maribavir. Risk C: Monitor therapy

Mavacamten: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Mavacamten. Risk X: Avoid combination

Mefloquine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Mefloquine. Risk C: Monitor therapy

Meperidine: CYP3A4 Inducers (Moderate) may increase serum concentrations of the active metabolite(s) of Meperidine. Specifically, concentrations of normeperidine, the CNS stimulating metabolite, may be increased. CYP3A4 Inducers (Moderate) may decrease the serum concentration of Meperidine. Risk C: Monitor therapy

Methadone: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Methadone. Risk C: Monitor therapy

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

Mianserin: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Mianserin. Risk C: Monitor therapy

Midazolam: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Midazolam. Risk C: Monitor therapy

Midostaurin: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Midostaurin. Risk C: Monitor therapy

MiFEPRIStone: CYP3A4 Inducers (Moderate) may decrease the serum concentration of MiFEPRIStone. Management: Avoid combined use in patients treated for Cushing's disease. When used for pregnancy termination, mifepristone efficacy may be reduced and an alternative pregnancy termination procedure may be warranted. Ensure a follow-up assessment after combined use. Risk D: Consider therapy modification

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

Mitapivat: May enhance the hepatotoxic effect of Lorlatinib. Lorlatinib may decrease the serum concentration of Mitapivat. Mitapivat may decrease the serum concentration of Lorlatinib. Management: Coadministration of lorlatinib and mitapivat should be avoided. If combined, increase the lorlatinib dose to 125 mg once daily and titrate mitapivat beyond 50 mg twice daily based on hemoglobin, if needed, to a maximum dose of 100 mg twice daily. Risk D: Consider therapy modification

Mobocertinib: CYP3A4 Inducers (Moderate) may decrease serum concentrations of the active metabolite(s) of Mobocertinib. CYP3A4 Inducers (Moderate) may decrease the serum concentration of Mobocertinib. Risk X: Avoid combination

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

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

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

Netupitant: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Netupitant. Risk C: Monitor therapy

Nevirapine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Nevirapine. Risk C: Monitor therapy

NIFEdipine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of NIFEdipine. Risk C: Monitor therapy

Nilotinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Nilotinib. Risk C: Monitor therapy

Nilvadipine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Nilvadipine. Risk C: Monitor therapy

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

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

Nirogacestat: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Nirogacestat. Risk X: Avoid combination

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

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

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

Olmutinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Olmutinib. Risk C: Monitor therapy

Olutasidenib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Olutasidenib. Risk X: Avoid combination

Omaveloxolone: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Omaveloxolone. Risk X: Avoid combination

Orelabrutinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Orelabrutinib. Risk X: Avoid combination

Osimertinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Osimertinib. Risk C: Monitor therapy

OxyCODONE: CYP3A4 Inducers (Moderate) may decrease the serum concentration of OxyCODONE. Risk C: Monitor therapy

PACLitaxel (Conventional): CYP3A4 Inducers (Moderate) may decrease the serum concentration of PACLitaxel (Conventional). Risk C: Monitor therapy

PACLitaxel (Protein Bound): CYP3A4 Inducers (Moderate) may decrease the serum concentration of PACLitaxel (Protein Bound). Risk C: Monitor therapy

Pacritinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Pacritinib. Risk X: Avoid combination

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

Palovarotene: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Palovarotene. Risk X: Avoid combination

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

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

Perampanel: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Perampanel. Management: Increase perampanel starting dose to 4 mg/day if used with moderate CYP3A4 inducers. Increase perampanel dose by 2 mg/day no more than once weekly based on response and tolerability. Dose adjustments may be needed if the inducer is discontinued. Risk D: Consider therapy modification

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

Piperaquine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Piperaquine. Risk C: Monitor therapy

Pirtobrutinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Pirtobrutinib. Management: Avoid concomitant use if possible. If combined, if the current pirtobrutinib dose is 200 mg once daily, increase to 300 mg once daily. If current pirtobrutinib dose is 50 mg or 100 mg once daily, increase the dose by 50 mg. Risk D: Consider therapy modification

PONATinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of PONATinib. Risk C: Monitor therapy

Pralsetinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Pralsetinib. Management: If this combo cannot be avoided, increase pralsetinib dose from 400 mg daily to 600 mg daily; from 300 mg daily to 500 mg daily; and from 200 mg daily to 300 mg daily. Risk D: Consider therapy modification

Praziquantel: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Praziquantel. Management: Consider alternatives to this combination whenever possible. If combined, monitor closely for reduced praziquantel efficacy. If possible, stop the moderate CYP3A4 inducer 2 to 4 weeks before praziquantel initiation. Risk D: Consider therapy modification

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

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

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

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

QUEtiapine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of QUEtiapine. Risk C: Monitor therapy

QuiNIDine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of QuiNIDine. Risk C: Monitor therapy

QuiNINE: CYP3A4 Inducers (Moderate) may decrease the serum concentration of QuiNINE. Risk C: Monitor therapy

Quizartinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Quizartinib. Risk X: Avoid combination

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

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

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

Relugolix, Estradiol, and Norethindrone: Inducers of CYP3A4 (Moderate) and P-glycoprotein may decrease the serum concentration of Relugolix, Estradiol, and Norethindrone. Risk C: Monitor therapy

Repaglinide: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Repaglinide. Risk C: Monitor therapy

Repotrectinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Repotrectinib. Risk X: Avoid combination

Ribociclib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Ribociclib. Risk C: Monitor therapy

Rilpivirine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Rilpivirine. Risk C: Monitor therapy

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

Ripretinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Ripretinib. Management: Avoid this combination if possible. If concomitant use is required, increase ripretinib to 150 mg twice daily. Decrease ripretinib to 150 mg once daily 14 days after stopping a moderate CYP3A4 inducer. Monitor patients for ripretinib response and toxicity Risk D: Consider therapy modification

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

Ritlecitinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Ritlecitinib. Risk C: Monitor therapy

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

Roflumilast (Systemic): CYP3A4 Inducers (Moderate) may decrease serum concentrations of the active metabolite(s) of Roflumilast (Systemic). CYP3A4 Inducers (Moderate) may decrease the serum concentration of Roflumilast (Systemic). Risk C: Monitor therapy

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

Samidorphan: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Samidorphan. Risk C: Monitor therapy

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

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

Sertraline: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Sertraline. Risk C: Monitor therapy

Sildenafil: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Sildenafil. Risk C: Monitor therapy

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

Simvastatin: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Simvastatin. Risk C: Monitor therapy

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

Sirolimus (Protein Bound): P-glycoprotein/ABCB1 Inducers may decrease the serum concentration of Sirolimus (Protein Bound). Risk X: Avoid combination

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

Solriamfetol: May enhance the hypertensive effect of Hypertension-Associated Agents. Risk C: Monitor therapy

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

SORAfenib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of SORAfenib. Risk C: Monitor therapy

Sparsentan: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Sparsentan. Risk C: Monitor therapy

SUFentanil: CYP3A4 Inducers (Moderate) may decrease the serum concentration of SUFentanil. Risk C: Monitor therapy

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

Suvorexant: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Suvorexant. Risk C: Monitor therapy

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

Tadalafil: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Tadalafil. Risk C: Monitor therapy

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

Tasimelteon: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Tasimelteon. Risk C: Monitor therapy

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

Temsirolimus: CYP3A4 Inducers (Moderate) may decrease serum concentrations of the active metabolite(s) of Temsirolimus. Specifically, sirolimus concentrations may be decreased. CYP3A4 Inducers (Moderate) may decrease the serum concentration of Temsirolimus. Risk C: Monitor therapy

Tenofovir Alafenamide: P-glycoprotein/ABCB1 Inducers may decrease the serum concentration of Tenofovir Alafenamide. Management: Consider alternatives to the use of P-gp inducers with tenofovir alafenamide. If combined, monitor for reduced tenofovir alafenamide concentrations and efficacy, and for the development of resistance. Risk D: Consider therapy modification

Tetrahydrocannabinol: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Tetrahydrocannabinol. Risk C: Monitor therapy

Tetrahydrocannabinol and Cannabidiol: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Tetrahydrocannabinol and Cannabidiol. Risk C: Monitor therapy

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

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

Tivozanib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Tivozanib. Risk C: Monitor therapy

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

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

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

TraMADol: CYP3A4 Inducers (Moderate) may decrease the serum concentration of TraMADol. Risk C: Monitor therapy

TraZODone: CYP3A4 Inducers (Moderate) may decrease the serum concentration of TraZODone. Risk C: Monitor therapy

Triazolam: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Triazolam. Risk C: 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. Risk D: Consider therapy modification

Ulipristal: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Ulipristal. Risk X: Avoid combination

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

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

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

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

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

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

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

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

Voclosporin: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Voclosporin. Risk X: Avoid combination

Vonoprazan: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Vonoprazan. Risk X: Avoid combination

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

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

Voxelotor: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Voxelotor. Management: Avoid concomitant use of voxelotor and moderate CYP3A4 inducers. If unavoidable, increase the voxelotor dose to 2,000 mg once daily. For children ages 4 to less than 12 years, weight-based dose adjustments are required. See full monograph for details. Risk D: Consider therapy modification

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

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

Zanubrutinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Zanubrutinib. Management: Avoid this combination if possible. If coadministration of zanubrutinib and a moderate CYP3A4 inducer is required, increase the zanubrutinib dose to 320 mg twice daily. Risk D: Consider therapy modification

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

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

Zuranolone: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Zuranolone. Risk X: Avoid combination

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.

Breastfeeding Considerations

It is not known if lorlatinib is present in breast milk.

Due to the potential for serious adverse reactions in the breastfed infant, the manufacturer does not recommend breastfeeding during therapy and for 7 days after the last lorlatinib dose.

Monitoring Parameters

ALK positivity (in tumor specimen). Monitor serum cholesterol and triglycerides (prior to initiating lorlatinib, at 1 and 2 months after lorlatinib initiation, and periodically thereafter); LFTs (as clinically indicated); fasting serum glucose (prior to initiating lorlatinib and periodically thereafter). Evaluate pregnancy status (prior to treatment in females of reproductive potential). Monitor ECG (prior to lorlatinib initiation and periodically thereafter) and BP (2 weeks after lorlatinib initiation and at least monthly thereafter). Monitor for signs/symptoms of CNS adverse events and interstitial lung disease/pneumonitis. Monitor adherence.

The American Society of Clinical Oncology hepatitis B virus (HBV) screening and management provisional clinical opinion (ASCO [Hwang 2020]) recommends HBV screening with hepatitis B surface antigen, hepatitis B core antibody, total Ig or IgG, and antibody to hepatitis B surface antigen prior to beginning (or at the beginning of) systemic anticancer therapy; do not delay treatment for screening/results. Detection of chronic or past HBV infection requires a risk assessment to determine antiviral prophylaxis requirements, monitoring, and follow-up.

Additional cardiovascular monitoring: Comprehensive assessment prior to treatment including a history and physical examination, screening for cardiovascular disease risk factors such as hypertension, diabetes, dyslipidemia, obesity, and smoking (ASCO [Armenian 2017]; ESC [Lyon 2022]). Consider home BP monitoring; assess cholesterol profile every 3 to 6 months (ESC [Lyon 2022]).

Mechanism of Action

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.

Pharmacokinetics (Adult Data Unless Noted)

Absorption: Rapid (Shaw 2017).

Distribution: Vss: 305 L.

Protein binding: 66%; to plasma proteins.

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

Bioavailability: 81%.

Half-life elimination: 24 hours.

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.

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

Clearance (CL/F), mean: 11 L/hour (following a single 100 mg dose) and 18 L/hour at steady state.

Pharmacokinetics: Additional Considerations (Adult Data Unless Noted)

Altered kidney function: Following a single 100 mg dose, AUC increased by 42% in subjects with severe renal impairment, compared to subjects with normal renal function.

Brand Names: International
International Brand Names by Country
For country code abbreviations (show table)

  • (AE) United Arab Emirates: Lorbrena | Lorbrexen;
  • (AR) Argentina: Tigify;
  • (AT) Austria: Lorviqua;
  • (AU) Australia: Lorviqua;
  • (BE) Belgium: Lorviqua;
  • (BG) Bulgaria: Lorviqua;
  • (BR) Brazil: Lorbrena;
  • (CH) Switzerland: Lorviqua;
  • (CL) Chile: Lorbrena;
  • (CZ) Czech Republic: Lorviqua;
  • (DE) Germany: Lorviqua;
  • (EE) Estonia: Lorviqua;
  • (ES) Spain: Lorviqua;
  • (FI) Finland: Lorviqua;
  • (FR) France: Lorviqua;
  • (GB) United Kingdom: Lorviqua;
  • (HU) Hungary: Lorviqua;
  • (ID) Indonesia: Lorlak;
  • (IE) Ireland: Lorviqua;
  • (IN) India: Lorbriqua;
  • (IT) Italy: Lorviqua;
  • (JP) Japan: Lorbrena;
  • (KW) Kuwait: Lorbrena;
  • (LB) Lebanon: Lorbrena;
  • (LV) Latvia: Lorviqua;
  • (MX) Mexico: Lorbrena;
  • (MY) Malaysia: Lorviqua;
  • (NL) Netherlands: Lorviqua;
  • (NO) Norway: Lorviqua;
  • (PL) Poland: Lorviqua;
  • (PR) Puerto Rico: Lorbrena;
  • (PT) Portugal: Lorviqua;
  • (QA) Qatar: Lorbrena;
  • (RO) Romania: Lorviqua;
  • (SA) Saudi Arabia: Lorbrena;
  • (SE) Sweden: Lorviqua;
  • (SG) Singapore: Lorviqua;
  • (SI) Slovenia: Lorviqua;
  • (SK) Slovakia: Lorviqua;
  • (TR) Turkey: Lorviqua;
  • (TW) Taiwan: Lorbrena | Lorviqua;
  • (ZA) South Africa: Lorbrena
  1. <800> Hazardous Drugs—Handling in Healthcare Settings. United States Pharmacopeia and National Formulary (USP 43-NF 38). Rockville, MD: United States Pharmacopeia Convention; 2020:74-92.
  2. Armenian SH, Lacchetti C, Barac A, et al. Prevention and monitoring of cardiac dysfunction in survivors of adult cancers: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. 2017;35(8):893-911. doi:10.1200/JCO.2016.70.5400 [PubMed 27918725]
  3. Hwang JP, Feld JJ, Hammond SP, et al. Hepatitis B virus screening and management for patients with cancer prior to therapy: ASCO provisional clinical opinion update. J Clin Oncol. 2020;38(31):3698-3715. doi:10.1200/JCO.20.01757 [PubMed 32716741]
  4. Lorbrena (lorlatinib) [prescribing information]. New York, NY: Pfizer Labs; March 2021.
  5. Lorbrena (lorlatinib) [product monograph]. Kirkland, Quebec, Canada: Pfizer Canada ULC; May 2022.
  6. Lyon AR, López-Fernández T, Couch LS, et al; ESC Scientific Document Group. 2022 ESC guidelines on cardio-oncology developed in collaboration with the European Hematology Association (EHA), the European Society for Therapeutic Radiology and Oncology (ESTRO) and the International Cardio-Oncology Society (IC-OS). Eur Heart J. 2022;43(41):4229-4361. doi:10.1093/eurheartj/ehac244 [PubMed 36017568]
  7. Shaw AT, Bauer TM, de Marinis F, et al; CROWN Trial Investigators. First-line lorlatinib or crizotinib in advanced ALK-positive lung cancer. N Engl J Med. 2020;383(21):2018-2029. doi:10.1056/NEJMoa2027187 [PubMed 33207094]
  8. Shaw AT, Felip E, Bauer TM, et al. Lorlatinib in non-small-cell lung cancer with ALK or ROS1 rearrangement: an international, multicentre, open-label, single-arm first-in-man phase 1 trial. Lancet Oncol. 2017;18(12):1590-1599. [PubMed 29074098]
  9. Shaw AT, Solomon BJ, Chiari R, et al. Lorlatinib in advanced ROS1-positive non-small-cell lung cancer: a multicentre, open-label, single-arm, phase 1-2 trial. Lancet Oncol. 2019;20(12):1691-1701. doi:10.1016/S1470-2045(19)30655-2 [PubMed 31669155]
  10. US Department of Health and Human Services; Centers for Disease Control and Prevention; National Institute for Occupational Safety and Health. NIOSH list of antineoplastic and other hazardous drugs in healthcare settings 2016. https://www.cdc.gov/niosh/docs/2016-161/default.html. Accessed November 6, 2018.
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