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Lorlatinib

Class: Antineoplastic Agents
- ALK Inhibitors
- ALK Tyrosine Kinase Inhibitors
- Anaplastic Lymphoma Kinase Inhibitors
- Kinase Inhibitors
- Receptor Tyrosine Kinase Inhibitors
- Tyrosine Kinase Inhibitors
Chemical Name: (10R)-7-Amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-4,8-methenopyrazolo[4,3-h][2,5,11]benzoxadiazacyclotetradecine-3-carbonitrile
Molecular Formula: C21H19FN6O2
CAS Number: 1454846-35-5
Brands: Lorbrena

Medically reviewed by Drugs.com. Last updated on Oct 7, 2019.

Introduction

Antineoplastic agent; an inhibitor of multiple tyrosine kinases, including anaplastic lymphoma kinase (ALK) and c-ros oncogene-1 (ROS-1).1 2 3 13

Uses for Lorlatinib

Non-small Cell Lung Cancer (NSCLC)

Treatment of ALK-positive metastatic NSCLC in patients whose disease has progressed on crizotinib and at least one other ALK inhibitor for metastatic disease, or progressed on alectinib as the initial ALK inhibitor for metastatic disease, or progressed on ceritinib as the initial ALK inhibitor for metastatic disease1 2 (designated an orphan drug by FDA for treatment of ALK-positive or ROS-1-positive NSCLC).7

Accelerated approval based on tumor response rate and duration of response; continued approval may be contingent on verification and description of clinical benefit in a confirmatory study.1

About 3–7% of patients with NSCLC have ALK-positive disease; such patients typically are nonsmokers or light smokers and younger in age and often have adenocarcinoma.2 6 8 9 10 11

Resistance mutations in ALK, amplification of gene expression, activation of alternate signaling pathways, and/or progression of brain metastases (because of poor distribution of crizotinib into the CSF) limits long-term therapeutic potential of several ALK inhibitors (e.g., alectinib, ceritinib, crizotinib).6 8 9 11 Lorlatinib is a brain-penetrant ALK inhibitor; responses to lorlatinib in patients with disease progression while receiving other ALK inhibitors (e.g., alectinib, ceritinib, crizotinib) have included CNS responses.1 2 3 (See Actions.)

Lorlatinib Dosage and Administration

General

  • Measure serum cholesterol and triglyceride concentrations prior to initiating lorlatinib therapy, 1 and 2 months after initiating therapy, and then periodically thereafter.1 (See Hyperlipidemia under Dosage and Administration.)

  • May cause AV block; monitor ECG prior to initiating therapy and periodically thereafter.1 (See AV Block under Dosage and Administration.)

Restricted Distribution

  • Available only through specialty pharmacies.12 Consult the Lorbrena website ([Web]) for specific availability information.12

Administration

Oral Administration

Administer once daily at the same time each day without regard to food.1 (See Food under Pharmacokinetics.) Swallow tablets whole; do not crush, chew, or split tablets.1 Do not take tablets if they are broken, cracked, or otherwise not intact.1

If a dose is missed, take the dose as soon as it is remembered unless the next dose is due in ≤4 hours.1 Do not take 2 doses at the same time.1 If vomiting occurs after taking a dose, take the next dose at the regularly scheduled time; do not take an additional dose.1

Dosage

Adults

NSCLC
Oral

100 mg once daily.1 Continue therapy until disease progression or unacceptable toxicity occurs.1

Dosage Modification for Toxicity
Oral

In the principal efficacy study, treatment interruption or dosage reduction because of adverse reactions was necessary in approximately 48 or 24%, respectively, of patients receiving lorlatinib at the recommended dosage (most commonly for edema, peripheral neuropathy, cognitive effects, or mood effects).1

If dosage reduction is necessary, initially reduce dosage to 75 mg once daily.1 If further dosage reduction is necessary, reduce dosage to 50 mg once daily.1 If a dosage of 50 mg once daily is not tolerated, permanently discontinue the drug.1

CNS Effects
Oral

If grade 1 adverse CNS effects occur, may continue therapy at same dosage or interrupt therapy until recovery to baseline; may resume therapy at same dosage or at next lower dosage.1

If grade 2 or 3 adverse CNS effects occur, interrupt therapy until recovery to grade 0 or 1; may resume therapy at next lower dosage.1

If grade 4 adverse CNS effects occur, permanently discontinue lorlatinib.1 (See CNS Effects under Cautions.)

Hyperlipidemia
Oral

If grade 4 hypercholesterolemia and/or hypertriglyceridemia (serum cholesterol concentration >500 mg/dL or serum triglyceride concentration >1000 mg/dL) occurs, interrupt therapy and initiate appropriate antilipemic therapy, increase dosage of existing antilipemic therapy, or switch to a new antilipemic therapy.1 14 May resume therapy at same dosage upon recovery to grade 2 or less.1

If severe hypercholesterolemia and/or hypertriglyceridemia recurs despite optimal antilipemic therapy, resume therapy at next lower dosage.1 14 (See Hyperlipidemia under Cautions.)

AV Block
Oral

If second-degree AV block occurs, interrupt therapy until PR interval <200 msec; may then resume therapy at the next lower dosage.1

If complete AV block occurs, interrupt therapy until a pacemaker is placed or PR interval <200 msec.1 If a pacemaker is placed, may resume therapy at same dosage.1 If a pacemaker is not placed, resume therapy at the next lower dosage.1

If complete AV block recurs, place a pacemaker or permanently discontinue lorlatinib.1 (See AV Block under Cautions.)

Interstitial Lung Disease/Pneumonitis
Oral

If treatment-related interstitial lung disease (ILD)/pneumonitis of any grade occurs, permanently discontinue drug.1 (See Interstitial Lung Disease/Pneumonitis under Cautions.)

Other Toxicity
Oral

If other grade 1 or 2 adverse reaction occurs, may continue therapy at same dosage or the next lower dosage.1

If other grade 3 or 4 adverse reaction occurs, interrupt therapy until recovery to grade 2 or less or to baseline; may then resume therapy at the next lower dosage.1

Concomitant Use with Drugs Affecting Hepatic Microsomal Enzymes
Oral

Concomitant use of lorlatinib with potent CYP3A inducers is contraindicated; avoid concomitant use with moderate CYP3A inducers and with potent CYP3A inhibitors.1 If concomitant use of a potent CYP3A inhibitor cannot be avoided, reduce lorlatinib dosage from 100 mg to 75 mg once daily or from 75 mg to 50 mg once daily.1 (See Interactions and also see Serious Hepatotoxicity with Concurrent Use of Potent CYP3A Inducers under Cautions.)

Special Populations

Hepatic Impairment

Mild hepatic impairment (total bilirubin not exceeding ULN with AST exceeding ULN, or total bilirubin >1 to 1.5 times ULN with any AST): No dosage adjustment needed.1

Moderate or severe hepatic impairment: Recommended dosage not established.1 (See Hepatic Impairment under Cautions.)

Renal Impairment

Mild or moderate renal impairment (Clcr 30–89 mL/minute): No dosage adjustment needed.1

Severe renal impairment (Clcr <30 mL/minute): Recommended dosage not established.1 (See Renal Impairment under Cautions.)

Geriatric Patients

No specific dosage recommendations.1

Cautions for Lorlatinib

Contraindications

  • Concurrent use of potent CYP3A inducers.1 (See Serious Hepatotoxicity with Concurrent Use of Potent CYP3A Inducers under Cautions.)

Warnings/Precautions

Serious Hepatotoxicity with Concurrent Use of Potent CYP3A Inducers

Severe hepatotoxicity occurred in most healthy individuals receiving a single dose of lorlatinib with multiple doses of rifampin, a potent CYP3A inducer, during a drug interaction study.1 Grade 3 or 4 elevations in ALT or AST concentrations occurred in 83% and grade 2 elevations occurred in 8% of individuals who received the drugs concurrently during the study.1 ALT or AST elevations occurred within 3 days of concomitant administration and returned to within normal limits after a median of 15 days (range: 7–34 days).1 The median time to recovery was 18 days following grade 3 or 4 elevations and 7 days following grade 2 elevations.1

Concomitant use with potent CYP3A inducers is contraindicated.1 Discontinue potent CYP3A inducers and allow 3 plasma half-lives of the potent CYP3A inducer to elapse prior to initiation of lorlatinib.1

Avoid concomitant use with moderate CYP3A inducers.1 If concomitant use cannot be avoided, monitor AST, ALT, and bilirubin concentrations 48 hours after initiation of lorlatinib and at least 3 times during first week of concomitant therapy.1 If grade 2 or higher hepatotoxicity persists during concomitant therapy, discontinue lorlatinib or the moderate CYP3A inducer, depending on the relative importance of each drug to the patient.1 (See Interactions.)

CNS Effects

A wide variety of adverse CNS effects, including seizures, hallucinations, and changes in cognitive function (including memory impairment, cognitive disorder, and amnesia), mood (including suicidal ideation/suicidality, irritability, anxiety, depression, and labile affect), speech, mental status, and sleep reported.1 2 14 Median time to first onset of any adverse CNS effect was 1.2 months (range: 1 day to 1.7 years).1 CNS effects are generally mild and intermittent and improve or resolve upon dosage modification.2 14

Treatment interruption, dosage reduction, or drug discontinuance may be required depending on severity.1 (See CNS Effects under Dosage and Administration.)

Hyperlipidemia

Hypercholesterolemia or hypertriglyceridemia occurred in ≥90% of patients receiving the recommended dosage of lorlatinib in the principal efficacy study; median time to onset was 15 days.1 Antilipemic therapy was initiated in 80% of patients after a median of 21 days on lorlatinib therapy.1

Assess serum cholesterol and triglycerides prior to initiating therapy, 1 and 2 months after initiating therapy, and periodically thereafter.1 Initiate antilipemic therapy or increase dosage of existing antilipemic therapy in patients with hyperlipidemia.1 14 Temporary interruption followed by resumption of lorlatinib therapy at the same or a reduced dosage may be necessary, depending on severity.1 14 (See Hyperlipidemia under Dosage and Administration.)

AV Block

PR-interval prolongation and AV block may occur.1 In the principal efficacy study, AV block occurred in 1% of lorlatinib-treated patients; 0.3% of these patients experienced grade 3 AV block and underwent pacemaker placement.1

Monitor ECG prior to initiating lorlatinib and periodically during therapy.1 If AV block occurs, interrupt therapy; dosage reduction or placement of a pacemaker may be necessary.1 If complete AV block recurs in patients without a pacemaker, permanently discontinue lorlatinib.1 (See AV Block under Dosage and Administration.)

Interstitial Lung Disease/Pneumonitis

Severe or life-threatening ILD/pneumonitis may occur.1 In the principal efficacy study, ILD or pneumonitis occurred in 1.5% of patients receiving lorlatinib at any dosage, and grade 3 or 4 ILD or pneumonitis occurred in 1.2% of patients receiving the drug.1

Promptly evaluate patients who present with worsening respiratory symptoms indicative of ILD or pneumonitis (e.g., dyspnea, cough, fever).1 (See Advice to Patients.) In patients with suspected ILD/pneumonitis, immediately interrupt therapy.1 Permanently discontinue lorlatinib in patients with treatment-related ILD or pneumonitis of any severity.1 (See Interstitial Lung Disease/Pneumonitis under Dosage and Administration.)

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; malformations, increased post-implantation loss, and abortion observed in animals.1

Avoid pregnancy during therapy.1 Confirmation of pregnancy status recommended prior to initiation of therapy in women of childbearing potential.1 Women of childbearing potential should use effective nonhormonal methods of contraception during therapy and for ≥6 months after drug discontinuance.1 Apprise pregnant women and women of reproductive potential of potential fetal hazard.1 (See Specific Drugs under Interactions and also see Advice to Patients.)

Men with female partners of childbearing potential should use effective methods of contraception during therapy and for ≥3 months after drug discontinuance.1

Impairment of Fertility

Based on animal studies, may transiently impair male fertility.1

Specific Populations

Pregnancy

May cause fetal harm.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Not known whether lorlatinib or its metabolites are distributed into milk or if drug has any effect on milk production or the nursing infant.1 Women should not breast-feed during therapy and for 7 days after drug discontinuance.1

Pediatric Use

Safety and efficacy not established in pediatric patients.1

Geriatric Use

In the principal efficacy study, approximately 18% of patients receiving therapy were ≥65 years of age; no clinically important differences in safety or efficacy observed between geriatric patients and younger adults.1

Hepatic Impairment

Mild hepatic impairment (total bilirubin not exceeding ULN with AST exceeding ULN, or total bilirubin >1 to 1.5 times ULN with any AST): Pharmacokinetics not substantially altered; no dosage adjustment needed.1 (See Special Populations under Pharmacokinetics.)

Moderate or severe hepatic impairment: Pharmacokinetics not studied.1

Renal Impairment

Mild or moderate renal impairment (Clcr 30–89 mL/minute): Pharmacokinetics not substantially altered; no dosage adjustment needed.1 (See Special Populations under Pharmacokinetics.)

Severe renal impairment (Clcr <30 mL/minute): Pharmacokinetics not studied.1

Common Adverse Effects

Adverse effects: Edema (including generalized and localized edema, swelling, and peripheral, eyelid, facial, or periorbital edema),1 2 peripheral neuropathy,1 2 cognitive effects (including memory impairment, cognitive disorder, and amnesia),1 14 dyspnea,1 fatigue/asthenia,1 weight gain,1 arthralgia,1 mood effects,1 diarrhea.1

Laboratory abnormalities: Hypercholesterolemia,1 2 hypertriglyceridemia,1 2 hyperglycemia,1 increased AST or ALT concentrations,1 hypoalbuminemia,1 anemia,1 thrombocytopenia,1 lymphopenia,1 increased lipase or amylase concentrations,1 increased alkaline phosphatase concentrations,1 hypophosphatemia,1 hyperkalemia,1 hypomagnesemia.1

Interactions for Lorlatinib

Metabolized principally by CYP3A4 and uridine diphosphate-glucuronosyltransferase (UGT) 1A4, with minor contributions by CYP isoenzymes 2C8, 2C19, and 3A5 and UGT1A3.1

In vitro, inhibits (in a time-dependent manner) and induces CYP3A and activates pregnane X receptor (PXR); net effect is induction in vivo.1 Induces CYP2B6 and activates the human constitutive androstane receptor (CAR).1

Inhibits P-glycoprotein (P-gp), organic cation transporter (OCT) 1, organic anion transporter (OAT) 3, multidrug and toxin extrusion (MATE) 1, and intestinal breast cancer resistance protein (BCRP).1

Lorlatinib and its major metabolite M8 do not inhibit CYP isoenzymes 1A2, 2B6, 2C8, 2C9, 2C19, or 2D6 nor UGT isoenzymes 1A1, 1A4, 1A6, 1A9, 2B7, or 2B15.1 M8 does not inhibit CYP3A nor induce CYP isoenzymes 1A2, 2B6, and CYP3A.1

Lorlatinib does not inhibit organic anion transporting polypeptide (OATP) 1B1, OATP1B3, OAT1, OCT2, MATE2K, and systemic BCRP.1 M8 does not inhibit P-gp, BCRP, OATP1B1, OATP1B3, OAT1, OAT3, OCT1, OCT2, MATE1, and MATE2K.1

Drugs Affecting Hepatic Microsomal Enzymes

Potent CYP3A inducers: Risk of severe hepatotoxicity.1 Concomitant use contraindicated.1 In addition, possible decreased peak plasma concentration and exposure of lorlatinib.1 Discontinue potent CYP3A inducers and allow 3 plasma half-lives of the potent CYP3A inducer to elapse prior to initiation of lorlatinib.1 (See Serious Hepatotoxicity with Concurrent Use of Potent CYP3A Inducers under Cautions.)

Moderate CYP3A inducers: Risk of hepatotoxicity not known.1 Avoid concomitant use.1 If concomitant use cannot be avoided, monitor ALT, AST, and bilirubin 48 hours after initiation of lorlatinib and ≥3 times during the first week of concomitant therapy.1 If grade 2 or higher hepatotoxicity persists during concomitant therapy, discontinue lorlatinib or the moderate CYP3A inducer, taking into account the relative importance of each drug to the patient.1

Potent CYP3A inhibitors: Possible increased plasma concentrations of lorlatinib, which may increase incidence and severity of adverse effects.1 Avoid concomitant use.1 If concomitant use cannot be avoided, reduce dosage of lorlatinib from 100 mg to 75 mg once daily or from 75 mg to 50 mg once daily.1 If the potent CYP3A inhibitor is discontinued, allow 3 plasma half-lives of the potent CYP3A inhibitor to elapse, then resume the lorlatinib dosage that was tolerated prior to initiation of the potent CYP3A inhibitor.1

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP3A: Possible decreased plasma concentrations and reduced efficacy of the CYP3A substrate.1

Avoid concomitant use with CYP3A substrates where minimal concentration changes may result in serious therapeutic failure.1 If concomitant use cannot be avoided, the CYP3A substrate may require dosage adjustment; consult specific product labeling of the CYP3A substrate.1

Specific Drugs

Drug

Interaction

Comments

Contraceptives, hormonal

Possible reduced efficacy1

Use effective nonhormonal contraception during and for ≥6 months after discontinuing lorlatinib therapy1

Itraconazole

Increased peak plasma concentrations and AUC of lorlatinib1 6

Avoid concomitant use; if concomitant use cannot be avoided, reduce dosage of lorlatinib from 100 mg to 75 mg once daily or from 75 mg to 50 mg once daily1

If itraconazole is discontinued, allow 3 plasma half-lives of itraconazole to elapse, then resume the lorlatinib dosage that was tolerated prior to initiation of itraconazole1

Midazolam

Decreased peak plasma concentration and AUC of orally administered midazolam (a CYP3A substrate)1

Rabeprazole

No clinically important effect on pharmacokinetics of lorlatinib1

Rifampin

Possible hepatotoxicity; grade 3 or 4 elevations in serum ALT and/or AST concentrations occurred within 3 days of concomitant administration1

Decreased peak plasma concentration and AUC of lorlatinib1

Concomitant use contraindicated1

Discontinue rifampin and allow 3 plasma half-lives of rifampin to elapse prior to initiation of lorlatinib therapy1

Lorlatinib Pharmacokinetics

Absorption

Bioavailability

Peak plasma concentrations attained at a median of 1.2 hours (range: 0.5–4 hours) following single-dose oral administration and 2 hours (range: 0.5–23 hours) following multiple-dose oral administration at steady state.1

Mean absolute bioavailability is 81%.1

Steady-state peak plasma concentration is dose proportional and systemic exposure is slightly less than dose proportional over an oral dosage range of 10–200 mg once daily.1

Food

High-fat, high-calorie meal does not substantially affect pharmacokinetics of lorlatinib.1

Special Populations

Mild hepatic impairment does not substantially affect pharmacokinetics of lorlatinib.1

Moderate or severe hepatic impairment: Effect on pharmacokinetics not known.1

Mild or moderate renal impairment does not substantially affect pharmacokinetics of lorlatinib.1

Severe renal impairment: Effect on pharmacokinetics not known.1

Age (19–85 years), sex, race/ethnicity, body weight, and CYP3A5 or CYP2C19 metabolizer phenotype do not substantially affect lorlatinib pharmacokinetics.1

Distribution

Extent

Distributed into CSF at a CSF-to-plasma ratio of 0.75.3

Not known whether lorlatinib or its metabolites distribute into human milk.1

Plasma Protein Binding

66%.1

Elimination

Metabolism

Metabolized principally by CYP3A4 and UGT1A4, with minor contributions by CYP 2C8, 2C19, and 3A5, and UGT1A3.1

Major metabolite, M8, is pharmacologically inactive.1

Oral clearance of lorlatinib is higher at steady state than following a single dose, suggesting autoinduction occurs.1

Elimination Route

Eliminated in urine (48%; <1% as unchanged drug) and feces (41%; about 9% as unchanged drug).1

Half-life

24 hours.1

Stability

Storage

Oral

Tablets

20–25°C (may be exposed to 15–30°C).1

Actions

  • Inhibits multiple tyrosine kinases, including ALK and ROS-1 as well as TYK1, FER, FPS, TRKA, TRKB, TRKC, FAK, FAK2, and ACK.1 2 3 13

  • Inhibits phosphorylation of ALK1 and ALK-mediated signal transduction, specifically, STAT3, AKT, ERK, and S6.13

  • Activating mutations or translocations of the ALK gene identified in several malignancies and can result in the expression of oncogenic fusion proteins (e.g., echinoderm microtubule-associated protein-like 4 [EML4]-ALK).3 8 9 10 11 Formation of ALK fusion proteins results in activation and dysregulation of the gene's expression and signaling, which can contribute to increased cell proliferation and survival in tumors expressing these proteins.9 10 11

  • ALK rearrangements identified in approximately 3–7% of patients with NSCLC.2 8 9 10

  • Clinical resistance to crizotinib attributed to several mechanisms, including acquired resistance mutations of ALK, amplification of gene expression, and activation of alternate signaling pathways.2 5 8 9 11 13 More potent ALK inhibitors (e.g., alectinib, ceritinib) were developed to overcome resistance to crizotinib; however, resistance to these drugs also develops over time.2 5 13

  • CNS is a common site of disease progression in crizotinib-treated patients because of poor distribution of the drug into CSF.3 6 8 9 11 13

  • Lorlatinib demonstrates greater potency than alectinib, ceritinib, and crizotinib in its activity against wild-type ALK in vitro and is active against cell lines expressing ALK mutations that confer resistance to crizotinib, including G1202R (which also confers resistance to alectinib and ceritinib), G1269A, and L1196M.2 3 5 6 13

  • Exhibits dose-dependent antitumor activity in mice bearing NSCLC tumor xenografts expressing EML4-ALK fusions with ALK variant 1 or ALK mutations, including G1202R and I1171T mutations that were detected in tumors of patients at the time of disease progression during therapy with other ALK inhibitors.1 13

  • Demonstrates antitumor activity and prolonged survival in mice bearing intracranial EML4-ALK-positive tumor xenografts.1 3 13 Demonstrated antitumor activity in patients with CNS metastases who had received prior treatment with ALK inhibitors (e.g., alectinib, ceritinib, crizotinib).1 2

Advice to Patients

  • Importance of reading the manufacturer's patient information.1

  • Importance of advising patients to take lorlatinib exactly as prescribed and of not altering the dosage or discontinuing therapy unless advised to do so by their clinician.1 Importance of advising patients to swallow lorlatinib tablets whole without regard to food and not to crush, chew, or split the tablets.1 If a dose is missed, the missed dose should be taken as soon as possible unless it is within 4 hours of the next dose, in which case the missed dose should not be taken.1 Inform patients to not take 2 doses at the same time to make up for a missed dose.1 If vomiting occurs after taking a dose, the next dose should be taken at the regularly scheduled time; an additional dose should not be taken.1

  • Risk of severe hepatotoxicity when used concomitantly with potent CYP3A inducers.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs (e.g., antilipemic agents, rifampin, oral contraceptives) and dietary or herbal supplements (e.g., St. John's wort), as well as any concomitant illnesses (e.g., history of depression or other mood disorders, hyperlipidemia, cardiac arrhythmias, pulmonary disease).1

  • Risk of adverse CNS effects.1 Patients should notify their clinician if they experience new or worsening CNS symptoms such as changes in cognitive function or mood, suicidal ideation, hallucinations, or seizures.1

  • Risk of hyperlipidemia.1 Importance of informing patients about the need for monitoring serum cholesterol and triglyceride concentrations during therapy.1 Advise patients that initiation of antilipemic therapy or an increase in the dosage of existing antilipemic agents may be required.1

  • Risk of AV block.1 Importance of patients immediately contacting their clinician if they experience new or worsening cardiac symptoms such as dizziness, faintness, or arrhythmia during therapy.1

  • Risk of severe or life-threatening ILD/pneumonitis.1 Importance of advising patients that symptoms may be similar to those of lung cancer and to contact their clinician immediately if they experience any new or worsening respiratory symptoms (e.g., dyspnea or shortness of breath, cough, fever).1

  • Risk of fetal harm.1 Necessity of advising women of childbearing potential that they should use effective, nonhormonal methods of contraception while receiving lorlatinib and for ≥6 months after discontinuance of therapy and of also advising such women that oral contraceptives and other hormonal forms of contraception may not be effective during lorlatinib therapy.1 Importance of advising men with female partners of childbearing potential to use effective methods of contraception while receiving the drug and for ≥3 months after the drug is discontinued.1 Importance of also advising men of reproductive potential that lorlatinib may transiently impair fertility and to discuss any concerns about fertility with their clinician.1

  • Importance of women informing their clinicians if they are or plan to become pregnant.1 Advise of potential fetal risk.1

  • Importance of advising women to avoid breast-feeding while receiving lorlatinib and for 7 days after discontinuance of therapy.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Distribution of lorlatinib is restricted.1 (See Restricted Distribution under Dosage and Administration.)

Lorlatinib

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

25 mg

Lorbrena

Pfizer

100 mg

Lorbrena

Pfizer

AHFS DI Essentials™. © Copyright 2021, Selected Revisions October 7, 2019. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. Pfizer Inc. Lorbrena (lorlatinib) film-coated tablets prescribing information. New York, NY; 2018 Nov.

2. Solomon BJ, Besse B, Bauer TM et al. Lorlatinib in patients with ALK-positive non-small-cell lung cancer: results from a global phase 2 study. Lancet Oncol. 2018; 19:1654-1667. http://www.ncbi.nlm.nih.gov/pubmed/30413378?dopt=AbstractPlus

3. Syed YY. Lorlatinib: first global approval. Drugs. 2019; 79:93-98. http://www.ncbi.nlm.nih.gov/pubmed/30604291?dopt=AbstractPlus

4. A study of lorlatinib versus crizotinib in first line treatment of patients with ALK-positive NSCLC. From ClinicalTrials.gov registry. Accessed 2019 Mar 19.

5. 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; 18:1590-1599. http://www.ncbi.nlm.nih.gov/pubmed/29074098?dopt=AbstractPlus

6. US Food and Drug Administration. Center for Drug Evaluation and Research: Application number 210868Orig1s000: Multi-discipline review. 2018 Nov 2. From FDA website. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210868Orig1s000MultidisciplineR.pdf

7. US Food and Drug Administration. FDA Application: Search orphan drug designations and approvals. Silver Spring, MD. From FDA website. http://www.accessdata.fda.gov/scripts/updlisting/oopd/index.cfm

8. Sullivan I, Planchard D. ALK inhibitors in non-small cell lung cancer: the latest evidence and developments. Ther Adv Med Oncol. 2016; 8:32-47. http://www.ncbi.nlm.nih.gov/pubmed/26753004?dopt=AbstractPlus

9. Awad MM, Shaw AT. ALK inhibitors in non-small cell lung cancer: crizotinib and beyond. Clin Adv Hematol Oncol. 2014; 12:429-39. http://www.ncbi.nlm.nih.gov/pubmed/25322323?dopt=AbstractPlus

10. Sasaki T, Jänne PA. New strategies for treatment of ALK-rearranged non-small cell lung cancers. Clin Cancer Res. 2011; 17:7213-8. http://www.ncbi.nlm.nih.gov/pubmed/22010214?dopt=AbstractPlus

11. Wu J, Savooji J, Liu D. Second- and third-generation ALK inhibitors for non-small cell lung cancer. J Hematol Oncol. 2016; 9:19. http://www.ncbi.nlm.nih.gov/pubmed/26951079?dopt=AbstractPlus

12. Pfizer Inc. Personalized support. From the Lorbrena website. Accessed 2019 Mar 27. https://www.lorbrena.com/personalized-support

13. Zou HY, Friboulet L, Kodack DP et al. PF-06463922, an ALK/ROS1 Inhibitor, Overcomes Resistance to First and Second Generation ALK Inhibitors in Preclinical Models. Cancer Cell. 2015; 28:70-81. http://www.ncbi.nlm.nih.gov/pubmed/26144315?dopt=AbstractPlus

14. Bauer TM, Felip E, Solomon BJ et al. Clinical Management of Adverse Events Associated with Lorlatinib. Oncologist. 2019; http://www.ncbi.nlm.nih.gov/pubmed/30890623?dopt=AbstractPlus

Frequently asked questions