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lorlatinib
Lorlatinib is a selective, reversible, inhibitor of ALK and ROS1 tyrosine kinases. It has demonstrated activity against multiple mutant forms of the ALK enzyme that may be resistant to first and second generation ALK inhibitors.
Rapidly absorbed
| Bioavailability |
81% |
| Effects with food |
Food has no clinically important effects. Administration with a high fat, high calorie meal resulted in a 5% increase in AUC and 9% decrease in Cmax compared to overnight fasting. |
| T max |
1.2 hours following a single 100 mg dose; 2 hours following 100 mg once daily multiple dosing. |
| Cross blood brain barrier? |
Yes |
| PPB |
66% with moderate binding to both albumin and α1-acid glycoprotein. |
Oxidation and glucuronidation are the primary metabolic pathways by CYP3A4 and UGT1A4, with minor contribution from CYP2C8, CYP2C19, CYP3A5, and UGT1A3.
| Inactive metabolites |
Yes |
| Urine |
48% (< 1% as unchanged drug) |
| Feces |
41% (9% as unchanged drug) |
| Half-life |
24 hours (plasma) |
- Non-small cell lung cancer (NSCLC)
Refer to the product monograph for a full list and details of approved indications.
Emetogenic Potential:
The following adverse effects include those reported in ≥ 10% of patients in a randomized, multicenter Phase III study of previously untreated ALK-positive metastatic NSCLC patients on lorlatinib compared to crizotinib. Severe or life-threatening adverse events from other studies or post-marketing may also be included.
| ORGAN SITE | SIDE EFFECT* (%) | ONSET** | |||
|---|---|---|---|---|---|
| Cardiovascular | Arterial/venous thromboembolism (rare) | E | |||
| Atrioventricular block (2%) | E | ||||
| Hypertension (18%) (10% severe) | E | ||||
| QT interval prolonged (1%) (> 500 msec) | E | ||||
| Dermatological | Rash (11%) | E | |||
| Gastrointestinal | Constipation (17%) | E | |||
| Diarrhea (22%) | E | ||||
| Nausea, vomiting (15%) | E | ||||
| Weight gain (38%) | D | ||||
| General | Edema (56%) | E | |||
| Fatigue (20%) | E D | ||||
| Hematological | Anemia (19%) | E D | |||
| Myelosuppression ± infection (7%) (neutropenia) | E D | ||||
| Hepatobiliary | ↑ Amylase / lipase (9%) | E | |||
| ↑ LFTs (17%) | E | ||||
| Metabolic / Endocrine | ↑ Cholesterol (70%) (16% severe) | E | |||
| Hyperglycemia (9%) (3% severe) | E | ||||
| ↑ Triglycerides (64%) (20% severe) | E | ||||
| Musculoskeletal | Musculoskeletal pain (19%) | E | |||
| Nervous System | Cognitive disturbance (22%) | D | |||
| Dizziness (11%) | E | ||||
| Hallucinations (3%) | E | ||||
| Headache (17%) | E | ||||
| Mood changes (16%) | D | ||||
| Other - speech effects (7%) | D | ||||
| Peripheral neuropathy (34%) (2% severe) | D | ||||
| Seizure (2%) | E | ||||
| Sleep disorder (11%) | E | ||||
| Ophthalmic | Visual disorders (18%) | E | |||
| Respiratory | Cough, dyspnea (20%) (3% severe) | D | |||
| Pneumonitis (2%) (severe or life-threatening) | E D | ||||
| Respiratory failure (3%) | E D | ||||
* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare"
may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,
isolated data or anecdotal
reports.
** I = immediate (onset in hours to days)
E = early (days to weeks)
D = delayed (weeks to months)
L = late (months to years)
The most common side effects for lorlatinib include ↑ cholesterol, ↑ triglycerides, edema, weight gain, peripheral neuropathy, cognitive disturbance, diarrhea, cough, dyspnea, fatigue and anemia.
Lorlatinib has been associated with hypercholesterolemia and hypertriglyceridemia. The median onset for both was 15 days. The median duration was 451 and 427 days, respectively. A majority of patients with hypercholesterolemia and hypertriglyceridemia required initiation of lipid-lowering medications, usually at ~17 days after lorlatinib initiation.
Hyperglycemia has also occurred with lorlatinib with a median onset of ~5 months.
Central nervous system (CNS) effects have been reported with lorlatinib. The effects were generally mild, transient, and reversible upon dose delay and/or dose reduction. The median time to first onset of any CNS effect was 1.4 months (1 day to 3.4 years).
PR interval prolongation and Atrioventricular (AV) block events have been reported in patients receiving lorlatinib. During clinical trials, 1 patient (0.2%) experienced Grade 3 AV block and underwent pacemaker placement.
Hypertension including grade 4 events were reported. The median time to onset of hypertension was 6.4 months (1 day to 2.8 years).
Refer to protocol by which patient is being treated.
Patients must have a documented ALK-positive status, based on a validated ALK assay, prior to starting treatment with lorlatinib.
Blood pressure should be controlled prior to initiation of lorlatinib.
| Dose level | Dose (mg/day) |
| 0 | 100 |
| -1 | 75 |
| -2 | 50 |
| -3 | Discontinue |
| Toxicity | Grade |
Action |
|
|
Hypercholesterolemia |
Grade 1 or 2 (ULN to 10.34 mmol/L) |
Continue at same dose level. Introduce or modify lipid-lowering therapy. |
|
| Grade 3 (10.35 to 12.92 mmol/L) |
Continue at same dose level. Introduce lipid-lowering therapy. If currently on lipid-lowering therapy, increase the dose of this therapy or change to a new lipid-lowering therapy. |
||
| Grade 4 (>12.92 mmol/L) |
Hold.* Introduce lipid-lowering therapy. If currently on lipid-lowering therapy, increase the dose of this therapy or change to a new lipid-lowering therapy Resume at same dose level. If recurs despite maximal lipid-lowering therapy, resume at 1 dose level ↓. |
||
| Hypertriglyceridemia | Grade 1 or 2 (1.71 to 5.7 mmol/L) |
Continue at same dose level Introduce or modify lipid-lowering therapy. |
|
| Grade 3 (5.71 to 11.4 mmol/L) |
Continue at same dose level. Introduce lipid-lowering therapy. If currently on lipid-lowering therapy, increase the dose of this therapy or change to a new lipid-lowering therapy. |
||
| Grade 4 (>11.4 mmol/L) |
Hold.* Introduce lipid-lowering therapy. If currently on lipid-lowering therapy, increase the dose of this therapy or change to a new lipid-lowering therapy Resume at same dose level. If recurs despite maximal lipid-lowering therapy, resume at 1 dose level ↓. |
||
| Central Nervous System Effects (e.g., psychotic effects [including hallucination], changes in cognitive function, mood, speech, or mental status) | Grade 1 |
Continue at same dose level. OR Hold dose until recovery to baseline. Resume at same dose or 1 dose level ↓. |
|
|
Grade 2 or 3 |
Hold dose*. Resume at 1 dose level ↓. |
||
| Grade 4 | Discontinue. | ||
| Symptoms of Interstitial Lung Disease (ILD)/Pneumonitis (treatment–related) | Discontinue. | ||
|
Hypertension |
Grade 3 |
Hold.* Resume at same dose level. If recurs, hold* and resume with at least 1 dose level ↓. If adequate control cannot be achieved, discontinue. |
|
| Grade 4 |
Hold.* Resume with at least 1 dose level ↓.or discontinue. If recurs, discontinue. |
||
|
Hyperglycemia |
Grade 3 (> 13.9 mmol/L despite anti-hyperglycemic therapy) |
Hold until adequately controlled. Resume at 1 dose level ↓. If adequate control cannot be achieved, discontinue. |
|
| Grade 4 | |||
| All other toxicity | Grade 1 or 2 | Continue at same dose or at 1 dose level ↓ as clinically indicated. | |
| > Grade 3 |
Hold.* Resume at 1 dose level ↓. |
||
| Asymptomatic | Symptomatic | ||
| Action | |||
| First-degree AV block |
Continue at same dose level. Monitor closely.1,2 |
Hold. Monitor closely.1,2 If symptoms resolve, resume at same dose level or at 1 dose level ↓. |
|
| Second-degree AV block |
Hold. Monitor closely.1,2 If subsequent ECG does not show second-degree block, resume at same dose level or 1 dose level ↓. |
Hold. Monitor closely.1 Refer for cardiac observation and monitoring. Consider pacemaker placement if symptomatic AV block persists. If symptoms and the second-degree block resolve or if patients revert to asymptomatic first-degree AV block, resume at 1 dose level ↓. |
|
| Complete AV Block |
|
||
1Assess medications and electrolyte imbalance that may prolong PR interval.
2Monitor ECG/symptoms potentially related to AV block closely.
| Hepatic impairment | Lorlatinib Dose |
|
Mild (total bilirubin ≤ ULN with AST > ULN or total bilirubin > 1 to 1.5 x ULN with any AST) |
No dose adjustment required. |
| Moderate or Severe | No data available. |
| Renal impairment | Lorlatinib Starting Dose |
| Mild or Moderate (CrCl ≥ 30 mL/min) |
No dose adjustment required. |
| Severe (CrCl < 30 mL/min) |
75 mg daily |
| Requiring dialysis | Not recommended. Limited data available. |
No dose adjustment required. The following adverse events were more frequently reported in elderly patients in clinical trials: cognitive effects, dyspnea, fatigue, arthralgia, diarrhea, anemia, myalgia, vomiting, back pain and rash. No clinically relevant differences in safety and efficacy were observed between patients ≥ 65 years and younger patients.
Safety and efficacy in children have not been established.
- Lorlatinib should be taken at approximately the same time each day with or without food.
- Tablets should be swallowed whole and should not be chewed, crushed or split.
- Avoid grapefruit, starfruit, Seville oranges, their juices or products during lorlatinib treatment.
- If a dose is missed, patient may take if there are > 4 hours until the next dose. If there are < 4 hours until the next dose, the dose should be skipped and the next dose should be taken at the scheduled time. Patients should not take 2 doses at the same time to make up for a missed dose.
- If the patient vomits after taking lorlatinib, do not give an extra dose; give the following dose at the next scheduled time.
- Store at room temperature (15⁰C to 30⁰C) in the original package. Protect from light.
- Patients who are hypersensitive to this drug or to any ingredient in the formulation
- Concomitant use of strong CYP3A inducers due to the potential for serious hepatotoxicity (Refer to Interactions section)
- Avoid concomitant use of lorlatinib with moderate CYP3A inducers.
- Lorlatinib should not be used in patients with severe acute or chronic medical or psychiatric conditions, including recent or active suicidal ideation or behaviour. (Refer to EAP criteria.) Some exclusion criteria from the clinical trial included the presence of chronic or uncontrolled conditions, such as vascular or nonvascular conditions, predisposing characteristics for acute pancreatitis, lung disease, or psychiatric conditions. (See full details in Shaw et al.)
- Patients at risk for AV block/PR prolongation should be monitored closely.
- Use caution when driving or operating machinery due to CNS effects.
- Tablets contain lactose; carefully consider use in patients with hereditary galactose intolerance, severe lactase deficiency or glucose-galactose malabsorption.
Other Drug Properties:
-
Carcinogenicity:
Unknown
Carcinogenicity studies have not been performed.
-
Genotoxicity:
No
-
Embryotoxicity:
Documented in animals
-
Fetotoxicity:
Documented in animals
Lorlatinib is not recommended for use in pregnancy or in women of childbearing potential who are not using contraception.
Adequate contraception should be used by both sexes during treatment, and for at least 21 days after the last dose (for females) and 97 days after the last dose (for males). A highly effective non-hormonal contraception method is required for female patients during lorlatinib treatment. If a hormonal contraception method must be used, then a condom must be used together with the hormonal contraception.
-
Excretion into breast milk:
Unknown
Breastfeeding is not recommended during treatment, and for at least 7 days after the last dose.
-
Fertility effects:
Probable
Patients wishing to have children in the future should seek advice on effective fertility preservation before treatment.
Lorlatinib is metabolized primarily by CYP3A4 and UGT1A4, with minor contributions from CYP2C8, CYP2C19, CYP3A5, and UGT1A3.
Lorlatinib induces CYP3A4 and, in vivo, results in weak induction of CYP2C9, UGT and CYP2B6. Concurrent use of lorlatinib with CYP2B6 substrates may result in decreased plasma concentrations of the substrate.
Lorlatinib has the potential to inhibit BCRP, OCT1, MATE1, and OAT3.
Severe hepatotoxicity has occurred in 10 of 12 patients receiving a single dose of lorlatinib with multiple daily doses of a strong CYP3A inducer (i.e. rifampin). ALT or AST elevations occurred within 3 days and returned to normal after a median of 15 days (7 to 34 days); the median time to recovery was 18 days in patients with Grade 3 or 4 ALT or AST elevations and 7 days in patients with Grade 2 ALT or AST elevations.
No dose adjustment is necessary with proton pump inhibitors, H2 receptor antagonists, or antacids.
| AGENT | EFFECT | MECHANISM | MANAGEMENT |
|---|---|---|---|
| CYP3A4 inhibitors (i.e. ketoconazole, clarithromycin, ritonavir, fruit or juice from grapefruit, Seville oranges or starfruit) | ↑ lorlatinib concentration (↑ AUC by 42% and ↑ Cmax by 24% with itraconazole) and/or toxicity | ↓ metabolism of lorlatinib | Avoid use with strong CYP3A4 inhibitors. Consider alternative with less CYP3A4 inhibition. If co-administration with a strong CYP3A4 inhibitor is unavoidable, ↓ lorlatinib dose to 75 mg daily. If the strong CYP3A4 inhibitor is discontinued, resume at the dose used prior to initiation of the strong CYP3A4 inhibitor, after a washout period of 3 to 5 half-lives of the CYP3A4 inhibitor. |
| Fluconazole | ↑ lorlatinib concentration and/or toxicity | ↓ metabolism of lorlatinib | Avoid use with fluconazole. If co-administration is unavoidable, ↓ lorlatinib dose to 75 mg daily. |
| Strong CYP3A4 inducers (i.e. phenytoin, rifampin, carbamazepine, enzalutamide, St. John’s Wort, etc) | ↑ risk of severe hepatotoxicity and/or ↓ lorlatinib concentration (↓ AUC by 85% and ↓ Cmax by 76% with rifampin) | ↑ metabolism of lorlatinib | CONTRAINDICATED with strong CYP3A4 inducers. Discontinue strong CYP3A4 inducers for at least 3 plasma half-lives before starting lorlatinib. |
| Moderate CYP3A4 inducers (i.e. bosentan, efavirenz, etravirine, phenobarbital, primidone) | ↑ risk of hepatotoxicity (theoretical) and/or ↓ lorlatinib concentration | ↑ metabolism of lorlatinib | Avoid use with moderate CYP3A4 inducers. If co-administration is unavoidable, ↑ lorlatinib dose to 125 mg daily. |
| CYP3A4 substrates (e.g. hormonal contraceptives, cyclosporine, pimozide, tacrolimus, triazolo-benzodiazepines, dihydropyridine calcium-channel blockers, certain HMG-CoA reductase inhibitors) | ↓ substrate concentration and/or efficacy | Lorlatinib is a CYP3A4 inducer. | Avoid with drugs with narrow therapeutic index. |
| P-glycoprotein substrates with narrow therapeutic index (i.e. digoxin) | ↓ substrate concentration and/or efficacy | Lorlatinib is a P-gp inducer in vivo. | Caution if drugs with narrow therapeutic index. |
Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.
| Monitor Type | Monitor Frequency |
|---|---|
Liver function tests |
Baseline and as clinically indicated. (If co-administration with a moderate CYP3A inducer is unavoidable: 48 hours after initiating lorlatinib and at least 3 times during the first week after initiation.) |
ECG |
Baseline, monthly (especially in patients with risk factors for clinically significant cardiac events), and as clinically indicated |
Blood pressure |
Baseline, 2 weeks after initiation, and at least monthly during treatment |
Cholesterol and triglycerides |
Baseline, 2, 4, and 8 weeks after initiation, and as clinically indicated |
Lipase, amylase |
Baseline and as clinically indicated |
Blood glucose |
Baseline and as clinically indicated |
Clinical toxicity assessment for CNS adverse events (e.g. hallucination, seizure, and changes in cognition, mood, mental status, or speech), edema, peripheral neuropathy, thromboembolism, GI effects and pneumonitis |
At each visit |
Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version
Exceptional Access Program (EAP Website)
- lorlatinib - For the treatment of adult patients with anaplastic lymphoma kinase (ALK)-positive locally advanced or metastatic non-small cell lung cancer.
Lorlatinib. Lexicomp, Inc. Accessed Jan 22, 2020.
National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology: Antiemesis: Version 2.2022, 2022.
Prescribing Information: Lorbrena (lorlatinib). Pfizer Inc. March 2021.
Product Monograph: Lorbrena (lorlatinib). Pfizer Canada ULC. May 16, 2022.
Shaw AT, Bauer TM, de Marinis F, et al. First-line lorlatinib or crizotinib in advanced ALK-positive lung cancer. N Engl J Med. 2020 Nov 19;383(21):2018-2029. doi: 10.1056/NEJMoa2027187.
August 2023 Updated Supplementary public funding section; modified Dose modifications and Warnings/precautions sections
Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.
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