(lorlatinib)

Prescribing Information
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12 CLINICAL PHARMACOLOGY

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Lorlatinib is a kinase inhibitor with in vitro activity against ALK and ROS1 as well as TYK1, FER, FPS, TRKA, TRKB, TRKC, FAK, FAK2, and ACK. Lorlatinib demonstrated in vitro activity against multiple mutant forms of the ALK enzyme, including some mutations detected in tumors at the time of disease progression on crizotinib and other ALK inhibitors.

In mice subcutaneously implanted with tumors harboring EML4 fusions with either ALK variant 1 or ALK mutations, including the G1202R and I1171T mutations detected in tumors at the time of disease progression on ALK inhibitors, administration of lorlatinib resulted in antitumor activity. Lorlatinib also demonstrated anti-tumor activity and prolonged survival in mice implanted intracranially with EML4-ALK-driven tumor cell lines. The overall antitumor activity of lorlatinib in in vivo models was dose-dependent and correlated with inhibition of ALK phosphorylation.

12.2 Pharmacodynamics

Exposure-response relationships for Grade 3 or 4 hypercholesterolemia and for any Grade 3 or 4 adverse reaction were observed at steady-state exposures achieved at the recommended dosage, with higher probability of the occurrence of adverse reactions with increasing lorlatinib exposure.

Cardiac Electrophysiology

In 295 patients who received LORBRENA at the recommended dosage of 100 mg once daily and had an ECG measurement in Study B7461001, the maximum mean change from baseline for PR interval was 16.4 ms (2-sided 90% upper confidence interval [CI] 19.4 ms). Among the 284 patients with PR interval <200 ms at baseline, 14% had PR interval prolongation ≥200 ms after starting LORBRENA. The prolongation of PR interval occurred in a concentration-dependent manner. Atrioventricular block occurred in 1% of patients.

In 275 patients who received LORBRENA at the recommended dosage in the activity-estimating portion of Study B7461001, no large mean increases from baseline in the QTcF interval (i.e., >20 ms) were detected.

12.3 Pharmacokinetics

At the recommended dosage, the mean (coefficient of variation [CV] %) maximum plasma concentration (Cmax) is 577 ng/mL (42%) and the AUC0-24h is 5,650 ng·h/mL (39%). Steady-state lorlatinib Cmax increases proportionally and AUC increased slightly less than proportionally over the dose range of 10 mg to 200 mg orally once daily (0.1 to 2 times the recommended dosage).

Absorption

The median lorlatinib Tmax is 1.2 hours (0.5 to 4 hours) following a single oral 100 mg dose and 2 hours (0.5 to 23 hours) following 100 mg orally once daily at steady‑state.

The mean absolute bioavailability is 81% (90% CI 76%, 86%).

Effect of Food

No clinically significant differences in lorlatinib pharmacokinetics were observed following administration of a high fat, high calorie meal (approximately 1000 calories with 150 calories from protein, 250 calories from carbohydrate, and 500 to 600 calories from fat).

Distribution

Lorlatinib is 66% bound to plasma proteins, in vitro. The blood-to-plasma ratio is 0.99, in vitro.

Elimination

The mean plasma half‑life (t½) of lorlatinib was 24 hours (40%) after a single oral 100 mg dose of LORBRENA. The mean oral clearance (CL/F) was 11 L/h (35%) following a single oral 100 mg dose and increased to 18 L/h (39%) at steady‑state, suggesting autoinduction.

Metabolism

Lorlatinib is metabolized primarily by CYP3A4 and UGT1A4, with minor contribution from CYP2C8, CYP2C19, CYP3A5, and UGT1A3.

In plasma, a benzoic acid metabolite (M8) of lorlatinib resulting from the oxidative cleavage of the amide and aromatic ether bonds of lorlatinib accounted for 21% of the circulating radioactivity. The oxidative cleavage metabolite, M8, is pharmacologically inactive.

Excretion

Following a single oral 100 mg dose of radiolabeled lorlatinib, 48% of the radioactivity was recovered in urine (<1% as unchanged) and 41% in feces (about 9% as unchanged).

Specific Populations

No clinically significant differences in lorlatinib pharmacokinetics were observed based on age (19 to 85 years), sex, race/ethnicity (52% White, 8% Black, 27% Asian), body weight (32-156 kg), CLcr 30 to 89 mL/min (estimated by Cockcroft Gault), mild (total bilirubin ≤ ULN and AST > ULN or total bilirubin > 1 to 1.5 × ULN and any AST) to moderate (Child-Pugh B) hepatic impairment, or metabolizer phenotypes for CYP3A5 and CYP2C19.

Patients with Moderate or Severe Hepatic Impairment

Following administration of a single oral 100 mg dose of LORBRENA, lorlatinib AUC increased 1.1-fold in non-cancer subjects with moderate hepatic impairment (Child-Pugh B) and 1.8-fold in non-cancer subjects with severe hepatic impairment (Child-Pugh C).

Patients with Renal Impairment

Following administration of a single oral 100 mg dose of LORBRENA, lorlatinib AUC increased 1.4-fold in subjects with CLcr 15 to <30 mL/min (estimated by Cockcroft Gault). The pharmacokinetics of lorlatinib have not been studied in patients with end-stage renal disease requiring hemodialysis.

Drug Interaction Studies

Clinical Studies and Model-Informed Approaches

Strong CYP3A Inducers: Rifampin (a strong CYP3A inducer that also activates PXR) 600 mg once daily for 8 days (Days 1 to 8) coadministered with a single oral 100 mg dose of LORBRENA on Day 8 reduced the mean lorlatinib AUC by 85% and Cmax by 76%. Grade 2 to 4 increases in ALT or AST occurred within 3 days. Grade 4 ALT or AST elevations occurred in 50%, Grade 3 ALT or AST elevations in 33%, and Grade 2 ALT or AST elevations occurred in 8% of subjects. ALT and AST returned to within normal limits within 7 to 34 days (median 15 days).

Moderate CYP3A Inducers: Modafinil (a moderate CYP3A inducer) decreased lorlatinib AUC by 23% and Cmax by 22% of a single oral 100 mg dose of LORBRENA.

Strong CYP3A Inhibitors: Itraconazole (a strong CYP3A inhibitor) increased lorlatinib AUC 1.4-fold and Cmax 1.2-fold of a single oral 100 mg dose of LORBRENA.

Fluconazole: Fluconazole is predicted to increase lorlatinib AUC 1.6-fold and Cmax 1.3-fold following concomitant oral administration of 100 mg of LORBRENA once daily and 200 mg fluconazole once daily.

Moderate CYP3A Inhibitors: No clinically significant effect on lorlatinib pharmacokinetics is predicted when used concomitantly with verapamil or erythromycin.

CYP3A Substrates: LORBRENA 150 mg orally once daily for 15 days decreased AUC by 64% and Cmax by 50% of a single oral 2 mg dose of midazolam (a sensitive CYP3A substrate).

CYP2B6 Substrates: LORBRENA 100 mg orally once daily for 15 days decreased AUC by 25% and Cmax by 27% of a single oral 100 mg dose of bupropion (a sensitive CYP2B6 substrate).

CYP2C9 Substrates: LORBRENA 100 mg orally once daily for 15 days decreased AUC by 43% and Cmax by 15% of a single oral 100 mg dose of tolbutamide (a sensitive CYP2C9 substrate).

UGT1A Substrates: LORBRENA 100 mg orally once daily for 15 days decreased AUC by 45% and Cmax by 28% of a single oral 100 mg dose of acetaminophen (a UGT1A substrate).

P-gp Substrates: LORBRENA 100 mg orally once daily for 15 days decreased AUC by 67% and Cmax by 63% of a single oral 60 mg dose of fexofenadine (a P-gp substrate).

Acid-Reducing Agents: Concomitant use of a proton pump inhibitor, rabeprazole, did not have a clinically significant effect on lorlatinib pharmacokinetics.

In Vitro Studies

CYP Enzymes: Lorlatinib is a time-dependent inhibitor as well as an inducer of CYP3A and activates PXR, with the net effect in vivo being induction. Lorlatinib induces CYP2B6 and activates the human constitutive androstane receptor (CAR). Lorlatinib and the major circulating metabolite, M8, do not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2D6. M8 does not inhibit CYP3A.

M8 does not induce CYP1A2, CYP2B6, or CYP3A.

UDP-glucuronosyltransferase (UGT): Lorlatinib and M8 do not inhibit UGT1A1, UGT1A4, UGT1A6, UGT1A9, UGT2B7, or UGT2B15.

Transporter Systems: Lorlatinib is an inhibitor of P-gp and activates PXR (potential to induce P-gp), with the net effect in vivo being induction.

Lorlatinib inhibits OCT1, OAT3, MATE1, and intestinal BCRP. Lorlatinib does not inhibit OATP1B1, OATP1B3, OAT1, OCT2, MATE2K, or systemic BCRP. M8 does not inhibit P‑gp, BCRP, OATP1B1, OATP1B3, OAT1, OAT3, OCT1, OCT2, MATE1, or MATE2K.

Medication Guide

MEDICATION GUIDE

PATIENT INFORMATION
LORBRENA (lor-BREN-ah)
(lorlatinib)
tablets
This Patient Information has been approved by the U.S. Food and Drug Administration.     Revised: January 2026

What is the most important information I should know about LORBRENA?

LORBRENA can cause serious side effects, including:

•
Liver problems due to interactions with other medicines. Liver problems can be severe. It is important to know what medicines not to take during treatment with LORBRENA. See “Tell your healthcare provider about all the medicines you take, including.”
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Central nervous system (CNS) effects. CNS effects can be severe. Tell your healthcare provider if you get any new or worsening symptoms of CNS effects, including:
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problems with thinking, such as forgetfulness or confusion
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changes in mood, such as depression and thoughts about suicide or dying
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psychotic effects, such as seeing or hearing things that are not real (hallucinations)
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seizures
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changes in speech
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changes in sleep
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Increases in the cholesterol and triglycerides (lipid) levels in your blood. Most people will get an increase in the lipid levels in their blood during treatment with LORBRENA.
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If you get increases in the lipid levels in your blood, your healthcare provider may start you on a new medicine or increase your dose if you are already taking a medicine to lower the lipid levels in your blood.
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Your healthcare provider will do blood tests to check the lipid levels in your blood before starting treatment, 1 and 2 months after starting treatment, and during treatment with LORBRENA.
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Heart problems. LORBRENA can cause very slow or abnormal heartbeats. Your healthcare provider will check your heart rhythm (electrocardiogram or EKG) before starting and during treatment with LORBRENA. In some people, these problems are severe, and you may need to get a pacemaker. Tell your healthcare provider right away if you feel dizzy or faint or have abnormal heartbeats.
•
Lung problems. LORBRENA can cause severe or life-threatening swelling (inflammation) of the lungs during treatment that can lead to death. Symptoms may be like those from lung cancer. Tell your healthcare provider right away if you get any new or worsening symptoms of lung problems, including trouble breathing, shortness of breath, cough, or fever.
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High blood pressure (hypertension). Your healthcare provider will check your blood pressure before starting treatment, 2 weeks after starting treatment, and then at least every month during treatment with LORBRENA. Your healthcare provider may start or change your blood pressure medicine if you get high blood pressure. Tell your healthcare provider right away if you get signs or symptoms of high blood pressure, including: headaches, dizziness, blurred vision, chest pain or shortness of breath.
•
High blood sugar (hyperglycemia). LORBRENA can cause new or worsening increases in your blood sugar levels. Your healthcare provider will do blood tests to check your blood sugar levels before starting and during treatment with LORBRENA. Your healthcare provider may start or change your blood sugar medicine if you get high blood sugar. Tell your healthcare provider right away if you get any signs and symptoms of high blood sugar, including:
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feeling very thirsty
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needing to urinate more than usual
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feeling very hungry
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feeling sick to your stomach
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feeling weak or tired
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feeling confused

If you get serious side effects during treatment, your healthcare provider may change your dose, temporarily stop, or permanently stop treatment with LORBRENA.
See "What are possible side effects of LORBRENA?" for more information about side effects.

What is LORBRENA?

LORBRENA is a prescription medicine used to treat adults with non-small cell lung cancer (NSCLC):

•
that is caused by an abnormal anaplastic lymphoma kinase (ALK) gene, and
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that has spread to other parts of your body (metastatic).

Your healthcare provider will perform a test to make sure that LORBRENA is right for you.
It is not known if LORBRENA is safe and effective in children.

Do not take LORBRENA if you take certain other medicines called strong CYP3A inducers. Ask your healthcare provider for a list of these medicines if you are not sure.

Before taking LORBRENA, tell your healthcare provider about all of your medical conditions, including if you:

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have kidney problems
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have liver problems
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have had episodes of depression or seizures
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have high levels of cholesterol or triglycerides in your blood
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have problems with your heart beat
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have lung or breathing problems
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have high blood pressure
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have diabetes or high blood sugar
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are pregnant or plan to become pregnant. LORBRENA can harm your unborn baby.
 
Females who are able to become pregnant:
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Your healthcare provider will do a pregnancy test before you start treatment with LORBRENA.
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Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with LORBRENA.
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Use effective non-hormonal birth control during treatment and for at least 6 months after the final dose of LORBRENA.
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Birth control pills (oral contraceptives) and other hormonal forms of birth control may not be effective if used during treatment with LORBRENA. Talk to your healthcare provider about birth control choices that are right for you during this time.
 
Males with female partners who are able to become pregnant:
o
Use effective birth control during treatment and for at least 3 months after the final dose of LORBRENA.
•
are breastfeeding or plan to breastfeed. It is not known if LORBRENA passes into your breast milk. Do not breastfeed during treatment and for 7 days after the final dose of LORBRENA. Talk to your healthcare provider about the best way to feed your baby during this time.

Tell your healthcare provider about all the medicines you take, including prescription medicines, over-the-counter medicines, vitamins, and herbal supplements. Taking LORBRENA with certain other medicines may increase your risk of side effects and may affect the way LORBRENA or the other medicines work.
Know the medicines you take. Keep a list of them to show to your healthcare provider and pharmacist when you get a new medicine.

How should I take LORBRENA?

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Take LORBRENA exactly as your healthcare provider tells you to take it. Do not change your dose or stop taking LORBRENA unless your healthcare provider tells you to.
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Swallow LORBRENA tablets whole. Do not chew, crush, or split LORBRENA tablets. Do not take LORBRENA tablets if they are broken, cracked, or not intact.
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Take LORBRENA 1 time a day, at the same time each day.
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You may take LORBRENA with or without food.
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If you miss a dose, take it as soon as you remember. However, if it is within 4 hours of the time to take your next dose, just take your next dose at your regular time. Do not take 2 doses of LORBRENA at the same time to make up for the missed dose.
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If you vomit after taking a dose of LORBRENA, do not take an extra dose. Take your next dose at your regular time.

What are the possible side effects of LORBRENA?

•
See "What is the most important information I should know about LORBRENA?"

The most common side effects of LORBRENA include:

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swelling in your arms, legs, hands and feet (edema)
•
numbness and tingling feeling in your joints or arms and legs (peripheral neuropathy)
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weight gain
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problems with thinking, such as forgetfulness or confusion
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tiredness (fatigue)
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difficulty breathing
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pain in your joints
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diarrhea
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changes in mood, such as depression and irritability
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increased cholesterol and triglyceride levels in the blood
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cough

LORBRENA may cause decreased fertility in males, which may affect your ability to have children. Talk to your healthcare provider if you have concerns about fertility.

These are not all of the possible side effects of LORBRENA.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1‑800‑FDA‑1088.

How should I store LORBRENA?

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Store LORBRENA at room temperature between 68°F to 77°F (20°C to 25°C).
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LORBRENA comes in a bottle that contains a child resistant cap.

Keep LORBRENA and all medicines out of the reach of children.

General information about the safe and effective use of LORBRENA.

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use LORBRENA for a condition for which it was not prescribed. Do not give LORBRENA to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for more information about LORBRENA that is written for health professionals.

What are the ingredients in LORBRENA?

Active ingredient: lorlatinib

Inactive ingredients: microcrystalline cellulose, dibasic calcium phosphate anhydrous, sodium starch glycolate, and magnesium stearate.

Film-coating contains: hydroxypropyl methylcellulose (HPMC) 2910/hypromellose, lactose monohydrate, macrogol/polyethylene glycol (PEG) 3350, triacetin, titanium dioxide, ferrosoferric oxide/black iron oxide, and iron oxide red.

For more information, go to www.Pfizer.com.

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