LORBRENA® (lorlatinib) 6 ADVERSE REACTIONS

(lorlatinib)

Prescribing Information

6 ADVERSE REACTIONS

The following adverse reactions are described elsewhere in the labeling:

•: Risk of Serious Hepatotoxicity with Concomitant Use of Strong CYP3A Inducers [see Warnings and Precautions (5.1)]
•: Central Nervous System Effects [see Warnings and Precautions (5.2)]
•: Hyperlipidemia [see Warnings and Precautions (5.3)]
•: Atrioventricular Block [see Warnings and Precautions (5.4)]
•: Interstitial Lung Disease/Pneumonitis [see Warnings and Precautions (5.5)]
•: Hypertension [see Warnings and Precautions (5.6)]
•: Hyperglycemia [see Warnings and Precautions (5.7)]

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The pooled safety population described in the Warnings and Precautions section reflects exposure to LORBRENA in 476 patients who received 100 mg LORBRENA once daily in Study B7461001 (N=327) and Study B7461006 (N=149). Among 476 patients who received LORBRENA, 75% were exposed for 6 months or longer and 61% were exposed for greater than 1 year. In this pooled safety population, the most frequent adverse reactions in ≥ 20% of 476 patients who received LORBRENA were edema (56%), peripheral neuropathy (44%), weight gain (31%), cognitive effects (28%), fatigue (27%), dyspnea (27%), arthralgia (24%), diarrhea (23%), mood effects (21%), and cough (21%). The most frequent Grade 3–4 laboratory abnormalities in ≥ 20% of 476 patients who received LORBRENA were hypercholesterolemia (21%) and hypertriglyceridemia (21%).

Previously Untreated ALK-Positive Metastatic NSCLC (CROWN Study)

The safety of LORBRENA was evaluated in 149 patients with ALK-positive NSCLC in a randomized, open-label, active-controlled trial for the treatment of patients with ALK-positive, locally advanced or metastatic, NSCLC who had not received previous systemic treatment for advanced disease [see Clinical Studies (14)]. The median duration of exposure to LORBRENA was 16.7 months (4 days to 34.3 months) and 76% received LORBRENA for at least 12 months.

Serious adverse reactions occurred in 34% of patients treated with LORBRENA; the most frequently reported serious adverse reactions were pneumonia (4.7%), dyspnea (2.7%), respiratory failure (2.7%), cognitive effects (2.0%), and pyrexia (2.0%). Fatal adverse reactions occurred in 3.4% of patients treated with LORBRENA and included pneumonia (0.7%), respiratory failure (0.7%), cardiac failure acute (0.7%), pulmonary embolism (0.7%), and sudden death (0.7%).

Permanent discontinuation of LORBRENA due to adverse reactions occurred in 6.7% of patients. The most frequent adverse reaction that led to permanent discontinuation of LORBRENA was cognitive effects (1.3%). Adverse reactions leading to dose interruptions occurred in 49% of patients treated with LORBRENA. The most frequent adverse reactions that led to dose interruptions of LORBRENA were hypertriglyceridemia (7%), edema (5%), pneumonia (4.7%) cognitive effects (4.0%), mood effects (4.0%), and hypercholesterolemia (3.4%). Adverse reactions leading to dose reductions occurred in 21% of patients treated with LORBRENA. The most frequent adverse reactions that led to dose reductions were edema (5%), hypertriglyceridemia (4.0%), and peripheral neuropathy (3.4%).

Tables 2 and 3 summarize most frequent adverse reactions and laboratory abnormalities, respectively, in patients treated with LORBRENA in Study B7461006.

Table 2 Adverse Reactions (≥10% for all NCI CTCAE Grades or ≥2% for Grades 3–4) in Patients Treated with LORBRENA in Study B7461006*
Adverse Reaction	LORBRENA N=149		Crizotinib N=142
Adverse Reaction	All Grades (%)	Grade 3 or 4 (%)	All Grades (%)	Grade 3 or 4 (%)
Abbreviations: NCI CTCAE=National Cancer Institute Common Terminology Criteria for Adverse Events; SOC=System organ class.
* Adverse reactions were graded using NCI CTCAE version 4.03. † Mood effects (including affective disorder, affect lability, agitation, anger, anxiety, bipolar I disorder, depressed mood, depression, depressive symptom, euphoric mood, intentional self-injury, irritability, mood altered, mood swings, stress). ‡ Peripheral neuropathy (including dysesthesia, gait disturbance, hypoesthesia, motor dysfunction, muscular weakness, neuralgia, neuropathy peripheral, paresthesia, peripheral motor neuropathy, peripheral sensory neuropathy). § Cognitive effects (including events from SOC Nervous system disorders: amnesia, cognitive disorder, disturbance in attention, memory impairment, mental impairment; and also including events from SOC Psychiatric disorders: confusional state, delirium, disorientation). ¶ Sleep effects (including insomnia, nightmare, sleep disorder, somnambulism). # Vision disorder (including diplopia, photophobia, photopsia, vision blurred, visual acuity reduced, visual impairment, vitreous floaters). Þ Myalgia (including musculoskeletal pain, myalgia). ß Edema (including edema, edema peripheral, eyelid edema, face edema, generalized edema, localized edema, periorbital edema, peripheral swelling, swelling). à Fatigue (including asthenia, fatigue). è Upper respiratory tract infection (including upper respiratory infection). ð Rash (including dermatitis acneiform, maculopapular rash, rash).
Psychiatric
Mood effects†	16	2	5	0
Nervous system
Peripheral neuropathy‡	34	2	15	0.7
Cognitive effects§	21	2	6	0
Headache	17	0	18	0.7
Dizziness	11	0	14	0
Sleep effects¶	11	1.3	10	0
Respiratory
Dyspnea	20	2.7	16	2.1
Cough	16	0	18	0
Respiratory failure	2.7	2	0	0
Vascular disorders
Hypertension	18	10	2.1	0
Ocular
Vision disorder#	18	0	39	0.7
Gastrointestinal
Diarrhea	21	1.3	52	0.7
Nausea	15	0.7	52	2.1
Constipation	17	0	30	0.7
Vomiting	13	0.7	39	1.4
Musculoskeletal and connective tissue
Arthralgia	19	0.7	11	0
MyalgiaÞ	15	0.7	7	0
Back pain	15	0.7	11	0
Pain in extremity	17	0	8	0
General
Edemaß	56	4	40	1.4
Weight gain	38	17	13	2.1
Fatigueà	19	1.3	32	2.8
Pyrexia	17	1.3	13	1.4
Chest pain	11	1.3	14	0.7
Infections
Upper respiratory tract infectionè	11	0.7	7.7	1.4
Pneumonia	7.4	2	8.5	3.5
Bronchitis	6.7	2	2.1	0
Skin
Rashð	11	0	8.5	0

Additional clinically significant adverse reactions occurring at an incidence between 1% and 10% were speech effects (6.7%) and psychotic effects (3.4%).

Table 3 Laboratory Abnormalities Worsening from Baseline in ≥20% of Patients in Study B7461006
Laboratory Abnormality	LORBRENA N=149		Crizotinib N=142
Laboratory Abnormality	All Grades (%)	Grade 3 or 4 (%)	All Grades (%)	Grade 3 or 4 (%)
Abbreviations: ALT=alanine aminotransferase; AST=aspartate aminotransferase; CPK=creatine phosphokinase; GGT=gamma glutamyl transferase; NCI CTCAE=National Cancer Institute Common Terminology Criteria for Adverse Events; PTT=partial thromboplastin time.
N=number of patients who had at least one on-study assessment for the parameter of interest.
* N=149 (LORBRENA). † N=141 (crizotinib). ‡ N=148 (LORBRENA). § N=138 (LORBRENA). ¶ N=135 (crizotinib).
Chemistry
Hypertriglyceridemia*†	95	22	27	0
Hypercholesterolemia*†	91	19	12	0
Increased creatinine*†	81	0.7	99	2.1
Increased GGT*†	52	6	41	6
Increased AST*†	48	2	75	3.5
Hyperglycemia*†	48	7	27	2.1
Increased ALT*†	44	2.7	75	4.3
Increased CPK*†	39	2	64	5
Hypoalbuminemia*†	36	0.7	61	6
Increased lipase*†	28	7	34	5
Increased alkaline phosphatase*†	23	0	50	0.7
Hyperkalemia*†	21	1.3	27	2.1
Increased amylase‡†	20	1.4	32	1.4
Hematology
Anemia*†	48	2	38	2.8
Activated PTT§¶	25	0	14	0
Lymphopenia*†	23	2.7	43	6
Thrombocytopenia*†	23	0	7	0.7

Previously Treated ALK-Positive Metastatic NSCLC

The data described below reflect exposure to LORBRENA in 295 patients with ALK-positive or ROS1-positive metastatic NSCLC who received LORBRENA 100 mg orally once daily in Study B7461001, a multi-cohort, non-comparative trial [see Clinical Studies (14)]. The median duration of exposure to LORBRENA was 12.5 months (1 day to 35 months) and 52% received LORBRENA for ≥12 months. Patient characteristics were: median age of 53 years (19 to 85 years), age ≥65 years (18%), female (58%), White (49%), Asian (37%), and ECOG performance status 0 or 1 (96%).

The most frequent (≥20%) adverse reactions were edema, peripheral neuropathy, cognitive effects, dyspnea, fatigue, weight gain, arthralgia, mood effects, and diarrhea. Of the worsening laboratory values occurring in ≥20% of patients, the most frequent were hypercholesterolemia, hypertriglyceridemia, anemia, hyperglycemia, increased AST, hypoalbuminemia, increased ALT, increased lipase, and increased alkaline phosphatase.

Serious adverse reactions occurred in 32% of the 295 patients; the most frequently reported serious adverse reactions were pneumonia (3.4%), dyspnea (2.7%), pyrexia (2%), mental status changes (1.4%), and respiratory failure (1.4%). Fatal adverse reactions occurred in 2.7% of patients and included pneumonia (0.7%), myocardial infarction (0.7%), acute pulmonary edema (0.3%), embolism (0.3%), peripheral artery occlusion (0.3%), and respiratory distress (0.3%). Permanent discontinuation of LORBRENA for adverse reactions occurred in 8% of patients.

The most frequent adverse reactions that led to permanent discontinuation were respiratory failure (1.4%), dyspnea (0.7%), myocardial infarction (0.7%), cognitive effects (0.7%) and mood effects (0.7%). Approximately 48% of patients required dose interruption. The most frequent adverse reactions that led to dose interruptions were edema (7%), hypertriglyceridemia (6%), peripheral neuropathy (5%), cognitive effects (4.4%), increased lipase (3.7%), hypercholesterolemia (3.4%), mood effects (3.1%), dyspnea (2.7%), pneumonia (2.7%), and hypertension (2.0%). Approximately 24% of patients required at least 1 dose reduction for adverse reactions. The most frequent adverse reactions that led to dose reductions were edema (6%), peripheral neuropathy (4.7%), cognitive effects (4.1%), and mood effects (3.1%).

Tables 4 and 5 summarize most frequent adverse reactions and laboratory abnormalities, respectively, in patients treated with LORBRENA in Study B7461001.

Table 4 Adverse Reactions Occurring in ≥10% of Patients in Study B7461001*
Adverse Reaction	LORBRENA (N=295)
Adverse Reaction	All Grades (%)	Grade 3 or 4 (%)
Abbreviations: NCI CTCAE=National Cancer Institute Common Terminology Criteria for Adverse Events; SOC=System organ class.
* Adverse reactions were graded using NCI CTCAE version 4.03. † Mood effects (including affective disorder, affect lability, aggression, agitation, anxiety, depressed mood, depression, euphoric mood, irritability, mania, mood altered, mood swings, personality change, stress, suicidal ideation). ‡ Peripheral neuropathy (including burning sensation, carpal tunnel syndrome, dysesthesia, formication, gait disturbance, hypoesthesia, muscular weakness, neuralgia, neuropathy peripheral, neurotoxicity, paresthesia, peripheral sensory neuropathy, sensory disturbance). § Cognitive effects (including events from SOC Nervous system disorders: amnesia, cognitive disorder, dementia, disturbance in attention, memory impairment, mental impairment; and also including events from SOC Psychiatric disorders: attention deficit/hyperactivity disorder, confusional state, delirium, disorientation, reading disorder). ¶ Speech effects (including aphasia, dysarthria, slow speech, speech disorder) # Sleep effects (including abnormal dreams, insomnia, nightmare, sleep disorder, sleep talking, somnambulism) Þ Vision disorder (including blindness, diplopia, photophobia, photopsia, vision blurred, visual acuity reduced, visual impairment, vitreous floaters). ß Myalgia (including musculoskeletal pain, myalgia). à Edema (including edema, edema peripheral, eyelid edema, face edema, generalized edema, localized edema, periorbital edema, peripheral swelling, swelling). è Fatigue (including asthenia, fatigue). ð Upper respiratory infection (including fungal upper respiratory infection, upper respiratory infection, viral upper respiratory infection). ø Rash (including dermatitis acneiform, maculopapular rash, pruritic rash, rash).
Psychiatric
Mood effects†	23	1.7
Nervous system
Peripheral neuropathy‡	47	2.7
Cognitive effects§	27	2
Headache	18	0.7
Dizziness	16	0.7
Speech effects¶	12	0.3
Sleep effects#	10	0
Respiratory
Dyspnea	27	5
Cough	18	0
Ocular
Vision disorderÞ	15	0.3
Gastrointestinal
Diarrhea	22	0.7
Nausea	18	0.7
Constipation	15	0
Vomiting	12	1
Musculoskeletal and connective tissue
Arthralgia	23	0.7
Myalgiaß	17	0
Back pain	13	0.7
Pain in extremity	13	0.3
General
Edemaà	57	3.1
Fatigueè	26	0.3
Weight gain	24	4.4
Pyrexia	12	0.7
Infections
Upper respiratory tract infectionð	12	0
Skin
Rashø	14	0.3

Additional clinically significant adverse reactions occurring at an incidence between 1% and 10% were psychotic effects (7%).

Table 5 Worsening Laboratory Values Occurring in ≥20% of Patients in Study B7461001*
Laboratory Abnormality	LORBRENA
Laboratory Abnormality	All Grades (%)	Grade 3 or 4 (%)
Abbreviations: ALT=alanine aminotransferase; AST=aspartate aminotransferase; NCI CTCAE=National Cancer Institute Common Terminology Criteria for Adverse Events.
N=number of patients who had at least one on-study assessment for the parameter of interest.
* Grades using NCI CTCAE version 4.03. † N=292. ‡ N=293. § N=291. ¶ N=290. # N=284.
Chemistry
Hypercholesterolemia†	96	18
Hypertriglyceridemia†	90	18
Hyperglycemia‡	52	5
Increased AST†	37	2.1
Hypoalbuminemia§	33	1
Increased ALT†	28	2.1
Increased lipase¶	24	10
Increased alkaline phosphatase†	24	1
Increased amylase#	22	3.9
Hypophosphatemia†	21	4.8
Hyperkalemia‡	21	1
Hypomagnesemia†	21	0
Hematology
Anemia‡	52	4.8
Thrombocytopenia‡	23	0.3
Lymphopenia†	22	3.4

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.” • 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: o problems with thinking, such as forgetfulness or confusion o changes in mood, such as depression and thoughts about suicide or dying o psychotic effects, such as seeing or hearing things that are not real (hallucinations) o seizures o changes in speech o changes in sleep • 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. o 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. o 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. • 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. • 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:
	o feeling very thirsty o needing to urinate more than usual o feeling very hungry	o feeling sick to your stomach o feeling weak or tired o 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 • 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:
• have kidney problems • have liver problems • have had episodes of depression or seizures • have high levels of cholesterol or triglycerides in your blood • have problems with your heart beat • have lung or breathing problems • have high blood pressure • have diabetes or high blood sugar • are pregnant or plan to become pregnant. LORBRENA can harm your unborn baby. Females who are able to become pregnant: o Your healthcare provider will do a pregnancy test before you start treatment with LORBRENA. o Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with LORBRENA. o Use effective non-hormonal birth control during treatment and for at least 6 months after the final dose of LORBRENA. o 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?
• 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. • 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. • Take LORBRENA 1 time a day, at the same time each day. • You may take LORBRENA with or without food. • 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. • 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:
	• swelling in your arms, legs, hands and feet (edema) • numbness and tingling feeling in your joints or arms and legs (peripheral neuropathy) • weight gain • problems with thinking, such as forgetfulness or confusion • tiredness (fatigue)	• difficulty breathing • pain in your joints • diarrhea • changes in mood, such as depression and irritability • increased cholesterol and triglyceride levels in the blood • 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?
• Store LORBRENA at room temperature between 68°F to 77°F (20°C to 25°C). • 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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