Lorbrena

Recurrent complete AV block Place pacemaker or permanently discontinue LORBRENA. 5) ] Any Grade treatment–related ILD/Pneumonitis Permanently discontinue LORBRENA. 6) ] Grade 3 (SBP greater than or equal to 160 mmHg or DBP greater than or equal to 100 mmHg; medical intervention indicated; more than one antihypertensive drug, or more intensive therapy than previously used indicated) Withhold LORBRENA until hypertension has recovered to Grade 1 or less (SBP less than 140 mmHg and DBP less than 90 mmHg), then resume LORBRENA at the same dose.

If Grade 3 hypertension recurs, withhold LORBRENA until recovery to Grade 1 or less, and resume at a reduced dose. If adequate hypertension control cannot be achieved with optimal medical management, permanently discontinue LORBRENA.

Grade 4 (life-threatening consequences, urgent intervention indicated) Withhold LORBRENA until recovery to Grade 1 or less, and resume at a reduced dose or permanently discontinue LORBRENA. If Grade 4 hypertension recurs, permanently discontinue LORBRENA.

7) ] Grade 3 (greater than 250 mg/dL) despite optimal anti-hyperglycemic therapy OR Grade 4 Withhold LORBRENA until hyperglycemia is adequately controlled, then resume LORBRENA at the next lower dosage. If adequate hyperglycemic control cannot be achieved with optimal medical management, permanently discontinue LORBRENA.

Other Adverse Reactions Grade 1 OR Grade 2 Continue LORBRENA at same dose or reduced dose. Grade 3 OR Grade 4 Withhold LORBRENA until symptoms resolve to less than or equal to Grade 2 or baseline. Resume LORBRENA at reduced dose. 4 Dosage Modifications for Drug Interactions Strong CYP3A Inducers LORBRENA is contraindicated in patients taking strong CYP3A inducers.

3) ] . Moderate CYP3A Inducers Avoid concomitant use of moderate CYP3A inducers with LORBRENA. 3) ] . Strong CYP3A Inhibitors Avoid concomitant use of LORBRENA with strong CYP3A inhibitors. If concomitant use with a strong CYP3A inhibitor is unavoidable, reduce the starting dose of LORBRENA from 100 mg orally once daily to 75 mg orally once daily.

In patients who have had a dose reduction to 75 mg orally once daily due to adverse reactions and who initiate a strong CYP3A inhibitor, reduce the LORBRENA dose to 50 mg orally once daily. 3) ] . 3) ] . 3) ] . 3) ] . 3) ] .

4%). Tables 2 and 3 summarize most frequent adverse reactions and laboratory abnormalities, respectively, in patients treated with LORBRENA in Study B7461006. 03. Adverse Reaction LORBRENA N=149 Crizotinib N=142 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.

Psychiatric Mood effects 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).

16 2 5 0 Nervous system Peripheral neuropathy Peripheral neuropathy (including dysesthesia, gait disturbance, hypoesthesia, motor dysfunction, muscular weakness, neuralgia, neuropathy peripheral, paresthesia, peripheral motor neuropathy, peripheral sensory neuropathy).

7 Cognitive effects 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).

7 Dizziness 11 0 14 0 Sleep effects Sleep effects (including insomnia, nightmare, sleep disorder, somnambulism). 1 0 Ocular Vision disorder Vision disorder (including diplopia, photophobia, photopsia, vision blurred, visual acuity reduced, visual impairment, vitreous floaters).

7 11 0 Myalgia Myalgia (including musculoskeletal pain, myalgia). 7 11 0 Pain in extremity 17 0 8 0 General Edema Edema (including edema, edema peripheral, eyelid edema, face edema, generalized edema, localized edema, periorbital edema, peripheral swelling, swelling).

1 Fatigue Fatigue (including asthenia, fatigue). 7 Infections Upper respiratory tract infection Upper respiratory tract infection (including upper respiratory infection). 1 0 Skin Rash Rash (including dermatitis acneiform, maculopapular rash, rash).

4%). Table 3 Laboratory Abnormalities Worsening from Baseline in ≥20% of Patients in Study B7461006 Laboratory Abnormality LORBRENA N=149 Crizotinib N=142 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. Chemistry Hypertriglyceridemia N=149 (LORBRENA). N=141 (crizotinib). 1 Increased amylase N=148 (LORBRENA). 8 Activated PTT N=138 (LORBRENA). N=135 (crizotinib).

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) ] .

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.

4%). 3%). Permanent discontinuation of LORBRENA for adverse reactions occurred in 8% of patients. 7%). Approximately 48% of patients required dose interruption. 0%). Approximately 24% of patients required at least 1 dose reduction for adverse reactions.

1%). Tables 4 and 5 summarize most frequent adverse reactions and laboratory abnormalities, respectively, in patients treated with LORBRENA in Study B7461001. 03. Adverse Reaction LORBRENA (N=295) All Grades (%) Grade 3 or 4 (%) Abbreviations: NCI CTCAE=National Cancer Institute Common Terminology Criteria for Adverse Events; SOC=System organ class.

Psychiatric Mood effects 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).

7 Nervous system Peripheral neuropathy 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).

7 Cognitive effects 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).

3 Sleep effects Sleep effects (including abnormal dreams, insomnia, nightmare, sleep disorder, sleep talking, somnambulism) 10 0 Respiratory Dyspnea 27 5 Cough 18 0 Ocular Vision disorder Vision disorder (including blindness, diplopia, photophobia, photopsia, vision blurred, visual acuity reduced, visual impairment, vitreous floaters).

7 Myalgia Myalgia (including musculoskeletal pain, myalgia). 3 General Edema Edema (including edema, edema peripheral, eyelid edema, face edema, generalized edema, localized edema, periorbital edema, peripheral swelling, swelling). 1 Fatigue Fatigue (including asthenia, fatigue).

7 Infections Upper respiratory tract infection Upper respiratory infection (including fungal upper respiratory infection, upper respiratory infection, viral upper respiratory infection). 12 0 Skin Rash Rash (including dermatitis acneiform, maculopapular rash, pruritic rash, rash).

3 Additional clinically significant adverse reactions occurring at an incidence between 1% and 10% were psychotic effects (7%). 03. Laboratory Abnormality LORBRENA 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. Chemistry Hypercholesterolemia N=292. 96 18 Hypertriglyceridemia 90 18 Hyperglycemia N=293. 1 Hypoalbuminemia N=291. 1 Increased lipase N=290.

24 10 Increased alkaline phosphatase 24 1 Increased amylase N=284. 4

Grade 4 alanine aminotransferase (ALT) or aspartate aminotransferase (AST) elevations occurred in 50% of subjects, Grade 3 ALT or AST elevations occurred in 33% and Grade 2 ALT or AST elevations occurred in 8%. 1) ] . LORBRENA is contraindicated in patients taking strong CYP3A inducers.

1) ] . 2 Central Nervous System Effects A broad spectrum of central nervous system (CNS) effects can occur in patients receiving LORBRENA. These include seizures, psychotic effects and changes in cognitive function, mood (including suicidal ideation), speech, mental status, and sleep.

1) ] . 9% of these events were severe (Grade 3 or 4). 7% of these events were severe. 6% of these events were severe. 6% of these events were severe. 1% of these events were severe. 9% of patients, sometimes in conjunction with other neurologic findings.

Sleep effects occurred in 12% of patients. 4 years). 1% of patients required permanent discontinuation of LORBRENA for a CNS effect; 10% required temporary discontinuation and 8% required dose reduction. 3) ] . 1) ] . Grade 3 or 4 elevations in total cholesterol occurred in 18% and Grade 3 or 4 elevations in triglycerides occurred in 19% of the 476 patients who received 100 mg LORBRENA once daily.

The median time to onset was 15 days for both hypercholesterolemia and hypertriglyceridemia. Approximately 4% and 7% of patients required temporary discontinuation and 1% and 3% of patients required dose reduction of LORBRENA for elevations in cholesterol and in triglycerides in Study B7461001 and Study B7461006, respectively.

Eighty-three percent of patients required initiation of lipid-lowering medications, with a median time to onset of start of such medications of 17 days. Initiate or increase the dose of lipid-lowering agents in patients with hyperlipidemia.

Monitor serum cholesterol and triglycerides before initiating LORBRENA, 1 and 2 months after initiating LORBRENA, and periodically thereafter. 3) ]. 2) ]. 2% experienced Grade 3 AV block and underwent pacemaker placement. Monitor ECG prior to initiating LORBRENA and periodically thereafter.

Withhold and resume at a reduced dose or at the same dose in patients who undergo pacemaker placement. 3) ] . 5 Interstitial Lung Disease/Pneumonitis Severe or life-threatening pulmonary adverse reactions consistent with interstitial lung disease (ILD)/pneumonitis can occur with LORBRENA.

6% of patients. 8%) discontinued LORBRENA for ILD/pneumonitis. , dyspnea, cough, and fever). Immediately withhold LORBRENA in patients with suspected ILD/pneumonitis. 3) ] . 1) ] . Hypertension occurred in 13% of patients who received 100 mg LORBRENA once daily, including Grade 3 or 4 in 6% of patients.

3% of patients temporarily discontinued LORBRENA for hypertension. Control blood pressure prior to initiation of LORBRENA. Monitor blood pressure after 2 weeks and at least monthly thereafter during treatment with LORBRENA. 3) ] . 1) ] .

2% of patients. 8% of patients temporarily discontinued LORBRENA for hyperglycemia. Assess fasting serum glucose prior to initiation of LORBRENA and monitor periodically thereafter. 3) ] . 8 Embryo-Fetal Toxicity Based on findings from animal studies and its mechanism of action, LORBRENA can cause fetal harm when administered to a pregnant woman.

Administration of lorlatinib to pregnant rats and rabbits by oral gavage during the period of organogenesis resulted in malformations, increased post-implantation loss, and abortion at maternal exposures that were equal to or less than the human exposure at the recommended dose of 100 mg once daily based on area under the curve (AUC).

Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use an effective non-hormonal method of contraception, since LORBRENA can render hormonal contraceptives ineffective, during treatment with LORBRENA and for at least 6 months after the final dose.

1) ] .