LORBRENA Film-coated tablet Ref.[10864] Active ingredients: Lorlatinib

5.1 Risk of Serious Hepatotoxicity with Concomitant Use of Strong CYP3A Inducers

Severe hepatotoxicity occurred in 10 of 12 healthy subjects receiving a single dose of LORBRENA with multiple daily doses of rifampin, a strong CYP3A inducer. 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%. ALT or AST elevations occurred within 3 days and returned to within normal limits after a median of 15 days (7 to 34 days); the median time to recovery was 18 days in subjects with Grade 3 or 4 ALT or AST elevations and 7 days in subjects with Grade 2 ALT or AST elevations [see Drug Interactions (7.1)].

LORBRENA is contraindicated in patients taking strong CYP3A inducers. Discontinue strong CYP3A inducers for 3 plasma half-lives of the strong CYP3A inducer prior to initiating LORBRENA [see Contraindications (4), Drug Interactions (7.1)].

Depending upon the relative importance of each drug, discontinue LORBRENA or the CYP3A inducer for persistent Grade 2 or higher hepatotoxicity [see Clinical Pharmacology (12.3)].

5.2 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. Overall, CNS effects occurred in 54% of patients receiving LORBRENA [see Adverse Reactions (6.1)]. Cognitive effects occurred in 29% of the 332 patients who received LORBRENA at any dose in Study B7461001; 2.1% of these events were severe (Grade 3 or 4). Mood effects occurred in 24% of patients; 1.8% of these events were severe. Speech effects occurred in 14% of patients; 0.3% of these events were severe. Psychotic effects occurred in 7% of patients; 0.6% of these events were severe. Mental status changes occurred in 2.1% of patients; 1.8% of these events were severe. Seizures occurred in 3% of patients, sometimes in conjunction with other neurologic findings. Sleep effects occurred in 10% of patients. The median time to first onset of any CNS effect was 1.2 months (1 day to 1.7 years). Overall, 1.5% of patients required permanent discontinuation of LORBRENA for a CNS effect; 9% required temporary discontinuation and 8% required dose reduction.

Withhold and resume at the same dose or at a reduced dose or permanently discontinue LORBRENA based on severity [see Dosage and Administration (2.2)].

5.3 Hyperlipidemia

Increases in serum cholesterol and triglycerides can occur in patients receiving LORBRENA [see Adverse Reactions (6.1)]. Grade 3 or 4 elevations in total cholesterol occurred in 17% and Grade 3 or 4 elevations in triglycerides occurred in 17% of the 332 patients who received LORBRENA in Study B7461001. The median time to onset was 15 days for both hypercholesterolemia and hypertriglyceridemia. Approximately 7% of patients required temporary discontinuation and 3% of patients required dose reduction of LORBRENA for elevations in cholesterol and in triglycerides. Eighty percent of patients required initiation of lipid-lowering medications, with a median time to onset of start of such medications of 21 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. Withhold and resume at the same dose for the first occurrence; resume at the same or a reduced dose of LORBRENA for recurrence based on severity [see Dosage and Administration (2.2)].

5.4 Atrioventricular Block

PR interval prolongation and atrioventricular (AV) block can occur in patients receiving LORBRENA [see Adverse Reactions (6.1), Clinical Pharmacology (12.2)]. In 295 patients who received LORBRENA at a dose of 100 mg orally once daily in Study B7461001 and who had a baseline electrocardiography (ECG), 1% experienced AV block and 0.3% 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. Permanently discontinue for recurrence in patients without a pacemaker [see Dosage and Administration (2.2)].

5.5 Interstitial Lung Disease/Pneumonitis

Severe or life-threatening pulmonary adverse reactions consistent with interstitial lung disease (ILD)/pneumonitis can occur with LORBRENA. ILD/pneumonitis occurred in 1.5% of patients who received LORBRENA at any dose in Study B7461001, including Grade 3 or 4 ILD/pneumonitis in 1.2% of patients. One patient (0.3%) discontinued LORBRENA for ILD/pneumonitis.

Promptly investigate for ILD/pneumonitis in any patient who presents with worsening of respiratory symptoms indicative of ILD/pneumonitis (e.g., dyspnea, cough, and fever). Immediately withhold LORBRENA in patients with suspected ILD/pneumonitis. Permanently discontinue LORBRENA for treatment-related ILD/pneumonitis of any severity [see Dosage and Administration (2.2)].

5.6 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. Advise males with female partners of reproductive potential to use effective contraception during treatment with LORBRENA and for 3 months after the final dose [see Drug Interactions (7.2), Use in Specific Populations (8.1, 8.3), Nonclinical Toxicology (13.1)].

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)]

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 data in Warnings and Precautions reflect exposure to LORBRENA in 332 patients with ALK-positive or ROS1-positive, metastatic non-small cell lung cancer (NSCLC) enrolled in a multi-cohort, multinational, non-comparative, dose-finding, and activity-estimating trial (Study B7461001) who received LORBRENA at doses ranging from 10 mg to 200 mg daily in single or divided doses.

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. 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 a median age of 53 years (19 to 85 years), age ≥65 years (18%), female (58%), White (49%), Asian (37%), and Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 (96%).

The most common (≥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 common 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 2 and 3 summarize common adverse reactions and laboratory abnormalities, respectively, in patients treated with LORBRENA in Study B7461001.

Table 2. Adverse Reactions Occurring in ≥10% of Patients in Study B7461001*:

Abbreviations: NCI CTCAE=National Cancer Institute Common Terminology Criteria for Adverse Events; SOC=System organ class.
^* Adverse reactions were graded using NCI CTCAE version 4.0.
^† 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).

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

Table 3. Worsening Laboratory Values Occurring in ≥20% of Patients in Study B7461001*:

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 .0.
^† N=292.
^‡ N=293.
^§ N=291.
^¶ N=290.
^# N=284.

7.1 Effect of Other Drugs on LORBRENA

Strong CYP3A Inducers

Concomitant use of LORBRENA with a strong CYP3A inducer decreased lorlatinib plasma concentrations [see Clinical Pharmacology (12.3)], which may decrease the efficacy of LORBRENA.

Severe hepatotoxicity occurred in healthy subjects receiving LORBRENA with rifampin, a strong CYP3A inducer. In 12 healthy subjects receiving a single 100 mg dose of LORBRENA with multiple daily doses of rifampin, Grade 3 or 4 increases in ALT or AST occurred in 83% of subjects and Grade 2 increases in ALT or AST occurred in 8%. A possible mechanism for hepatotoxicity is through activation of the pregnane X receptor (PXR) by LORBRENA and rifampin, which are both PXR agonists.

LORBRENA is contraindicated in patients taking strong CYP3A inducers [see Contraindication (4)]. Discontinue strong CYP3A inducers for 3 plasma half-lives of the strong CYP3A inducer prior to initiating LORBRENA [see Dosage and Administration (2.3)].

Moderate CYP3A Inducers

Concomitant use of LORBRENA with a moderate CYP3A inducer decreased lorlatinib plasma concentrations, which may decrease the efficacy of LORBRENA [see Clinical Pharmacology (12.3)]. Avoid concomitant use of moderate CYP3A inducers with LORBRENA. If concomitant use is unavoidable, increase the LORBRENA dose [see Dosage and Administration (2.4)].

Strong CYP3A Inhibitors

Concomitant use with a strong CYP3A inhibitor increased lorlatinib plasma concentrations [see Clinical Pharmacology (12.3)], which may increase the incidence and severity of adverse reactions of LORBRENA. Avoid concomitant use of LORBRENA with a strong CYP3A inhibitor. If concomitant use cannot be avoided, reduce the LORBRENA dosage [see Dosage and Administration (2.5)].

7.2 Effect of LORBRENA on Other Drugs

Certain CYP3A Substrates

LORBRENA is a moderate CYP3A inducer. Concomitant use of LORBRENA decreases the concentration of CYP3A substrates [see Clinical Pharmacology (12.3)], which may reduce the efficacy of these substrates. Avoid concomitant use of LORBRENA with certain CYP3A substrates, for which minimal concentration changes may lead to serious therapeutic failures. If concomitant use is unavoidable, increase the CYP3A substrate dosage in accordance with approved product labeling.

Certain P-glycoprotein (P-gp) Substrates

LORBRENA is a moderate P-gp inducer. Concomitant use of LORBRENA decreases the concentration of P-gp substrates [see Clinical Pharmacology (12.3)], which may reduce the efficacy of these substrates. Avoid concomitant use of LORBRENA with certain P-gp substrates for which minimal concentration changes may lead to serious therapeutic failures. If concomitant use is unavoidable, increase the P-gp substrate dosage in accordance with approved product labeling.

Risk Summary

Based on findings from animal studies and its mechanism of action [see Clinical Pharmacology (12.1)], LORBRENA can cause embryo-fetal harm when administered to a pregnant woman. There are no available data on LORBRENA use in pregnant women. 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 AUC (see Data). Advise a pregnant woman of the potential risk to a fetus.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies are 2 to 4% and 15 to 20%, respectively.

Data

Animal Data

Preliminary embryo-fetal development studies investigating the administration of lorlatinib during the period of organogenesis were conducted in rats and rabbits. In rabbits, lorlatinib administration resulted in abortion and total loss of pregnancy at doses of 15 mg/kg (approximately 3 times the human exposure at the recommended dose of 100 mg) or greater. At a dose of 4 mg/kg (approximately 0.6 times the human exposure at the recommended dose of 100 mg) toxicities included increased post-implantation loss and malformations including rotated limbs, malformed kidneys, domed head, high arched palate, and dilation of the cerebral ventricles. In rats, administration of lorlatinib resulted in total loss of pregnancy at doses of 4 mg/kg (approximately 5 times the human exposure at the recommended dose of 100 mg) or greater. At a dose of 1 mg/kg (approximately equal to the human exposure at the recommended dose of 100 mg) there was increased post-implantation loss, decreased fetal body weight, and malformations including gastroschisis, rotated limbs, supernumerary digits, and vessel abnormalities.

Risk Summary

There are no data on the presence of lorlatinib or its metabolites in either human or animal milk or its effects on the breastfed infant or on milk production. Because of the potential for serious adverse reactions in breastfed infants, instruct women not to breastfeed during treatment with LORBRENA and for 7 days after the final dose.

Pregnancy Testing

Verify pregnancy status in females of reproductive potential prior to initiating LORBRENA [see Use in Specific Populations (8.1)].

Contraception

LORBRENA can cause embryo-fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

Females

Advise female patients of reproductive potential to use effective non-hormonal contraception during treatment with LORBRENA and for at least 6 months after the final dose. Advise females of reproductive potential to use a non-hormonal method of contraception, because LORBRENA can render hormonal contraceptives ineffective [see Drug Interactions (7.2)].

Males

Based on genotoxicity findings, advise males with female partners of reproductive potential to use effective contraception during treatment with LORBRENA and for at least 3 months after the final dose [see Nonclinical Toxicology (13.1)].

Infertility

Males

Based on findings from animal studies, LORBRENA may transiently impair male fertility [see Nonclinical Toxicology (13.1)].

The safety and effectiveness of LORBRENA in pediatric patients have not been established.

Of the 295 patients in Study B7461001 who received 100 mg LORBRENA orally once daily, 18% of patients were aged 65 years or older. Although data are limited, no clinically important differences in safety or efficacy were observed between patients aged 65 years or older and younger patients.

No dose adjustment is recommended for patients with mild or moderate renal impairment (creatinine clearance [CLcr] 30 to 89 mL/min estimated by Cockcroft-Gault). The recommended dose of LORBRENA has not been established for patients with severe renal impairment (CLcr 15 to 29 mL/min estimated by Cockcroft-Gault) [see Clinical Pharmacology (12.3)].

No dose adjustment is recommended for patients with mild hepatic impairment (total bilirubin ≤ upper limit of normal [ULN] with AST > ULN or total bilirubin >1 to 1.5 × ULN with any AST). The recommended dose of LORBRENA has not been established for patients with moderate (total bilirubin ≥1.5 to 3.0 × ULN with any AST) or severe (total bilirubin >3.0 × ULN with any AST) hepatic impairment [see Clinical Pharmacology (12.3)].