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Lorlatinib Tablets

TABLE OF CONTENTS

1. DESCRIPTION 7. DRUG INTERACTIONS
2. INDICATIONS AND USAGE 8. USE IN SPECIFIC POPULATIONS
3. DOSAGE AND ADMINISTRATION 10. MECHANISM OF ACTION
4. CONTRAINDICATIONS 11. PHARMACODYNAMICS
5. WARNINGS AND PRECAUTIONS 12. PHARMACOKINETICS
6. ADVERSE REACTIONS 13. HOW SUPPLIED/STORAGE AND HANDLING

 

1. DESCRIPTION

Lorlatinib is a kinase inhibitor for oral administration. The chemical name is (10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-4,8-methenopyrazolo[4,3-h][2,5,11] benzoxadiazacyclotetradecine-3-carbonitrile. The chemical structure is shown below:

Empirical formula: C21H19FN6O2 - Molecular weight: 406.41 Daltons

Lorlatinib is a white to off-white powder with a pKa of 4.92. The solubility of lorlatinib in aqueous media decreases over the range pH 2.55 to pH 8.02 from 32.38 mg/mL to 0.17 mg/mL. The log of the distribution coefficient (octanol/water) at pH 9 is 2.45.

Lorlatinib is supplied as tablets containing 25 mg or 100 mg of lorlatinib with the following inactive ingredients: microcrystalline cellulose, dibasic calcium phosphate anhydrous, sodium starch glycolate, and magnesium stearate. The 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.

2. INDICATIONS AND USAGE

Lorlatinib is indicated for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) whose disease has progressed on

 crizotinib and at least one other ALK inhibitor for metastatic disease; or

 alectinib as the first ALK inhibitor therapy for metastatic disease; or

 ceritinib as the first ALK inhibitor therapy for metastatic disease.

This indication is approved under accelerated approval based on tumor response rate and duration of response [see Clinical Studies]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

3. DOSAGE AND ADMINISTRATION

3.1 Recommended Dosage

The recommended dosage of lorlatinib is 100 mg orally once daily, with or without food, until disease progression or unacceptable toxicity [see Clinical Pharmacology].

Swallow tablets whole. Do not chew, crush or split tablets. Do not ingest if tablets are broken, cracked, or otherwise not intact.

Take lorlatinib at the same time each day. If a dose is missed, then take the missed dose unless the next dose is due within 4 hours. Do not take 2 doses at the same time to make up for a missed dose.

Do not take an additional dose if vomiting occurs after lorlatinib but continue with the next scheduled dose.

3.2 Dosage Modifications for Adverse Reactions

The recommended dose reductions are:

 First dose reduction: lorlatinib 75 mg orally once daily

 Second dose reduction: lorlatinib 50 mg orally once daily

Permanently discontinue lorlatinib in patients who are unable to tolerate 50 mg orally once daily.

Dosage modifications for adverse reactions of lorlatinib are provided in Table 1.

Table 1: Recommended Lorlatinib Dosage Modifications for Adverse Reactions

Abbreviation: AV=atrioventricular.

a Grade based on National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.

3.3 Concomitant Use of Strong or Moderate CYP3A Inducers

Lorlatinib 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 lorlatinib. Avoid concomitant use of lorlatinib with moderate CYP3A inducers [see Warnings and Precautions (5.1), Clinical Pharmacology].

3.4 Dosage Modification for Strong CYP3A Inhibitors

Avoid concomitant use of lorlatinib with strong CYP3A inhibitors. If concomitant use with a strong CYP3A inhibitor cannot be avoided, reduce the starting dose of lorlatinib 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 lorlatinib dose to 50 mg orally once daily.

If concomitant use of a strong CYP3A inhibitor is discontinued, increase the lorlatinib dose (after 3 plasma half-lives of the strong CYP3A inhibitor) to the dose that was used before starting the strong inhibitor [see Clinical Pharmacology].

4. CONTRAINDICATIONS

Lorlatinib is contraindicated in patients taking strong CYP3A inducers, due to the potential for serious hepatotoxicity [see Warnings and Precautions (5.1)].

5. WARNINGS AND PRECAUTIONS

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 lorlatinib 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.

Lorlatinib 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 lorlatinib.

Avoid concomitant use of lorlatinib with moderate CYP3A inducers. If concomitant use of moderate CYP3A inducers cannot be avoided, monitor AST, ALT, and bilirubin 48 hours after initiating lorlatinib and at least 3 times during the first week after initiating lorlatinib.

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

5.2 Central Nervous System Effects

A broad spectrum of central nervous system (CNS) effects can occur in patients receiving lorlatinib. These include seizures, hallucinations, and changes in cognitive function, mood (including suicidal ideation), speech, mental status, and sleep. Overall, CNS effects occurred in 54% of patients receiving lorlatinib [see Adverse Reactions (6.1)]. Cognitive effects occurred in 29% of the 332 patients who received lorlatinib 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. Hallucinations 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 lorlatinib 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 lorlatinib based on severity [see Dosage and Administration (3.2)].

5.3 Hyperlipidemia

Increases in serum cholesterol and triglycerides can occur in patients receiving lorlatinib [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 lorlatinib 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 lorlatinib 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 lorlatinib, 1 and 2 months after initiating lorlatinib, and periodically thereafter. Withhold and resume at the same dose for the first occurrence; resume at the same or a reduced dose of lorlatinib for recurrence based on severity [see Dosage and Administration (3.2)].

5.4 Atrioventricular Block

PR interval prolongation and atrioventricular (AV) block can occur in patients receiving lorlatinib [see Adverse Reactions (6.1), Clinical Pharmacology]. In 295 patients who received lorlatinib 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 lorlatinib 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 (3.2)].

5.5 Interstitial Lung Disease/Pneumonitis

Severe or life-threatening pulmonary adverse reactions consistent with interstitial lung disease (ILD)/pneumonitis can occur with lorlatinib. ILD/pneumonitis occurred in 1.5% of patients who received lorlatinib at any dose in Study B7461001, including Grade 3 or 4 ILD/pneumonitis in 1.2% of patients. One patient (0.3%) discontinued lorlatinib 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 lorlatinib in patients with suspected ILD/pneumonitis. Permanently discontinue lorlatinib for treatment-related ILD/pneumonitis of any severity [see Dosage and Administration (3.2)].

5.6 Embryo-Fetal Toxicity

Based on findings from animal studies and its mechanism of action, lorlatinib 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 lorlatinib can render hormonal contraceptives ineffective, during treatment with lorlatinib 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 lorlatinib and for 3 months after the final dose [see Drug Interactions (7.2), Use in Specific Populations (8.1, 8.3), Nonclinical Toxicology].

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)]

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 data in Warnings and Precautions reflect exposure to lorlatinib 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 lorlatinib at doses ranging from 10 mg to 200 mg daily in single or divided doses.

The data described below reflect exposure to lorlatinib in 295 patients with ALK-positive or ROS1-positive metastatic NSCLC who received lorlatinib 100 mg orally once daily in Study B7461001. The median duration of exposure to lorlatinib was 12.5 months (1 day to 35 months) and 52% received lorlatinib 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; the most common (≥20%) laboratory abnormalities 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 lorlatinib 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 lorlatinib in Study B7461001.

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

* Adverse reactions were graded using NCI CTCAE version 4.0.

Abbreviations: NCI CTCAE=National Cancer Institute Common Terminology Criteria for Adverse Events; SOC=System organ class.

a 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).

b 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).

c 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).

d Speech effects (including aphasia, dysarthria, slow speech, speech disorder)

e Sleep effects (including abnormal dreams, insomnia, nightmare, sleep disorder, sleep talking, somnambulism)

f Vision disorder (including blindness, diplopia, photophobia, photopsia, vision blurred, visual acuity reduced, visual impairment, vitreous floaters).

g Myalgia (including musculoskeletal pain, myalgia).

h Edema (including edema, edema peripheral, eyelid edema, face edema, generalized edema, localized edema, periorbital edema, peripheral swelling, swelling).

i Fatigue (including asthenia, fatigue).

j Upper respiratory infection (including fungal upper respiratory infection, upper respiratory infection, viral upper respiratory infection).

k Rash (including dermatitis acneiform, maculopapular rash, pruritic rash, rash).

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

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

* Grades using NCI CTCAE version 4.0.

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.

a N=292.

b N=293.

c N=291.

d N=290.

e N=284.

7. DRUG INTERACTIONS

7.1 Effect of Other Drugs on Lorlatinib

Effect of CYP3A Inducers

Concomitant use of lorlatinib with a strong CYP3A inducer decreased lorlatinib plasma concentrations, which may decrease the efficacy of lorlatinib. The effect of concomitant use of lorlatinib with a moderate CYP3A inducer on lorlatinib plasma concentrations has not been studied.

Severe hepatotoxicity occurred in healthy subjects receiving lorlatinib with rifampin, a strong CYP3A inducer. In 12 healthy subjects receiving a single 100 mg dose of lorlatinib 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 lorlatinib and rifampin, which are both PXR agonists. The risk of hepatotoxicity with concomitant use of lorlatinib and moderate CYP3A inducers that are also PXR agonists is unknown.

Lorlatinib 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 lorlatinib.

Avoid concomitant use of lorlatinib with moderate CYP3A inducers. If concomitant use of moderate CYP3A inducers cannot be avoided, monitor ALT, AST, and bilirubin as recommended [see Dosage and Administration (3.3), Warnings and Precautions (5.1), Clinical Pharmacology].

Effect of Strong CYP3A Inhibitors

Concomitant use with a strong CYP3A inhibitor increased lorlatinib plasma concentrations, which may increase the incidence and severity of adverse reactions of lorlatinib. Avoid the concomitant use of lorlatinib with a strong CYP3A inhibitor. If concomitant use cannot be avoided, reduce lorlatinib dose as recommended [see Dosage and Administration (3.4), Clinical Pharmacology].

7.2 Effect of Lorlatinib on Other Drugs

CYP3A Substrates

Concomitant use of lorlatinib decreases the concentration of CYP3A substrates [see Clinical Pharmacology], which may reduce the efficacy of these substrates. Avoid concomitant use of lorlatinib with CYP3A substrates, where 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.

8. USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Based on findings from animal studies and its mechanism of action [see Clinical Pharmacology], lorlatinib can cause embryo-fetal harm when administered to a pregnant woman. There are no available data on lorlatinib 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.

8.2 Lactation

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 lorlatinib and for 7 days after the final dose.

8.3 Females and Males of Reproductive Potential

Pregnancy Testing

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

Contraception

Lorlatinib 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 lorlatinib and for at least 6 months after the final dose. Advise females of reproductive potential to use a non-hormonal method of contraception, because lorlatinib 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 lorlatinib and for at least 3 months after the final dose [see Nonclinical Toxicology].

Infertility

Males

Based on findings from animal studies, lorlatinib may transiently impair male fertility [see Nonclinical Toxicology].

8.4 Pediatric Use

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

8.5 Geriatric Use

Of the 295 patients in Study B7461001 who received 100 mg lorlatinib 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.

8.6 Hepatic Impairment

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 lorlatinib has not been established for patients with moderate or severe hepatic impairment [see Clinical Pharmacology].

8.7 Renal Impairment

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 lorlatinib has not been established for patients with severe renal impairment [see Clinical Pharmacology].

10. 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.

11. PHARMACODYNAMICS

Exposure-Response Relationships

Based on the data from Study B7461001, 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 lorlatinib 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 lorlatinib. The prolongation of PR interval occurred in a concentration-dependent manner. Atrioventricular block occurred in 1% of patients.

In 275 patients who received lorlatinib 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. PHARMACOKINETICS

Steady-state lorlatinib maximum plasma concentration (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). At the recommended dosage, the mean (coefficient of variation [CV] %) Cmax was 577 ng/mL (42%) and the AUC0-24h was 5650 ng·h/mL (39%) in patients with cancer. Lorlatinib oral clearance increased at steady-state compared to single dose, indicating autoinduction.

Absorption

The median lorlatinib Tmax was 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 75.7%, 86.2%) after oral administration compared to intravenous administration.

Effect of Food

Administration of lorlatinib with 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) had no clinically meaningful effect on lorlatinib pharmacokinetics.

Distribution

In vitro, lorlatinib was 66% bound to plasma proteins at a concentration of 2.4 μM. The blood-to-plasma ratio was 0.99. The mean (CV%) steady state volume of distribution (Vss) was 305 L (28%) following a single intravenous dose.

Elimination

The mean plasma half-life (t½) of lorlatinib was 24 hours (40%) after a single oral 100 mg dose of lorlatinib. 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

In vitro, 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 in a human [14C] mass balance study. 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 meaningful differences in lorlatinib pharmacokinetics were observed based on age (19 to 85 years), sex, race/ethnicity, body weight, mild to moderate renal impairment (CLcr 30 to 89 mL/min), mild hepatic impairment (total bilirubin ≤ ULN and AST > ULN or total bilirubin > 1.5 × ULN and any AST), or metabolizer phenotypes for CYP3A5 and CYP2C19. The effect of moderate to severe hepatic impairment or severe renal impairment on lorlatinib pharmacokinetics is unknown [see Use in Specific Populations (8.6, 8.7)].

Drug Interaction Studies

Clinical Studies

Effect of CYP3A Inducers on Lorlatinib: Twelve healthy subjects received rifampin, a strong CYP3A inducer that also activates PXR, 600 mg once daily for 8 days (Days 1 to 8) and a single oral 100 mg dose of lorlatinib on Day 8. The coadministration of rifampin with lorlatinib reduced the mean lorlatinib AUCinf 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). The effect of the concomitant use of moderate CYP3A inducers on lorlatinib pharmacokinetics or the risk of hepatotoxicity with the concomitant use of moderate CYP3A inducers is unknown [see Drug Interactions (7.1)].

Effect of Strong CYP3A Inhibitors on Lorlatinib: Itraconazole, a strong CYP3A inhibitor, increased AUCinf by 42% and increased Cmax by 24% of a single oral 100 mg dose of lorlatinib [see Drug Interactions (7.1)].

Effect of Lorlatinib on CYP3A Substrates: Lorlatinib 150 mg orally once daily for 15 days decreased AUCinf by 64% and Cmax by 50% of a single oral 2 mg dose of midazolam (a sensitive CYP3A substrate) [see Drug Interactions (7.2)].

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

In Vitro Studies

Effect of Lorlatinib on CYP Enzymes: In vitro studies indicate that lorlatinib is a time-dependent inhibitor as well as an inducer of CYP3A and that it 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, and CYP2D6. M8 does not inhibit CYP3A.

M8 does not induce CYP1A2, CYP2B6, and CYP3A.

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

Effect of Lorlatinib on Transporters: Lorlatinib inhibits P-glycoprotein (P-gp), organic cation transporter (OCT)1, organic anion transporter (OAT)3, multidrug and toxin extrusion (MATE)1, and intestinal breast cancer resistance protein (BCRP). Lorlatinib does not inhibit organic anion transporting polypeptide (OATP)1B1, OATP1B3, OAT1, OCT2, MATE2K, and systemic BCRP. M8 does not inhibit P-gp, BCRP, OATP1B1, OATP1B3, OAT1, OAT3, OCT1, OCT2, MATE1, and MATE2K.

13. HOW SUPPLIED/STORAGE AND HANDLING

How Supplied:

Table 4 describes the available strengths and package configurations for LORBRENA:

Table 4: LORBRENA Tablets

Storage and Handling:

Store at 20° to 25°C (68° to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

Rx only

Rev 11/18