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LORBRENA (lorlatinib)

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Health Professional Information

INDICATIONS

LORBRENA (lorlatinib) is indicated as monotherapy for the treatment of adult patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) who have progressed on: crizotinib and at least one other ALK inhibitor, or patients who have progressed on ceritinib or alectinib.

The marketing authorization with conditions was based on a primary efficacy endpoint of tumor objective response rate and duration of response; no overall survival benefit has been demonstrated (see CLINICAL TRIALS).

Pediatrics

Pediatrics (<18 years of age): No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use.

Geriatrics

Geriatrics (≥ 65 years of age): Of the 275 ALK-positive NSCLC patients treated with LORBRENA, 53 (19.3%) were ≥65 years of age. The limited data on the safety and efficacy of lorlatinib in patients aged 65 years and older do not suggest that a dose adjustment is required in elderly patients (see ACTION AND CLINICAL PHARMACOLOGY).

Contraindications

LORBRENA (lorlatinib) is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. For a complete listing, see DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING.

Concomitant use of strong CYP3A inducers with LORBRENA is contraindicated due to the potential for serious hepatotoxicity (aspartate aminotransferase [AST] and alanine aminotransferase [ALT] elevations) (see DOSAGE AND ADMINISTRATION and DRUG INTERACTIONS).

Dosage And Administration

Dosing Considerations

Strong cytochrome P-450 (CYP)3A inhibitors:

Concurrent use of LORBRENA (lorlatinib) with strong CYP3A inhibitors may increase lorlatinib plasma concentrations. Concomitant use of LORBRENA with strong CYP3A inhibitors should be avoided. An alternative concomitant medicinal product with less potential to inhibit CYP3A should be considered (see DRUG INTERACTIONS). If a strong CYP3A inhibitor must be co-administered concomitantly, the LORBRENA dose of 100 mg once daily should be reduced to once daily 75 mg dose (see DRUG INTERACTIONS and ACTION AND CLINICAL PHARMACOLOGY). If concurrent use of a strong CYP3A inhibitor is discontinued, LORBRENA should be resumed at the dose used prior to the initiation of the strong CYP3A inhibitor and after a washout period of 3 to 5 half-lives of the CYP3A inhibitor.

Hepatic impairment:

A formal hepatic impairment study has not been conducted with lorlatinib. No dose adjustments are recommended for patients with mild hepatic impairment. Limited information is available for LORBRENA in patients with moderate or severe hepatic impairment (see ACTION AND CLINICAL PHARMACOLOGY).

Renal impairment:

A formal renal impairment study has not been conducted with lorlatinib. No dose adjustment is needed for patients with mild (creatinine clearance [CLcr]: 60-89 mL/min) or moderate (CLcr: 30-59 mL/min) renal impairment based on a population pharmacokinetic analysis. Information for LORBRENA use in patients with severe (CLcr: <30 mL/min) renal impairment is limited (n=1). (see ACTION AND CLINICAL PHARMACOLOGY).

Recommended Dose and Dosage Adjustment

Recommended Dose

The recommended dose of LORBRENA is 100 mg taken orally once daily continuously. Continue treatment with LORBRENA as long as the patient is deriving clinical benefit from therapy.

LORBRENA may be taken with or without food (see ACTION AND CLINICAL PHARMACOLOGY).

Pediatric patients:

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

Elderly (≥ 65 years):

The limited data on the safety and efficacy of LORBRENA in patients aged 65 years and older do not suggest that a dose adjustment is required in elderly patients.

Dose Modifications

Dosing interruption and/or dose reduction may be required based on individual safety and tolerability. Dose reduction levels are summarized below.

  • First dose reduction: LORBRENA 75 mg taken orally once daily
  • Second dose reduction: LORBRENA 50 mg taken orally once daily

LORBRENA should be permanently discontinued if the patient is unable to tolerate LORBRENA 50 mg taken orally once daily.

Dose modification recommendations for toxicities are provided in Table 1. Dose modification recommendations for patients who develop first-degree, second-degree, or complete atrioventricular (AV) block are provided in Table 2.

Table 1. LORBRENA Dose Modifications and Management Recommendations for Adverse Reactions
 

Abbreviations: CNS=central nervous system; CTCAE=Common Terminology Criteria for Adverse Events; HMG CoA=3-hydroxy-3-methylglutaryl coenzyme A; ULN=upper limit of normal.

a
Lipid‑lowering therapy may include: HMG CoA reductase inhibitor, nicotinic acid, fibric acid, or ethyl esters of omega-3 fatty acids.
b
Examples of CNS effects comprise hallucination and changes in cognition, mood, mental status or speech (seeWARNINGS AND PRECAUTIONSand ADVERSE REACTIONS).
c
Grade categories are based on CTCAE classifications.

Adverse Reaction

LORBRENA Dosing

Hypercholesterolemia or Hypertriglyceridemia

Mild hypercholesterolemia

(cholesterol between ULN and 300 mg/dL or between ULN and 7.75 mmol/L)

OR

Mild hypertriglyceridemia

(triglycerides between 150 and 300 mg/dL or 1.71 and 3.42 mmol/L)

Introduce or modify lipid-lowering therapya in accordance with respective prescribing information; continue LORBRENA at same dose.

Moderate hypercholesterolemia

(cholesterol between 301 and 400 mg/dL or between 7.76 and 10.34 mmol/L)

OR

Moderate hypertriglyceridemia

(triglycerides between 301 and 500 mg/dL or 3.43 and 5.7 mmol/L)

Severe hypercholesterolemia

(cholesterol between 401 and 500 mg/dL or between 10.35 and 12.92 mmol/L)

OR

Severe hypertriglyceridemia

(triglycerides between 501 and 1000 mg/dL or 5.71 and 11.4 mmol/L)

Introduce the use of lipid-lowering therapy;a if currently on lipid-lowering therapy, increase the dose of this therapya in accordance with respective prescribing information; or change to a new lipid‑lowering therapy. Continue LORBRENA at the same dose without interruption.

Grade 4 hypercholesterolemia (cholesterol over 500 mg/dL or over 12.92 mmol/L)

OR

Grade 4 hypertriglyceridemia (triglycerides over 1000 mg/dL or over 11.4 mmol/L)

Introduce the use of lipid-lowering therapya or increase the dose of this therapya in accordance with respective prescribing information or change to a new lipid‑lowering therapy. Withhold LORBRENA until recovery of hypercholesterolemia and/or hypertriglyceridemia to moderate or mild severity grade.

Re-challenge at same LORBRENA dose while maximizing lipid‑lowering therapya in accordance with respective prescribing information.

If severe hypercholesterolemia and/or hypertriglyceridemia recurs despite maximal lipid‑lowering therapya in accordance with respective prescribing information, reduce LORBRENA by 1 dose level.

Central nervous system effectsb,c

Grade 1: Mild

Continue at the same dose or withhold dose until recovery to baseline. Then resume LORBRENA at the same dose or reduce by 1 dose level.

Grade 2: Moderate

OR

Grade 3: Severe

Withhold dose until toxicity is less than or equal to Grade 1. Then resume LORBRENA at 1 reduced dose level.

Grade 4: Life-threatening/Urgent intervention indicated

Permanently discontinue LORBRENA.

Interstitial Lung Disease (ILD)/Pneumonitis

Any Grade treatment–related ILD/Pneumonitis

Permanently discontinue LORBRENA.

Other adverse reactionsc

Grade 1

OR

Grade 2

Consider no dose modification or reduce by 1 dose level, as clinically indicated.

Greater than or equal to Grade 3

Withhold LORBRENA until symptoms resolve to less than or equal to Grade 2 or baseline. Then resume LORBRENA at 1 reduced dose level.

Table 2. Recommended LORBRENA Dose Modifications - PR Interval Prolongation/Atrioventricular Block
 
Abbreviations: AV=atrioventricular; ECG=electrocardiogram.

Event

LORBRENA Dosing

Asymptomatic

Symptomatic

First-degree AV block

Continue LORBRENA at the same dose without interruption. Assess concomitant medications and electrolyte imbalance that may prolong PR interval. Monitor ECG/symptoms potentially related to AV block closely.

Withhold LORBRENA. Assess concomitant medications and electrolyte imbalance that may prolong PR interval. Monitor ECG/symptoms potentially related to AV block closely. If symptoms resolve, resume LORBRENA at same dose or at 1 reduced dose level.

Second-degree AV block

Withhold LORBRENA. Assess concomitant medications and electrolyte imbalance that may prolong PR interval. Monitor ECG/symptoms potentially related to AV block closely. If subsequent ECG does not show second‑degree block, resume LORBRENA at same dose or 1 reduced dose level.

Withhold LORBRENA. Assess concomitant medications and electrolyte imbalance that may prolong PR interval. Refer for cardiac observation and monitoring. Consider pacemaker placement if symptomatic AV block persists. If symptoms and the second‑degree block resolve or if patients revert to asymptomatic first‑degree AV block, resume LORBRENA at 1 reduced dose level.

Complete AV Block

Withhold LORBRENA dose. Assess concomitant medications and electrolyte imbalance that may prolong PR interval. Refer for cardiac observation and monitoring. Temporary pacemaker placement may be indicated for severe symptoms associated with AV block. If AV block does not resolve, placement of a permanent pacemaker may be considered.

If pacemaker placed, may resume LORBRENA at full dose. If no pacemaker placed, resume LORBRENA at 1 reduced dose level only when symptoms resolve AND PR interval is less than 200 msec.

Administration

Patients should be encouraged to take their dose of LORBRENA at approximately the same time each day. Tablets should be swallowed whole (tablets should not be chewed, crushed or split prior to swallowing). No tablet should be ingested if it is broken, cracked, or otherwise not intact.

Missed Dose

If a dose of LORBRENA is missed, then it should be taken as soon as the patient remembers unless it is less than 4 hours before the next dose, in which case the patient should not take the missed dose. Patients should not take 2 doses at the same time to make up for a missed dose.

Overdosage

There is no known antidote for LORBRENA (lorlatinib). The treatment of LORBRENA overdose should consist of general supportive measures. Given the dose‑dependent effect on PR interval, ECG monitoring is recommended.

For management of a suspected drug overdose, contact your regional poison control centre.

Dosage Forms, Strengths, Composition And Packaging

Table – Dosage Forms, Strengths, Composition and Packaging

Route of Administration

Dosage Form / Strength/Composition

Non-medicinal Ingredients

Oral

Film-coated tablet 25 mg, 100 mg

Tablet core contains: dibasic calcium phosphate anhydrous, magnesium stearate,

microcrystalline cellulose, sodium starch glycolate

Film-coating contains: ferrosofferic oxide/Black iron oxide,

hydroxypropyl methylcellulose (HPMC) 2910/hypromellose, iron oxide red, lactose monohydrate,

macrogol/polyethylene glycol (PEG) 3350, titanium dioxide, triacetin

25 mg: 8 mm round tan immediate release film-coated tablet, debossed with “Pfizer” on one side and “25” and “LLN” on the other side.

100 mg: oval (17 x 8.5 mm) lavender immediate release film-coated tablet, debossed with “Pfizer” on one side and “LLN 100” on the other side.

Packaging: LORBRENA (lorlatinib) is supplied as follows:
25 mg

  • high density polyethylene bottles containing 30, 60, or 100 tablets
  • aluminum foil blisters with aluminum foil backing containing 120 tablets (12 cards of 10 tablets)

100 mg

  • high density polyethylene bottles containing 30, 60, or 100 tablets
  • aluminum foil blisters with aluminum foil backing  containing 30 tablets (3 cards of 10 tablets)

Warnings And Precautions

Serious Warnings and Precautions

  • Hypercholesterolemia/Hypertriglyceridemia (see WARNINGS AND PRECAUTIONS, Hyperlipidemia)
  • Pneumonitis (see WARNINGS AND PRECAUTIONS, Respiratory)
  • Hepatotoxicity (see WARNINGS AND PRECAUTIONS, Drug-Drug Interactions, Risk of Serious Hepatotoxicity with Concomitant Use of Strong CYP3A Inducers)

LORBRENA should only be prescribed and supervised by a qualified physician experienced in the use of antineoplastic agents.

General

Patients treated with LORBRENA (lorlatinib) must have a documented ALK-positive status based on a validated ALK assay. Assessment of ALK-positive NSCLC should be performed by laboratories with demonstrated proficiency in the specific technology being utilized.

Drug‑Drug Interactions

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 6 subjects (50%), Grade 3 ALT or AST elevations occurred in 4 subjects (33%) and Grade 2 ALT or AST elevations occurred in 1 subject (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.

LORBRENA is contraindicatedin patients taking strong CYP3A inducers. Discontinue strong CYP3A inducers for 3 plasma half-lives of the strong CYP3A inducer prior to initiating LORBRENA.

Avoid concomitant use of LORBRENA with moderate CYP3A inducers (see CONTRAINDICATIONS and DRUG INTERACTIONS).

Cardiovascular

Atrioventricular (AV) Block
PR interval prolongation and atrioventricular (AV) block events have been reported in patients receiving LORBRENA. 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), 3 patients (1%) experienced AV block and 1 patient (0.3%) experienced Grade 3 AV block and underwent pacemaker placement.

For those patients who develop AV block, dose modification may be required (see DOSAGE AND ADMINISTRATION).

Driving and Operating Machinery

LORBRENA has moderate influence on the ability to drive and use machines. Caution should be exercised when driving or operating machines as patients may experience central nervous system effects (see ADVERSE REACTIONS, Nervous System Disorders).

Endocrine and Metabolism

Hyperlipidemia
The use of LORBRENA has been associated with increases in serum cholesterol and triglycerides (see ADVERSE REACTIONS). Grade 3 or 4 elevations in total cholesterol occurred in 54 patients (17%) and Grade 3 or 4 elevations in triglycerides occurred in 55 patients (17%) of the 332 patients who received LORBRENA in Study B7461001. No patient was permanently discontinued from treatment with lorlatinib associated with hypercholesterolemia or hypertriglyceridemia.

Initiation, or increase in the dose, of lipid-lowering agents is recommended (see DOSAGE AND ADMINISTRATION).

Neurologic

Central Nervous System Effects
Central nervous system (CNS) effects have been observed in patients receiving LORBRENA (see ADVERSE REACTIONS). Cognitive effects occurred in 95 (29%) of the 332 patients who received LORBRENA at any dose in Study B7461001; in 7 patients (2.1%) these events were severe (Grade 3 or 4). Mood effects occurred in 76 patients (23%); in 6 patients (1.8%) these events were severe. Speech effects occurred in 38 patients (11%); in 1 patient (0.3%) the event was severe. Hallucinations occurred in 23 patients (7%); in 2 patients (0.6%) these events were severe. Mental status changes occurred in 7 patients (2.1%); in 6 patients (1.8%) these events were severe. Dose modification may be required for those patients who develop CNS effects. Permanent discontinuation of LORBRENA is recommended in patients diagnosed with Grade 4 CNS effects (see DOSAGE AND ADMINISTRATION).

Respiratory

ILD/Pneumonitis
Severe or life-threatening pulmonary adverse reactions consistent with pneumonitis have occurred with LORBRENA. Pneumonitis occurred in 4 patients (1.2%) who received LORBRENA at any dose in Study B7461001, including Grade 3 or 4 pneumonitis in 3 patients (0.9%). 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).

Sexual Health

Reproduction
Women of childbearing potential should be advised to avoid becoming pregnant while receiving LORBRENA. A highly effective non-hormonal method of contraception is required for female patients during treatment with LORBRENA because lorlatinib can render hormonal contraceptives ineffective (see DRUG INTERACTIONS). If a hormonal method of contraception is unavoidable, then a condom must be used in combination with the hormonal method. Effective contraception must be continued for at least 21 days after completing therapy. During treatment with LORBRENA and for at least 97 days after the final dose, advise male patients with female partners of reproductive potential to use effective contraception, including a condom, and advise male patients with pregnant partners to use condoms.

Fertility
Based on nonclinical safety findings, male and female fertility may be compromised during treatment with LORBRENA (see NON-CLINICAL TOXICOLOGY). It is not known whether LORBRENA affects female fertility. Men should seek advice on effective fertility preservation before treatment.

Monitoring and Laboratory Tests

ALK Testing
Patients treated with LORBRENA must have a documented ALK-positive status based on a validated ALK assay. Assessment of ALK-positive NSCLC should be performed by laboratories with demonstrated proficiency in the specific technology being utilized.

Liver Function Tests
Avoid concomitant use of LORBRENA with moderate CYP3A inducers. If concomitant use of moderate CYP3A inducers cannot be avoided, monitor AST, ALT, and bilirubin 48 hours after initiating LORBRENA and at least 3 times during the first week after initiating LORBRENA (see WARNINGS AND PRECAUTIONS, Drug-Drug Interactions, Risk of Serious Hepatotoxicity with Concomitant Use of Strong CYP3A Inducers; DOSAGE AND ADMINISTRATION; ADVERSE REACTIONS).

Pancreatic enzymes - Lipase and amylase increase
Patients should be monitored for lipase and amylase elevations prior to the start of LORBRENA treatment and periodically thereafter as clinically indicated.

ECG Monitoring
Monitor ECG prior to initiating LORBRENA and monthly thereafter, particularly in patients with predisposing conditions to the occurrence of clinically significant cardiac events (see WARNINGS AND PRECAUTIONS, Cardiovascular;DOSAGE AND ADMINISTRATION).

Hyperlipidemia
Monitor serum cholesterol and triglycerides before initiating LORBRENA, 2, 4, and 8 weeks, after initiating LORBRENA, and periodically thereafter (see WARNINGS AND PRECAUTIONS, Endocrine and Metabolism; DOSAGE AND ADMINISTRATION; ADVERSE REACTIONS).

Special Populations

Pregnant Women

Studies in animals have shown embryo-fetal toxicity (see NON-CLINICAL TOXICOLOGY). There are no data in pregnant women using LORBRENA. LORBRENA may cause fetal harm when administered to a pregnant woman.

LORBRENA is not recommended during pregnancy or for women of childbearing potential not using contraception.

Breast-feeding

It is not known whether lorlatinib and its metabolites are excreted in human milk. A risk to the newborn child cannot be excluded.

LORBRENA should not be used during breast-feeding. Breast-feeding should be discontinued during treatment with LORBRENA and for 7 days after the last dose.

Pediatrics

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

Geriatrics

Among patients from Study B7461001 who received LORBRENA 100 mg (n=295), 241 patients were < 65 years and 54 patients were ≥ 65 years. The following adverse events were more frequently reported in patients ≥ 65 years: cognitive effects, dyspnea, fatigue, arthralgia, diarrhea, anemia, myalgia, vomiting, back pain and rash. The limited data on the safety and efficacy of LORBRENA in patients aged 65 years and older do not suggest that a dose adjustment is required in elderly patients (see ACTION AND CLINICAL PHARMACOLOGY). Although data are limited, no clinically relevant differences in safety or efficacy were observed between patients aged greater than or equal to 65 years and younger patients.

Adverse Reactions

Adverse Reaction Overview

The data in Warnings and Precautions reflect exposure to LORBRENA (lorlatinib) in 332 patients with ALK-positive or cros oncogene 1 (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 from B7461001 described below reflect exposure to LORBRENA in 295 adult patients with ALK positive or ROS1 positive metastatic NSCLC who received LORBRENA 100 mg orally once daily in study B7461001. The majority of subjects (232 subjects, 78.6%) had been previously treated with 1 or more ALK or ROS1 TKIs.

The median duration of treatment was 12.5 months (range: 1 day to 35 months), the median age was 53 years (range: 19 to 85 years), and 18% of patients were older than 65 years. A total of 170 patients (58%) were female, 145 patients (49%) were White, and 108 patients (37%) were Asian.

The most common (≥ 20%) adverse reactions were edema, peripheral neuropathy, cognitive effects, fatigue, weight increased, arthralgia, mood effects and diarrhea.

The most common (≥ 20%) laboratory abnormalities were hypercholesterolemia, hyp ertriglyceridemia, anemia, creatinine increased, hyperglycemia, hypoalbuminemia, AST elevations, lymphopenia, ALP elevations, ALT elevations, lipase increased, amylase increased, hypomagnesemia, platelet count decreased, hypophosphatemia, hyponatremia, and hyperkalemia.

Serious adverse reactions were reported in 18 patients (6.1%). The most frequent serious adverse reactions reported were mental status changes in 4 patients (1.4%) and cognitive effects in 3 patients (1.0%).

Dose reductions associated with adverse reactions occurred in 76 patients (25.8%) receiving LORBRENA. The most common adverse reactions that led to dose reductions were edema in 18 patients (6.1%) and peripheral neuropathy in 14 patients (4.7%). Permanent discontinuations associated with adverse reactions occurred in 8 patients (2.7%) receiving LORBRENA. The most frequent adverse reaction that led to a permanent discontinuation were hallucinations in 2 patients (0.7%), cognitive effects in 2 patients (0.7%), and mood effects in 2 patients (0.7%). Temporary discontinuations associated with adverse reactions occurred in 103 (34.9%) patients receiving LORBRENA. The most frequent adverse reaction that led to a temporary discontinuation were edema in 17 patients (5.8%), hypertriglyceridemia in 17 patients (5.8%), and peripheral neuropathy in 15 patients (5.1%).

Clinical Trial Adverse Reactions

Because clinical trials are conducted under very specific conditions, the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Table 3 summarizes adverse reactions in patients treated with LORBRENA.

Table 3. Adverse Reactions Reported in ≥ 10% of Patients in Study B7461001*
*
Adverse reactions were graded using NCI CTCAE version 4.0.
Event terms that represent the same medical concept or condition were grouped together and reported as a single adverse reaction in the table above. Terms actually reported in the studies up to the data cutoff date and contributing to the relevant adverse reaction are indicated in parentheses, as listed below.
Abbreviations: NCI CTCAE=National Cancer Institute Common Terminology Criteria for Adverse Events
a
Hypercholesterolemia (including blood cholesterol increased, hypercholesterolemia).
b
Hypertriglyceridemia including (blood triglycerides increased, hypertriglyceridemia).
c
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).
d
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).
e
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, reading disorder).
f
Speech effects (including aphasia, dysarthria, slow speech, speech disorder)
g
Sleep effects (including abnormal dreams, insomnia, nightmare, sleep disorder, sleep talking, somnambulism)
h
Vision disorder (including diplopia, photophobia, photopsia, vision blurred, visual acuity reduced, visual impairment, vitreous floaters).
i
Myalgia (including musculoskeletal pain, myalgia).
j
Edema (including edema, edema peripheral, eyelid edema, face edema, generalized edema, localized edema, periorbital edema, peripheral swelling, swelling).
k

Fatigue (including asthenia, fatigue).

l
Upper respiratory infection (including fungal upper respiratory infection, upper respiratory infection, viral upper respiratory infection).
m
Rash (including dermatitis acneiform, maculopapular rash, pruritic rash, rash).

Adverse Reaction

LORBRENA (N=295)

All Grades

n (%)

Grade 3-4

n (%)

Metabolism and nutrition disorders

Hypercholesterolemiaa

Hypertriglyceridemiab

249 (84.4)

197 (66.8)

49 (16.6)

48 (16.3)

Psychiatric disorders

Mood effectsc

65 (22.0)

5 (1.7)

Nervous system disorders

Peripheral neuropathyd

Cognitive effectse

Headache

Dizziness

Speech effectsf

Sleep effectsg

140 (47.5)

80 (27.1)

52 (17.6)

48 (16.3)

34 (11.5)

29 (9.8)

8 (2.7)

6 (2.0)

2 (0.7)

2 (0.7)

1 (0.3)

0

Respiratory

Dyspnea

Cough

79 (26.8)

54 (18.3)

16 (5.4)

0

Eye disorders

Vision disorderh

43 (14.6)

1 (0.3)

Gastrointestinal disorders

Diarrhea

Nausea

Constipation

Vomiting

64 (21.7)

52 (17.6)

45 (15.3)

34 (11.5)

2 (0.7)

2 (0.7)

0

3 (1.0)

Musculoskeletal and connective tissue disorders

Arthralgia

Myalgiai

Back pain

Pain in extremity

67 (22.7)

50 (16.9)

38 (12.9)

39 (13.2)

2 (0.7)

0

2 (0.7)

1 (0.3)

General disorders and administration site conditions

Edemaj

Fatiguek

Pyrexia

159 (53.9)

76 (25.8)

36 (12.2)

7 (2.4)

1 (0.3)

2 (0.7)

Infections

Upper respiratory tract infectionl

36 (12.2)

0

Skin and subcutaneous tissue disorders

Rashm

41 (13.9)

1 (0.3)

Investigations

Weight increased

71 (24.1)

13 (4.4)

Hypercholesterolemia/Hypertriglyceridemia

In B7461001, adverse reactions of increase in serum cholesterol or triglycerides were reported in 249 patients (84.4%) and 197 patients (66.8%) of patients, respectively. Mild or moderate adverse reactions of hypercholesterolemia or hypertriglyceridemia occurred in 200 (67.8%) and 149 (50.5%) patients, respectively (see DOSAGE AND ADMINISTRATION and WARNINGS AND PRECAUTIONS). No patient was discontinued from treatment with lorlatinib due to hypercholesterolemia or hypertriglyceridemia. The median time to onset for both hypercholesterolemia and hypertriglyceridemia was 15 days. The median duration of hypercholesterolemia and hypertriglyceridemia was 323 and 344 days, respectively.

Nervous system disorders

In B7461001, CNS reactions were primarily cognitive effects reported in 80 patients (27.1%), mood effects in 65 patients (22.0%), and speech effects in 28 patients (9.5%), and were generally mild, transient, and reversible upon dose delay and/or dose reduction (see DOSAGE AND ADMINISTRATION and WARNINGS AND PRECAUTIONS). The most common cognitive effect of any grade was memory impairment reported in 33 patients (11.2%). The most common mood effect of any grade was irritability, reported in 18 patients (6.1%). The most common speech effect of any grade was dysarthria reported in 11 patients (3.7%). Median time to onset for cognitive, mood, and speech effects was 81, 43, and 42 days, respectively. Median duration of cognitive, mood, and speech effects was 194, 73, and 99 days, respectively.

Less Common Clinical Trial Adverse Reactions

Additional clinically significant adverse reactions occurring at an overall incidence between 1% and 10% in patients treated with LORBRENA included speech effects in 28 patients (9.5%), hallucinations in 21 patients (7%), which include hallucination, hallucination auditory and hallucination visual, mental status changes in 5 patients (1.7%), and pneumonitis in 4 patients (1.4%), which include interstitial lung disease and pneuomonitis.

Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data

Table 4 summarizes laboratory abnormalities in patients treated with LORBRENA.

Table 4. 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.

Laboratory Abnormality

LORBRENA

All Grades

n (%)

Grade 3 or 4

n (%)

Chemistry

Hypercholesterolemiaa

Hypertriglyceridemiaa

Hyperglycemiab

Increased ASTa

Hypoalbuminemiac

Increased ALTa

Increased lipased

Increased alkaline phosphatasea

Increased amylasee

Hypophosphatemiaa

Hyperkalemiab

Hypomagnesemiaa

279 (96)

262 (90)

151 (52)

108 (37)

95 (33)

82 (28)

70 (24)

70 (24)

61 (22)

61 (21)

61 (21)

60 (21)

52 (18)

52 (18)

15 (5)

6 (2.1)

3 (1.0)

6 (2.1)

28 (10)

3 (1.0)

11 (3.9)

14 (4.8)

3 (1.0)

0

Hematology

Anemiab

Thrombocytopeniab

Lymphopeniaa

152 (52)

67 (23)

63 (22)

14 (4.8)

1 (0.3)

10 (3.4)

Clinical Trial Adverse Reactions (Pediatrics)

Not applicable.

Post-Market Adverse Reactions

Not applicable.

Drug Interactions

Overview

In vitro data indicate that LORBRENA (lorlatinib) is primarily metabolized by CYP3A4 and uridine diphosphate-glucuronosyltransferase (UGT) 1A4, with minor contributions from CYP2C8, CYP2C19, CYP3A5, and UGT1A3.

Drug-Drug Interactions

CYP3A inhibitors

Itraconazole, a strong inhibitor of CYP3A, administered at a dose of 200 mg once daily for 5 days, increased the mean area under the curve (AUC) by 42% and Cmax by 24% of a single 100 mg oral dose of lorlatinib in healthy volunteers. Concomitant administration of lorlatinib with strong CYP3A inhibitors (e.g., boceprevir, cobicistat, conivaptan, itraconazole, ketoconazole, posaconazole, telaprevir, troleandomycin, voriconazole, ritonavir, paritaprevir in combination with ritonavir and ombitasvir and/or dasabuvir, and ritonavir in combination with either danoprevir, elvitegravir, indinavir, lopinavir, saquinavir, or tipranavir) may increase lorlatinib plasma concentrations. Grapefruit products may also increase lorlatinib plasma concentrations. Concomitant use with a strong CYP3A inhibitor increased lorlatinib plasma concentrations, which may increase the incidence and severity of adverse reactions of LORBRENA. An alternative concomitant medicinal product with less potential to inhibit CYP3A should be considered. If a strong CYP3A inhibitor must be concomitantily administered, a dose reduction of lorlatinib is recommended (see DOSAGE AND ADMINISTRATION).

CYP3A inducers

Rifampin, a strong inducer of CYP3A, administered at a dose of 600 mg once daily for 9 days, reduced the mean lorlatinib AUC by 85% and Cmax by 76% of a single 100-mg dose of lorlatinib in healthy volunteers; increases in liver function tests (AST and ALT) were also observed. Concomitant administration of lorlatinib with strong CYP3A inducers (e.g., rifampin, carbamazepine, enzal uta mide, mitotane, phenytoin and St. John’s wort) may decrease lorlatinib plasma concentrations. Severe hepatotoxicity occurred in healthy subjects receiving LORBRENA with rifampin, a strong CYP3A inducer. The use of a strong CYP3A inducer with lorlatinib is contraindicated (see CONTRAINDICATIONS and DOSAGE AND ADMINISTRATION). 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. Any strong CYP3A inducers have to be discontinued for at least 3 plasma half-lives of the strong CYP3A inducer before lorlatinib treatment is started. Avoid concomitant use with moderate CYP3A inducers, as they may also reduce lorlatinib plasma concentrations.

Proton‑Pump inhibitors, H2-receptor antagonists, or locally acting antacids

The proton-pump inhibitor rabeprazole had a minimal effect on lorlatinib plasma exposure (90% CI for the AUCinf ratio, expressed as a percentage: 97.6%, 104.3%).

No dose adjustment is required when lorlatinib is taken with proton-pump inhibitors, H2-receptor antagonists, or locally acting antacids.

Drugs whose plasma concentrations may be altered by lorlatinib:

CYP3A substrates

Lorlatinib has a net induction effect on CYP3A both in vitro and in vivo. 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. Concurrent administration of lorlatinib in patients resulted in decreased mean oral midazolam AUC and Cmax than that observed when midazolam was administered alone, suggesting that lorlatinib is an inducer of CYP3A. Thus, coadministration of lorlatinib with CYP3A substrates with narrow therapeutic indices, including but not limited to hormonal contraceptives, alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus, should be avoided since the concentration of these drugs may be reduced by lorlatinib.

In vitro studies of other CYP inhibition and induction

In vitro studies indicated that clinical drug-drug interactions as a result of lorlatinib mediated inhibition of the metabolism of substrates for CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP2D6 are unlikely to occur.

In vitro, lorlatinib activates the human pregnane X receptor (PXR). In vitro studies also indicated that lorlatinib is an inducer of CYP2B6 and activates the human constitutive androstane receptor (CAR). Therefore, concomitant use of lorlatinib with CYP2B6 substrates (e.g., bupropion, efavirenz) may result in reduced plasma concentrations of the CYP2B6 substrate. In vitro, lorlatinib has a low potential to cause drug-drug interactions by induction of CYP1A2.

In vitro, the major circulating metabolite for lorlatinib showed a low potential to cause drug‑drug interaction by inhibiting CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A, or by inducing CYP1A2, CYP2B6, and CYP3A.

In vitro studies of UDP-glucuronysyltransferase (UGT) inhibition

In vitro studies indicated that clinical drug-drug interactions as a result of lorlatinib mediated inhibition of the metabolism of substrates for UGT1A1, UGT1A4, UGT1A6, UGT1A9, UGT2B7 and UGT2B15 are unlikely to occur.

In vitro studies indicated that clinical drug‑drug interactions as a result of inhibition by the major lorlatinib circulating metabolite of substrates for UGT1A1, UGT1A4, UGT1A6, UGT1A9, UGT2B7, and UGT2B15 are unlikely to occur.

In vitro studies with drug transporters

In vitro studies indicated that clinical drug‑drug interactions as a result of lorlatinib‑mediated inhibition of breast cancer resistance protein (BCRP, systemically), organic anion transporting polypeptide (OATP)1B1, OATP1B3, multidrug and toxin extrusion protein (MATE)2K, organic anion transporter (OAT)1, and organic cation transporter (OCT)2 are unlikely. Lorlatinib may have the potential to inhibit P‑glycoprotein (P‑gp, systemically and at the gastrointestinal [GI] tract), BCRP (GI tract), OCT1, MATE1, and OAT3 at clinically relevant concentrations.

In vitro studies indicated that clinical drug‑drug interactions as a result of inhibition by the major lorlatinib circulating metabolite of substrates for P‑gp, BCRP, OATP1B1, OATP1B3, OAT1, OAT3, OCT1, OCT2, MATE1, and MATE2K are unlikely to occur.

Drug-Food Interactions

Lorlatinib can be taken with or without food. Administration of lorlatinib with a high fat, high calorie meal resulted in 5% higher AUCinf and 9% lower Cmax (AUCinf ratio of 104.7%; 90% CI for the ratio: 101.3%, 108.3%; Cmax ratio of 90.89%; 90% CI for the ratio: 84.82%, 97.40%), compared to overnight fasting. However, taking lorlatinib with foods that are strong CYP3A inhibitors (e.g. Grapefruit products) may increase lorlatinib plasma concentrations and should be avoided.

Drug-Herb Interactions

Co-administration of lorlatinib with herbal products that are strong CYP3A inducers (e.g. St. John’s wort) may decrease lorlatinib plasma concentrations. The use of a strong CYP3A inducer with lorlatinib is contraindicated (see CONTRAINDICATIONS and DOSAGE AND ADMINISTRATION). Avoid concomitant use with herbal products that are moderate CYP3A inducers, if possible, as they may also reduce lorlatinib plasma concentrations.

Action And Clinical Pharmacology

Mechanism of Action

Lorlatinib is a selective, adenosine triphosphate (ATP) competitive, brain-penetrant, small molecule inhibitor of ALK and ROS1 tyrosine kinases that addresses mechanisms of resistance following previous treatment with ALK inhibitor therapy.

Pharmacodynamics

In nonclinical studies, lorlatinib potently inhibited catalytic activities of non‑mutated ALK and a broad range of clinically relevant ALK mutant kinases in recombinant enzyme and cell-based assays. The ALK mutations analyzed included those conferring resistance to other ALK inhibitors.

Lorlatinib demonstrated marked antitumor activity at low nanomolar free plasma concentrations in mice bearing tumor xenografts that express echinoderm microtubule‑associated protein‑like 4 (EML4) fusions with ALK variant 1 (v1), including ALK mutations L1196M, G1269A, G1202R, and I1171T. Two of these ALK mutants, G1202R and I1171T, are known to confer resistance to first and second generation ALK inhibitors. Lorlatinib is also capable of penetrating the blood‑brain barrier and achieved efficacious brain exposure in mice and rat. In mice bearing orthotropic EML4‑ALK or EML4‑ALKL1196M brain tumor implants, lorlatinib caused tumor shrinkage and prolonged survival.  The overall antitumor efficacy of lorlatinib was dose-dependent and correlated with inhibition of ALK phosphorylation.

Cardiac electrophysiology

QT interval

In B7461001, 2 patients (0.7%) had absolute Fridericia’s correction QTc (QTcF) values >500 msec, and 5 patients (1.8%) had a change in QTcF from baseline >60 msec.

In addition, the effect of a single oral dose of lorlatinib (50 mg, 75 mg, and 100 mg) with and without 200 mg once daily itraconazole was evaluated in a 2‑way crossover study in 16 healthy volunteers. No increases in the mean QTc interval were observed at the mean observed lorlatinib concentrations in this study.

PR interval

In 295 patients who received lorlatinib at the recommended dose of 100 mg once daily and had a ECG measurement in Study B7461001, the maximum mean change from baseline for PR interval was 16.4 ms (90% CI: 13.4, 19.4 ms).  Among the 284 patients with PR interval <200 ms, 14% (40 patients) had PR interval prolongation ≥200 ms after starting lorlatinib.  The prolongation of PR interval occurred in a concentration‑dependent manner. Atrioventricular block occurred in 1.0% of patients. 

For those patients who develop PR prolongation, dose modification may be required (see DOSAGE AND ADMINISTRATION).

Pharmacokinetics

Absorption: In patients with cancer, peak lorlatinib concentrations in plasma are rapidly reached with the median Tmax of 1.2 hours following a single 100 mg dose and 2.0 hours following 100 mg once daily multiple dosing.

After oral administration of lorlatinib tablets, the mean absolute bioavailability is 80.8% (90% CI: 75.7%, 86.2%) compared to intravenous administration.

Administration of lorlatinib with a high fat, high calorie meal resulted in 5% higher AUCinf and 9% lower Cmax (AUCinf ratio of 104.7%; 90% CI for the ratio: 101.3%, 108.3%; Cmax ratio of 90.89%; 90% CI for the ratio: 84.82%, 97.40%), compared to overnight fasting. Lorlatinib may be administered with or without food. The proton pump inhibitor rabeprazole had a minimal effect on lorlatinib plasma exposure (AUCinf ratio of 100.9%; 90% CI for the ratio: 97.6%, 104.3%). No dose adjustment is recommended when lorlatinib is taken with proton pump inhibitors, H2 receptor antagonists or locally acting antacids.

After multiple QD dose administration, lorlatinib Cmax increased dose-proportionally and AUCtau increased slightly less than dose-proportionally over the dose range of 10 mg to 200 mg QD.

At the 100 mg once daily lorlatinib dose, the Cycle 1 Day 15 geometric mean (geometric %CV) peak plasma concentration was 577 (42) ng/mL and the AUC24 5650 (39) ng h/mL in patients with cancer. The geometric mean (geometric %CV) oral clearance was 17.7 (39) L/h.

Distribution: In vitro binding of lorlatinib to human plasma proteins is 66% with moderate binding to both albumin and α1-acid glycoprotein.

The geometric mean (geometric %CV) steady state volume of distribution (Vss) of lorlatinib was 305 (28) L following 50 mg IV administration to healthy subjects. In patients with cancer, the geometric mean (geometric %CV) Vz/F after 100 mg single dose was 352 (37) L.

Metabolism: In humans, lorlatinib undergoes oxidation and glucuronidation as the primary metabolic pathways. In vitro data indicate that lorlatinib is metabolized primarily by CYP3A4 and UGT1A4, with minor contribution from CYP2C8, CYP2C19, CYP3A5, and UGT1A3.

In plasma, a benzoic acid metabolite of lorlatinib resulting from the oxidative cleavage of the amide and aromatic ether bonds of lorlatinib was observed as a major metabolite, accounting for 21% of the circulating radioactivity. The oxidative cleavage metabolite is pharmacologically inactive.

Elimination: In patients with cancer, the plasma half‑life of lorlatinib after a single 100 mg dose was 23.6 hours. At steady‑state, lorlatinib plasma exposures are lower than those expected from single dose pharmacokinetics, indicating a net auto‑induction effect on lorlatinib metabolism. Following oral administration of a 100 mg radiolabeled dose of lorlatinib, a mean 47.7% of the radioactivity was recovered in urine and 40.9% of the radioactivity was recovered in feces, with overall mean total recovery of 88.6%.

Unchanged lorlatinib was the major component of human plasma and feces, accounting for 44% and 9.1% of total radioactivity in plasma and feces, respectively. Less than 1% of unchanged lorlatinib was detected in urine.

Special Populations and Conditions

Pediatrics: The safety and efficacy of LORBRENA (lorlatinib) in pediatric patients have not been established.

Geriatrics: Of the 295 patients in safety population in B7461001, 18.3% of patients were aged 65 years or older. Of the 215 patients in the efficacy population in Study B7461001, 17.7% of patients were aged 65 years or older. Although data are limited, no clinically relevant differences in safety or efficacy were observed between patients aged greater than or equal to 65 years and younger patients (see DOSAGE AND ADMINISTRATION).

Age, gender, race, body weight, and phenotype: Population pharmacokinetic analyses in patients with advanced NSCLC and healthy volunteers indicate that there are no clinically relevant effects of age, gender, race, body weight, or phenotypes for CYP3A5 and CYP2C19.

Hepatic Insufficiency: As lorlatinib is metabolized in the liver, hepatic impairment is likely to increase lorlatinib plasma concentrations. Clinical studies that were conducted excluded patients with AST or ALT >2.5 × ULN, or if due to underlying malignancy, >5.0 × ULN or with total bilirubin >1.5 × ULN. Population pharmacokinetic analyses have shown that lorlatinib exposure was not clinically meaningfully altered in patients with mild hepatic impairment (n=50). No dose adjustments are recommended for patients with mild hepatic impairment (see DOSAGE AND ADMINISTRATION). LORBRENA has not been studied in patients with moderate or severe hepatic impairment.

Renal Insufficiency: Less than 1% of the administered dose is detected as unchanged lorlatinib in urine. Clinical studies excluded patients with serum creatinine >1.5 × ULN or estimated CLcr <60 mL/min. Population pharmacokinetic analyses have shown that lorlatinib steady state exposure was not clinically meaningfully altered in patients with mild (n=103, CLcr: 60‑89 mL/min) or moderate renal impairment (n=41, CLcr: 30‑59 mL/min). No dose adjustments are recommended for patients with mild or moderate renal impairment (see DOSAGE AND ADMINISTRATION). Information for lorlatinib use in patients with severe renal impairment (n=1, CLcr <30 mL/min) is limited.

Storage, Stability And Disposal

Store at 15°C to 30°C in the original package to protect from light.

Special Handling Instructions

LORBRENA does not require any special handling instructions.

 

Control #: 232764
January 17, 2020

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