LORVIQUA® (lorlatinib) as monotherapy is indicated for the first-line treatment of adult patients with anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC) or for patients with ALK-positive metastatic NSCLC whose disease has progressed after alectinib or ceritinib as the first ALK tyrosine kinase inhibitor (TKI) therapy, or crizotinib and at least one other ALK TKI1
Contraindications and Warnings & Precautions Summary of Safety Profile

Safety Profile

Safety Overview1

The data described here reflect exposure to LORVIQUA® in 476 adult patients with ALK+ or c-ros oncogene (ROS1)+ metastatic NSCLC who received LORVIQUA® 100 mg orally once daily in single-arm Study B7461001 or randomised, open-label, active-controlled Phase 3 Study B7461006.

Event

n=476(%)

Adverse drug reactions

Most frequent adverse drug reactions


Hypercholesterolaemia





Hypertriglyceridaemia

Oedema

Peripheral neuropathy

Weight increase

Cognitive effects

Fatigue

Arthralgia

Diarrhoea

Mood effects

 

81.1

67.2

55.7

43.7

30.9

27.7

27.3

23.5

22.9

21.0

• Median duration of LORVIQUA® treatment was 16.3 months (range: 0 day to 55 months), the median age was 55 years (range: 19 to 90 years), and 25% of patients were older than 65 years. A total of 57% of patients were female, 50% of patients were White, 39% of patients were Asian, and 1% were Black.

Serious adverse drug reactions

7.4%

The most frequent serious adverse drug reactions were cognitive effects and pneumonitis.

Dose reductions

20.0%

The most frequent adverse reactions that led to dose reductions were oedema and peripheral neuropathy 

Permanent discontinuations

3.2%

The most frequent adverse reactions that led to Permanent discontinuations of LORVIQUA® were cognitive effects peripheral neuropathy, and pneumonitis 

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Adverse Drug Reactions by System Organ Class1
Adverse drug reactions for LORVIQUA® within each system organ class (SOC) by decreasing medical seriousness.

System Organ Class 

Adverse Drug Reaction 

Metabolism and nutrition disorders 

Hypercholesterolaemiaa

​​​​​​​Hypertriglyceridaemiab

Hyperglycaemia 

Psychiatric disorders 

Mood effects

Psychotic effects

Mental status changes 

Nervous system disorders 

Cognitive effects

Peripheral neuropathy

Speech effectsg 

Sleep effects

Seizures

Eye disorders 

Vision disorder

Vascular disorders 

Hypertension

Respiratory, thoracic and mediastinal disorders Content

Pneumonitisj

Gastrointestinal disorders 

Diarrhoea 
Constipation 

Musculoskeletal and connective tissue disorders 

Arthralgia

General disorders and administration site conditions

Oedemak 
Fatiguel 

Investigations

Weight increased  

Lipase increased
​​​​​

​​​​​​​ Amylase increased 

Event terms that represent the same medical concept or condition were grouped together and reported as a single adverse drug reaction in the table above. Terms actually reported in the studies up to the data cut-off date (B7461001: 14May2019; B7461006: 20Mar2020) and contributing to the relevant adverse drug reaction are indicated in parentheses, as listed below. 

a Hypercholesterolaemia (including blood cholesterol increased, hypercholesterolaemia). 

b Hypertriglyceridaemia (including blood triglycerides increased, hypertriglyceridaemia). 

c Mood effects (including affective disorder, affect lability, aggression, agitation, anger, anxiety, bipolar I disorder, depressed mood, depression, depressive symptom, euphoric mood, irritability, mania, mood altered, mood swings, panic attack, personality change, stress, suicidal ideation). 

d Psychotic effects (including delusion, hallucination, hallucination auditory, hallucination visual, schizophreniform disorder). 

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, disorientation, reading disorder). Within these effects, terms from SOC Nervous system disorders were more frequently reported than terms from SOC Psychiatric disorders. 

f Peripheral neuropathy (including burning sensation, dysaesthesia, formication, gait disturbance, hypoaesthesia, motor dysfunction, muscular weakness, neuralgia, neuropathy peripheral, neurotoxicity, paraesthesia, peripheral motor neuropathy, peripheral sensory neuropathy, peroneal nerve palsy, sensory disturbance). 

g Speech effects (including dysarthria, slow speech, speech disorder). 

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

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

j Pneumonitis (including interstitial lung disease, lung opacity, pneumonitis). 

k Oedema (including generalised oedema, oedema, oedema peripheral, peripheral swelling, swelling). 

l Fatigue (including asthenia, fatigue). 

Description of Selected Adverse Drug Reactions

Hypercholesterolaemia/Hypertriglyceridaemia1

  • In clinical trials of patients with ALK+ or c-ros oncogene 1 (ROS1)+ metastatic NSCLC, adverse drug reactions of increase in serum cholesterol or triglycerides were reported in 81.1% and 67.2% of patients, respectively. Mild or moderate adverse drug reactions of hypercholesterolaemia or hypertriglyceridaemia occurred in 62.8% and 47.9% of patients, respectively
  • No patient was discontinued from treatment with LORVIQUA® due to hypercholesterolaemia or hypertriglyceridaemia
  • The median time to onset for both hypercholesterolaemia and hypertriglyceridaemia was 15 days. The median duration of hypercholesterolaemia and hypertriglyceridaemia was 451 and 427 days, respectively


Central nervous system effects1

  • In clinical trials of patients with ALK+ or c-ros oncogene 1 (ROS1)+ metastatic NSCLC, CNS adverse drug reactions were primarily cognitive effects, mood effects, speech effects, and psychotic effects, and were generally mild, transient, and reversible upon dose delay and/or dose reduction

Cognitive effects

27.7%

Most frequent adverse drug reactions of any grade

Memory impairment

Most frequent adverse drug reactions of Grade 3 or 4

Cognitive disorder

Confusional state

 

11.3%

 

0.8%

1.7%

Mood effects

21.0%

Most frequent adverse drug reactions of any grade

Anxiety

Most frequent adverse drug reactions of Grade 3 or 4

Irritability

Depression

 

6.5%

 

0.8%

0.4%

Speech effects

8.2%

Most frequent adverse drug reactions of any grade

Dysarthria

Most frequent adverse drug reactions of Grade 3 or 4

Dysarthria

Slow speech

Speech disorder

 

4.0%

 

0.2%

0.2%

0.2%

Psychotic effects

6.9%

Most frequent adverse drug reactions of any grade

Hallucination

Most frequent adverse drug reactions of Grade 3 or 4

Hallucination auditory

Hallucination visual

 

2.9%

 

0.2%

0.2%

• Median time to onset for cognitive, mood, speech, and psychotic effects was 109, 43, 49, and 23 days, respectively

• Median duration of cognitive, mood, speech, and psychotic effects was 223, 143, 147, and 78 days, respectively

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ALK, anaplasticlymphoma kinase; CNS, central nervous system; NSCLC, non-small cell lung cancer
Reference
1.Pfizer. LORVIQUA® (lorlatinib) Prescribing Information, Available from:  http://labeling.pfizer.com/ShowLabeling.aspx?id=12540 Accessed 5 January 2022.

The use of lorlatinib has been associated with increases in serum cholesterol and triglycerides. Serum cholesterol and triglycerides should be monitored before the initiation of lorlatinib; 2, 4, and 8 weeks after initiating lorlatinib, and periodically thereafter. Initiation, or increase in the dose, of lipid-lowering agents is required.
Central nervous system (CNS) effects have been observed in patients receiving lorlatinib including seizures, psychotic effects, changes in cognitive function, mood (including suicidal ideation), mental status, sleep, and speech. Dose modification or discontinuation may be required for those patients who develop CNS effects.
PR interval prolongation and atrioventricular (AV) block events have been reported in patients receiving lorlatinib. Monitor electrocardiogram (ECG) prior to initiating lorlatinib and monthly thereafter, particularly in patients with predisposing conditions to the occurrence of clinically significant cardiac events. Dose modification may be required for those patients who develop AV block.
Elevations of lipase and/or amylase have occurred in patients receiving lorlatinib. Median time of occurrence of increase in serum lipase and amylase is 70 days (range: 7 days to 696 days) and 41 days (range: 7 days to 489 days), respectively. Risk of pancreatitis should be considered in patients receiving lorlatinib due to concomitant hypertriglyceridemia and/or a potential intrinsic mechanism. Patients should be monitored for lipase and amylase elevations prior to the start of lorlatinib treatment and regularly thereafter as clinically indicated.
Severe or life threatening pulmonary adverse drug reactions consistent with ILD/pneumonitis have occurred with lorlatinib. Any patient who presents with worsening of respiratory symptoms indicative of ILD/pneumonitis (e.g., dyspnea, cough and fever) should be promptly evaluated for ILD/pneumonitis. Lorlatinib should be withheld and/or permanently discontinued based on severity.
Hypertension has been reported in patients receiving lorlatinib. Blood pressure should be controlled prior to the initiation of lorlatinib. Blood pressure should be monitored after 2 weeks and at least monthly thereafter during treatment with lorlatinib. Lorlatinib should be withheld and resumed at a reduced dose or permanently discontinued based on severity.
Hyperglycemia has occurred in patients receiving lorlatinib. Fasting serum glucose should be assessed prior to the initiation of lorlatinib and monitored periodically thereafter. Lorlatinib should be withheld and resumed at a reduced dose or permanently discontinued based on severity.
Concomitant use of any strong CYP3A inducer is contraindicated. 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. No clinically meaningful changes in liver function tests were seen in healthy subjects after receiving a combination of lorlatinib with the moderate CYP3A inducer modafinil.
Women of childbearing potential should be advised to avoid getting pregnant while receiving lorlatinib. Male fertility may be compromised during treatment with lorlatinib. Men should seek advice on effective fertility preservation before treatment.

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® Safety Profile
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