4.1. Therapeutic indications

Lorviqua as monotherapy is indicated for the treatment of adult patients with anaplastic lymphoma kinase (ALK)‑positive advanced non‑small cell lung cancer (NSCLC) previously not treated with an ALK inhibitor or whose disease has progressed after prior treatment with an ALK inhibitor.

4.2. Posology and method of administration

Treatment with lorlatinib should be initiated and supervised by a physician experienced in the use of anticancer medicinal products.

Detection of ALK-positive NSCLC is necessary for selection of patients for treatment with lorlatinib because these are the only patients for whom benefit has been shown. Assessment for ALK-positive NSCLC should be performed by laboratories with demonstrated proficiency in the specific technology being utilised. Improper assay performance can lead to unreliable test results.

Posology

The recommended dose is 100 mg lorlatinib taken orally once daily.

Duration of treatment

Treatment with lorlatinib is recommended as long as the patient is deriving clinical benefit from therapy without unacceptable toxicity.

Delayed or missed doses

If a dose of Lorviqua 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.

Dose modifications

Dosing interruption or dose reduction may be required based on individual safety and tolerability. Lorlatinib dose reduction levels are summarised below:

• First dose reduction: 75 mg taken orally once daily

• Second dose reduction: 50 mg taken orally once daily

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

Dose modification recommendations for toxicities and for patients who develop atrioventricular (AV) block are provided in Table 1.

Table 1. Recommended lorlatinib dose modifications for adverse reactions

Adverse reactiona

Lorlatinib dosing

Hypercholesterolaemia or hypertriglyceridaemia

Mild hypercholesterolaemia

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

OR

Moderate hypercholesterolaemia

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

OR

Mild hypertriglyceridaemia

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

OR

Moderate hypertriglyceridaemia

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

Introduce or modify lipid‑lowering therapyb in accordance with respective prescribing information; continue lorlatinib at same dose.

Severe hypercholesterolaemia

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

OR

Severe hypertriglyceridaemia

(triglycerides between 501 and 1,000 mg/dL or 5.71 and 11.4 mmol/L)

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

Life‑threatening hypercholesterolaemia

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

OR

Life‑threatening hypertriglyceridaemia

(triglycerides over 1,000 mg/dL or over 11.4 mmol/L)

Introduce the use of lipid‑lowering therapyb or increase the dose of this therapyb in accordance with respective prescribing information or change to a new lipid‑lowering therapyb. Withhold lorlatinib until recovery of hypercholesterolaemia and/or hypertriglyceridaemia to moderate or mild severity grade.

Re‑challenge at same lorlatinib dose while maximising lipid‑lowering therapyb in accordance with respective prescribing information.

If severe hypercholesterolaemia and/or hypertriglyceridaemia recur despite maximal lipid‑lowering therapyb in accordance with respective prescribing information, reduce lorlatinib by 1 dose level.

Central nervous system (CNS) effects (comprises psychotic effects and changes in cognition, mood, mental state or speech)

Grade 2: Moderate

OR

Grade 3: Severe

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

Grade 4: Life‑threatening/Urgent intervention indicated

Permanently discontinue lorlatinib.

Lipase/Amylase increase

Grade 3: Severe

OR

Grade 4: Life‑threatening/Urgent intervention indicated

Withhold lorlatinib until lipase or amylase returns to baseline. Then resume lorlatinib at 1 reduced dose level.

Interstitial lung disease (ILD)/Pneumonitis

Grade 1: Mild

OR

Grade 2: Moderate

Withhold lorlatinib until symptoms have returned to baseline and consider initiating corticosteroids. Resume lorlatinib at 1 reduced dose level.

Permanently discontinue lorlatinib if ILD/pneumonitis recurs or fails to recover after 6 weeks of lorlatinib hold and steroid treatment.

Grade 3: Severe

OR

Grade 4: Life‑threatening/Urgent intervention indicated

Permanently discontinue lorlatinib.

PR interval prolongation/Atrioventricular (AV) block

First degree AV block:

Asymptomatic

Continue lorlatinib at the same dose without interruption. Consider effects of concomitant medicinal products, and assess and correct electrolyte imbalance that may prolong PR interval. Monitor ECG/symptoms potentially related to AV block closely.

First degree AV block:

Symptomatic

Withhold lorlatinib. Consider effects of concomitant medicinal products, and assess and correct electrolyte imbalance that may prolong PR interval. Monitor ECG/symptoms potentially related to AV block closely. If symptoms resolve, resume lorlatinib at 1 reduced dose level.

Second degree AV block

Asymptomatic

Withhold lorlatinib. Consider effects of concomitant medicinal products, and assess and correct electrolyte imbalance that may prolong PR interval. Monitor ECG/symptoms potentially related to AV block closely. If subsequent ECG does not show second degree AV block, resume lorlatinib at 1 reduced dose level.

Second degree AV block

Symptomatic

Withhold lorlatinib. Consider effects of concomitant medicinal products, and assess and correct 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 AV block resolve or if patients revert to asymptomatic first‑degree AV block, resume lorlatinib at 1 reduced dose level.

Complete AV block

Withhold lorlatinib. Consider effects of concomitant medicinal products, and assess and correct electrolyte imbalance that may prolong PR interval. Refer for cardiac observation and monitoring. 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, resume lorlatinib at full dose. If no pacemaker placed, resume lorlatinib at 1 reduced dose level only when symptoms resolve, and PR interval is less than 200 msec.

Hypertension

Grade 3 (SBP greater than or equal to 160 mmHg or DBP greater than or equal to 100 mmHg; medical intervention indicated; more than one antihypertensive drug, or more intensive therapy than previously used indicated)

Withhold lorlatinib until hypertension has recovered to Grade 1 or less (SBP less than 140 mmHg and DBP less than 90 mmHg), then resume lorlatinib at the same dose.

If Grade 3 hypertension recurs, withhold lorlatinib until recovery to Grade 1 or less, and resume at a reduced dose.

If adequate hypertension control cannot be achieved with optimal medical management, permanently discontinue lorlatinib.

Grade 4 (Life-threatening consequences, urgent intervention indicated)

Withhold lorlatinib until recovery to Grade 1 or less, and resume at a reduced dose or permanently discontinue lorlatinib.

If Grade 4 hypertension recurs, permanently discontinue lorlatinib.

Hyperglycaemia

Grade 3 (greater than 250 mg/dL despite optimal anti-hyperglycaemic therapy)

OR

Grade 4

Withhold lorlatinib until hyperglycaemia is adequately controlled, then resume lorlatinib at the next lower dose.

If adequate hyperglycaemic control cannot be achieved with optimal medical management, permanently discontinue lorlatinib.

Other adverse reactions

Grade 1: Mild

OR

Grade 2: Moderate

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

Greater than or equal to Grade 3: Severe

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

Abbreviations: CNS=central nervous system; CTCAE=Common Terminology Criteria for Adverse Events; DBP=diastolic blood pressure; ECG=electrocardiogram; HMG CoA=3‑hydroxy‑3‑methylglutaryl coenzyme A; NCI=National Cancer Institute; SBP=systolic blood pressure; ULN=upper limit of normal.

a Grade categories are based on NCI CTCAE classifications.

b Lipid‑lowering therapy may include: HMG CoA reductase inhibitor, nicotinic acid, fibric acid derivatives, or ethyl esters of omega‑3 fatty acids.

Strong cytochrome P‑450 (CYP) 3A4/5 inhibitors

Concurrent use of lorlatinib with medicinal products that are strong CYP3A4/5 inhibitors and grapefruit juice products may increase lorlatinib plasma concentrations. An alternative concomitant medicinal product with less potential to inhibit CYP3A4/5 should be considered (see section 4.5). If a strong CYP3A4/5 inhibitor must be co‑administered, the starting lorlatinib dose of 100 mg once daily should be reduced to once daily 75 mg dose (see sections 4.5 and 5.2). If concurrent use of the strong CYP3A4/5 inhibitor is discontinued, lorlatinib should be resumed at the dose used prior to the initiation of the strong CYP3A4/5 inhibitor and after a washout period of 3 to 5 half‑lives of the strong CYP3A4/5 inhibitor.

Special populations

Elderly (≥ 65 years)

Due to the limited data on this population, no dose recommendation can be made for patients aged 65 years and older (see section 5.2).

Renal impairment

No dose adjustment is needed for patients with normal renal function and mild or moderate renal impairment [absolute estimated glomerular filtration rate (eGFR): ≥ 30 mL/min]. A reduced dose of lorlatinib is recommended in patients with severe renal impairment (absolute eGFR < 30 mL/min), e.g. a once daily starting dose of 75 mg taken orally (see section 5.2). No information is available for patients on renal dialysis.

Hepatic impairment

No dose adjustments are recommended for patients with mild or moderate hepatic impairment. A reduced starting dose of lorlatinib is recommended in patients with severe hepatic impairment (Child-Pugh C) from 100 mg to 50 mg orally once daily (see section 5.2).

Paediatric population

The safety and efficacy of lorlatinib in paediatric patients below 18 years have not been established. No data are available.

Method of administration

Lorviqua is for oral use.

Patients should be encouraged to take their dose of lorlatinib at approximately the same time each day with or without food (see section 5.2). The 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.

4.3. Contraindications

Hypersensitivity to lorlatinib or to any of the excipients listed in section 6.1.

Concomitant use of strong CYP3A4/5 inducers (see sections 4.4 and 4.5).

4.4. Special warnings and precautions for use

Hyperlipidaemia

The use of lorlatinib has been associated with increases in serum cholesterol and triglycerides (see section 4.8). Serum cholesterol and triglycerides should be monitored before initiation of lorlatinib; 2, 4 and 8 weeks after initiating lorlatinib; and regularly thereafter. Initiate or increase the dose of lipid‑lowering medicinal products, if indicated (see section 4.2).

Central nervous system effects

A broad spectrum of central nervous system (CNS) effects have been observed in patients receiving lorlatinib, including seizures, psychotic effects and changes in cognitive function, mood (including suicidal ideation), speech, mental status and sleep (see section 4.8). Dose modification or discontinuation may be required for those patients who develop CNS effects (see section 4.2).

Atrioventricular block

Lorlatinib was studied in a population of patients that excluded those with second‑degree or third‑degree AV block (unless paced) or any AV block with PR interval > 220 msec. PR interval prolongation and AV block have been reported in patients receiving lorlatinib (see section 5.2). 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 (see section 4.2).

Left ventricular ejection fraction decrease

A decrease in left ventricular ejection fraction (LVEF) has been reported in patients receiving lorlatinib who had baseline and at least one follow-up LVEF assessment. Based on the available clinical study data, it is not possible to determine a causal relationship between effects on changes in cardiac contractility and lorlatinib.

In patients with cardiac risk factors and those with conditions that can affect LVEF, cardiac monitoring, including LVEF assessment at baseline and during treatment, should be considered. In patients who develop relevant cardiac signs/symptoms during treatment, cardiac monitoring, including LVEF assessment, should be considered. Dosing interruption, dose reduction, or discontinuation should be considered as appropriate if such symptoms are observed.

Elevation of pancreatic enzymes

Elevations of lipase and/or amylase have occurred in patients receiving lorlatinib (see section 4.8). Lorlatinib was studied in a population of patients that excluded, at the discretion of the investigator, those with risk factors for pancreatitis, such as uncontrolled hyperglycaemia or gallstone disease. 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 (see section 4.2).

Interstitial lung disease/Pneumonitis

Severe or life‑threatening pulmonary adverse reactions consistent with ILD/pneumonitis have occurred with lorlatinib (see section 4.8). Any patient who presents with worsening of respiratory symptoms indicative of ILD/pneumonitis (e.g. dyspnoea, cough and fever) should be promptly evaluated for ILD/pneumonitis. Lorlatinib should be withheld and/or permanently discontinued based on severity (see section 4.2).

Visual disturbance

Visual disturbance adverse reactions have occurred in patients treated with lorlatinib (see section 4.8). Patients should be advised to report any visual symptoms. For new or worsening severe visual symptoms, an ophthalmologic evaluation and dose reduction should be considered (see section 4.2).

Hypertension

Hypertension has been reported in patients receiving lorlatinib (see section 4.8). Blood pressure should be controlled prior to 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 (see section 4.2).

Hyperglycaemia

Hyperglycaemia has occurred in patients receiving lorlatinib (see section 4.8). Fasting serum glucose should be assessed prior to initiation of lorlatinib and monitored periodically thereafter. Lorlatinib should be withheld and resumed at a reduced dose or permanently discontinued based on severity (see section 4.2).

Risk of serious hepatotoxicity with concomitant use of strong CYP3A inducers

In a study conducted in healthy volunteers, the concomitant use of lorlatinib and rifampin, a strong CYP3A4/5 inducer, was associated with increases of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) with no increase of total bilirubin and alkaline phosphatase (see section 4.5). Concomitant use of a strong CYP3A4/5 inducer is contraindicated and should be discontinued 3 plasma half-lives prior to initiating lorlatinib (see sections 4.3 and 4.5).

Other Drug - drug interactions

Concomitant use of moderate CYP3A inducers

No clinically meaningful changes in liver function tests were seen in healthy subjects after receiving a combination of lorlatinib with the moderate CYP3A4/5 inducer modafinil (see section 4.5).

Concomitant use of strong CYP3A inhibitors

Concomitant use with strong CYP3A inhibitors should be avoided (see section 4.5).

CYP3A4/5 substrates

Concurrent administration of lorlatinib with CYP3A4/5 substrates with narrow therapeutic indices, including but not limited to alfentanil, ciclosporin, dihydroergotamine, ergotamine, fentanyl, hormonal contraceptives, pimozide, quinidine, sirolimus and tacrolimus, should be avoided since the concentration of these medicinal products may be reduced by lorlatinib (see section 4.5).

Fertility and pregnancy

Lorlatinib may cause foetal harm. During treatment with lorlatinib and for at least 14 weeks after the final dose, male patients with female partners of childbearing potential must use effective contraception, including a condom, and male patients with pregnant partners must use condoms (see section 4.6). Male fertility may be compromised during treatment with lorlatinib (see section 5.3). Men should seek advice on effective fertility preservation before treatment. Women of childbearing potential should be advised to avoid becoming pregnant while receiving lorlatinib. A highly effective non‑hormonal method of contraception is required for female patients during treatment with lorlatinib, because lorlatinib can render hormonal contraceptives ineffective (see sections 4.5 and 4.6). 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 35 days after completing therapy (see section 4.6). It is not known whether lorlatinib affects female fertility.

Lactose intolerance

This medicinal product contains lactose as an excipient. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency, or glucose‑galactose malabsorption should not take this medicinal product.

Dietary sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per 25 mg or 100 mg tablet. Patients on low sodium diets should be informed that this product is essentially “sodium‑free”.

4.5. Interaction with other medicinal products and other forms of interaction

Pharmacokinetic interactions

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

Effect of medicinal products on lorlatinib

Strong CYP3A4/5 inducers

Rifampin, a strong inducer of CYP3A4/5, administered at oral doses of 600 mg once daily for 12 days, reduced the mean lorlatinib area under curve (AUCinf) by 85% and Cmax by 76% of a single 100 mg oral dose of lorlatinib in healthy volunteers; increases in AST and ALT were also observed. Concomitant administration of lorlatinib with strong CYP3A4/5 inducers (e.g. rifampicin, carbamazepine, enzalutamide, mitotane, phenytoin and St. John's wort) may decrease lorlatinib plasma concentrations. The use of a strong CYP3A4/5 inducer with lorlatinib is contraindicated (see sections 4.3 and 4.4).

Moderate CYP3A4/5 inducers

No clinically meaningful changes in liver function test results were seen after administration of the combination of a single 100 mg oral dose of lorlatinib with the moderate CYP3A4/5 inducer, modafinil (400 mg once daily for 19 days) in healthy volunteers. Concomitant use of modafinil reduced lorlatinib AUCinf by 23% which is not expected to influence the efficacy of lorlatinib.

CYP3A4/5 inhibitors

Itraconazole, a strong inhibitor of CYP3A4/5, administered at oral doses of 200 mg once daily for 5 days, increased the mean lorlatinib AUCinf by 42% and Cmax by 24% of a single 100 mg oral dose of lorlatinib in healthy volunteers.

Concomitant administration of lorlatinib with strong CYP3A4/5 inhibitors (e.g. boceprevir, cobicistat, itraconazole, ketoconazole, posaconazole, troleandomycin, voriconazole, ritonavir, paritaprevir in combination with ritonavir and ombitasvir and/or dasabuvir, and ritonavir in combination with either elvitegravir, indinavir, lopinavir or tipranavir) may increase lorlatinib plasma concentrations. Grapefruit products may also increase lorlatinib plasma concentrations and should be avoided. An alternative concomitant medicinal product with less potential to inhibit CYP3A4/5 should be considered. If a strong CYP3A4/5 inhibitor must be concomitantly administered, a dose reduction of lorlatinib is recommended (see section 4.2).

Effect of lorlatinib on other medicinal products

CYP3A4/5 substrates

In vitro studies indicated that lorlatinib is a time‑dependent inhibitor as well as an inducer of CYP3A4/5. Lorlatinib 150 mg orally once daily for 15 days decreased AUCinf and Cmax of a single oral 2 mg dose of midazolam (a sensitive CYP3A substrate) by 61% by 50%, respectively; hence, lorlatinib is a moderate CYP3A inducer. Thus, concurrent administration of lorlatinib with CYP3A4/5 substrates with narrow therapeutic indices, including but not limited to alfentanil, ciclosporin, dihydroergotamine, ergotamine, fentanyl, hormonal contraceptives, pimozide, quinidine, sirolimus and tacrolimus, should be avoided since the concentration of these medicinal products may be reduced by lorlatinib (see section 4.4).

CYP2B6 substrates

Lorlatinib 100 mg once daily for 15 days decreased AUCinf and Cmax of a single oral 100 mg dose of bupropion (a combined CYP2B6 and CYP3A4 substrate) by 25% and 27%, respectively. Thus, lorlatinib is a weak inducer of CYP2B6, and no dose adjustment is necessary when lorlatinib is used in combination with medicinal products that are mainly metabolised by CYP2B6.

CYP2C9 substrates

Lorlatinib 100 mg once daily for 15 days decreased AUCinf and Cmax of a single oral 500 mg dose of tolbutamide (a sensitive CYP2C9 substrate) by 43% and 15%, respectively. Thus, lorlatinib is a weak inducer of CYP2C9, and no dose adjustment is required for medicinal products that are mainly metabolised by CYP2C9. However, patients should be monitored in case of concomitant treatment with medicinal products with narrow therapeutic indices metabolised by CYP2C9 (e.g. coumarin anticoagulants).

UGT substrates

Lorlatinib 100 mg once daily for 15 days decreased AUCinf and Cmax of a single oral 500 mg dose of acetaminophen (a UGT, SULT and CYP1A2, 2A6, 2D6, and 3A4 substrate) by 45% and 28%, respectively. Thus, lorlatinib is a weak inducer of UGT, and no dose adjustment is required for medicinal products that are mainly metabolised by UGT. However, patients should be monitored in case of concomitant treatment with medicinal products with narrow therapeutic indices metabolised by UGT.

P-glycoprotein substrates

Lorlatinib 100 mg once daily for 15 days decreased AUCinf and Cmax of a single oral dose of 60 mgfexofenadine [a sensitive P-glycoprotein (P-gp) substrate] by 67% and 63%, respectively. Thus, lorlatinib is a moderate inducer of P-gp. Medicinal products that are P‑gp substrates with narrow therapeutic indices (e.g. digoxin, dabigatran etexilate) should be used with caution in combination with lorlatinib due to the likelihood of reduced plasma concentrations of these substrates.

In vitro inhibition and induction studies of other CYP enzymes

In vitro, lorlatinib has a low potential to cause drug‑drug interactions by induction of CYP1A2.

In vitro studies with drug transporters other than P‑gp

In vitro studies indicated that lorlatinib may have the potential to inhibit BCRP (gastrointestinal tract), OATP1B1, OATP1B3, OCT1, MATE1 and OAT3 at clinically relevant concentrations. Lorlatinib should be used with caution in combination with substrates of BCRP, OATP1B1, OATP1B3, OCT1, MATE1 and OAT3 as clinically relevant changes in the plasma exposure of these substrates cannot be ruled out.

4.6. Fertility, pregnancy and lactation

Women of childbearing potential/Contraception in males and females

Women of childbearing potential should be advised to avoid becoming pregnant while receiving lorlatinib. A highly effective non‑hormonal method of contraception is required for female patients during treatment with lorlatinib, because lorlatinib can render hormonal contraceptives ineffective (see sections 4.4 and 4.5). 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 35 days after completing therapy.

During treatment with lorlatinib and for at least 14 weeks after the final dose, male patients with female partners of childbearing potential must use effective contraception, including a condom, and male patients with pregnant partners must use condoms.

Pregnancy

Studies in animals have shown embryo‑foetal toxicity (see section 5.3). There are no data from the use of lorlatinib in pregnant women. Lorlatinib may cause foetal harm when administered to a pregnant woman.

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

Breast‑feeding

It is unknown whether lorlatinib and its metabolites are excreted in human milk. A risk to the newborns/infants cannot be excluded.

Lorlatinib should not be used during breast‑feeding. Breast‑feeding should be discontinued during treatment with lorlatinib and for 7 days after the final dose.

Fertility

Based on non-clinical safety findings, male fertility may be compromised during treatment with lorlatinib (see section 5.3). It is not known whether lorlatinib affects female fertility. Men should seek advice on effective fertility preservation before treatment.

4.7. Effects on ability to drive and use machines

Lorlatinib has moderate influence on the ability to drive and use machines. Caution should be exercised when driving or operating machines as patients may experience CNS effects (see section 4.8).

4.8. Undesirable effects

Summary of the safety profile

The frequencies of adverse reactions are based on all-cause adverse events.

The most frequently reported adverse reactions (≥20%) in patients treated with lorlatinib at the recommended dosing regimen were hypercholesterolaemia (79.0%), hypertriglyceridaemia (67.5%), oedema (55.4%), peripheral neuropathy (44.2%), fatigue (30.7%), weight gain (29.8%), arthralgia (27.8%), cognitive effects (27.4%), dyspnoea (27.4%), diarrhoea (22.7%) and mood effects (21.4%).

Serious adverse drug reactions were reported in 9.1% of patients receiving lorlatinib. The most frequent serious adverse drug reactions were cognitive effects and pneumonitis.

Dose reductions due to any adverse reactions occurred in 20.1% of patients receiving lorlatinib. The most common adverse reactions that led to dose reductions were oedema, cognitive effects and peripheral neuropathy. Permanent treatment discontinuation associated with adverse reactions occurred in 4.0% of patients receiving lorlatinib. The most frequent adverse reactions that led to permanent discontinuations were cognitive effects, peripheral neuropathy, pneumonitis and psychotic effects.

Tabulated list of adverse reactions

Table 2 presents adverse reactions occurring in 547 adult patients with advanced NSCLC from Study A (N=327), CROWN study (N=149) and Study B (N=71) who were treated with lorlatinib 100 mg once daily.

The adverse reactions listed in Table 2 are presented by system organ class and frequency categories, defined using the following convention: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000). Within each frequency grouping, undesirable effects are presented in order of decreasing medical seriousness.

Table 2. Adverse reactions

System organ class and adverse reaction

Frequency category

All Grades

%

Grades 3‑4

%

Blood and lymphatic system disorders

Anaemia

Very common

19.6

4.4

Metabolism and nutrition disorders

Hypercholesterolaemiaa

Hypertriglyceridaemiab

Hyperglycaemia

Very common

Very common

Common

79.0

67.5

9.7

19.2

20.3

3.7

Psychiatric disorders

Mood effectsc

Sleep effects

Psychotic effectsd

Mental status changes

Very common

Very common

Common

Common

21.4

10.8

6.9

1.1

1.3

0.4

0.9

0.9

Nervous system disorders

Cognitive effectse

Peripheral neuropathyf

Headache

Speech effectsg

Very common

Very common

Very common

Common

27.4

44.2

18.6

8.2

3.5

2.6

0.7

0.7

Eye disorders

Vision disorderh

Very common

16.1

0.2

Vascular disorders

Hypertension

Very common

14.8

6.0

Respiratory, thoracic and mediastinal disorders

Dyspnoea

Cough

Pneumonitisi

Very common

Very common

Common

27.4

21.0

2.4

5.7

0

0.7

Gastrointestinal disorders

Diarrhoea

Nausea

Constipation

Vomiting

Lipase increased

Amylase increased

Pancreatitis

Very common

Very common

Very common

Very common

Very common

Very common

Uncommon

22.7

17.6

16.8

14.1

12.8

11.3

0.5

1.8

0.9

0.2

1.1

6.8

2.7

0.2

Hepatobiliary disorders

Alanine aminotransferase increased

Aspartate aminotransferase increased

Gamma-glutamyl peptidase increased

Very common

Very common

Common

14.6

13.9

5.9

2.0

1.5

2.4

Skin and subcutaneous tissue disorders

Rashj

Very common

14.6

0.2

Renal and urinary disorders

Proteinuria

Common

3.7

0.4

Musculoskeletal and connective tissue disorders

Arthralgia

Myalgiak

Blood creatine phosphokinase increased

Very common

Very common

Common

27.8

15.0

7.3

0.7

0

1.3

General disorders and administration site conditions

Oedemal

Fatiguem

Dizziness

Very common

Very common

Very common

55.4

30.7

15.2

2.9

1.1

0.7

Investigations

Weight increased

Atrioventricular block

Very common

Common

29.8

0.4

11

0

Adverse reactions 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 and contributing to the relevant adverse 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).

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

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 (dysarthria, slow speech, speech disorder).

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

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

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

k Myalgia (including musculoskeletal pain, myalgia).

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

m Fatigue (including asthenia, fatigue).

Description of selected adverse reactions

Hypercholesterolaemia/hypertriglyceridaemia

Adverse reactions of increase in serum cholesterol or triglycerides were reported in 79.0% and 67.5% of patients, respectively. Grade 3 or 4 reactions of hypercholesterolaemia and hypertriglyceridaemia were reported in 11.5% and 18.1% of patients, respectively. The median time to onset for hypercholesterolaemia and hypertriglyceridaemia was 15 days (range: 1 to 1921 days) and 16 days (range: 1 to 1921 days), respectively. Median time of occurrence of grade 4 increase in serum cholesterol and triglycerides is 104 days (range: 29 to 518 days) and 120 days (range: 15 to 780 days), respectively. The median duration of hypercholesterolaemia and hypertriglyceridaemia was 526 and 519 days, respectively. Dose interruption due to hypercholesterolaemia and hypertriglyceridaemia occurred in 3.8% and 6.9% of patients, respectively. Dose reduction due to hypercholesterolaemia and hypertriglyceridaemia occurred in 1.3% and 2.7% of patients, respectively.

Central nervous system effects

CNS adverse reactions were primarily cognitive effects (27.4%), mood effects (21.4%), speech effects (8.2%) and psychotic effects (6.9%) (see sections 4.2 and 4.4). The most frequent cognitive effect was memory impairment (10.8%), and the most frequent Grade 3 or 4 reactions were confusional state and cognitive disorder (1.6% and 0.7% respectively). The most frequent mood effect was anxiety (7.3%), and the most frequent Grade 3 and 4 reactions were irritability (0.7%), depression (0.4%), anxiety, agitation and bipolar I disorder (0.2% each). The most frequent speech effect was dysarthria (3.8%), and the Grade 3 or 4 reactions were dysarthria (0.4%), slow speech and speech disorder (0.2% each). The most frequent psychotic effect was hallucination (2.7%) and the most frequent Grade 3 or 4 reactions were hallucination auditory and hallucination visual, delusion, acute psychosis and schizophrenic disorder (0.2% each). Median time to onset for cognitive, mood, speech and psychotic effects was 129, 57, 58 and 27 days, respectively. Median duration of cognitive, mood, speech and psychotic effects was 270, 145, 147 and 83.5 days, respectively. Dose interruption and dose reduction due to CNS adverse reactions occurred in 9.2% and 7.6% of patients, respectively. Permanent discontinuation due to CNS adverse reactions occurred in 1.9% of patients.

Elevation of pancreatic enzymes

Lipase and amylase increased were reported in 12.8% and 11.3% of patients. Grade 3 or 4 reactions of lipase and amylase increased were reported in 6.8% and 2.7%, respectively. Median time of onset of lipase and amylase increased were 141 days and 138 days, respectively. Median duration of these events was 28 and 71 days, respectively. Dose interruption due to lipase increased and amylase increased occurred in 3.4% and 2.1% of patients, respectively. Dose reduction due to lipase increased and amylase increased occurred in 0.8% and 0.4%, respectively.

Peripheral neuropathy

Adverse reactions of peripheral neuropathy were reported in 44.2% of patients. Grade 3 or 4 reactions of peripheral neuropathy were reported in 2.6% of patients. Median time to onset and duration of peripheral neuropathy were 85 days and 306 days, respectively. Dose interruption and dose reduction due to peripheral neuropathy occurred in 4% and 4.6% of patients, respectively. Permanent discontinuation due to peripheral neuropathy occurred in 0.6% of patients.

Hypertension

Hypertension was reported in 14.8% of patients. Grade 3 or 4 reactions were reported in in 6.0% of patients. Median time to onset and duration of hypertension were 295 days and 505 days, respectively. Dose interruption due to hypertension occurred in 2.1% of patients.

Hyperglycaemia

Hyperglycaemia was reported in 9.7% of patients. Grade 3 or 4 reactions were reported in 3.7% of patients. Median time to onset and duration of hyperglycaemia were 148 days and 118 days, respectively. Dose interruption occurred in 0.8% of patients.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Treatment of overdose with the medicinal product consists of general supportive measures. Given the dose‑dependent effect on PR interval, ECG monitoring is recommended. There is no antidote for lorlatinib.