LORVIQUA 25mg tablets medication leaflet

Lorviqua 25 mg film-coated tablets

Lorviqua 100 mg film-coated tablets

Lorviqua 25 mg film-coated tablets

Each film-coated tablet contains 25 mg of lorlatinib.

Each film-coated tablet contains 1.58 mg of lactose monohydrate.

Lorviqua 100 mg film-coated tablets

Each film-coated tablet contains 100 mg of lorlatinib.

Each film-coated tablet contains 4.20 mg of lactose monohydrate.

For the full list of excipients, see section 6.1.

Film-coated tablet (tablet).

Lorviqua 25 mg film-coated tablets

Round (8 mm) light pink immediate release film-coated tablet, debossed with “Pfizer” on one side and“25” and “LLN” on the other side.

Lorviqua 100 mg film-coated tablets

Oval (8.5 × 17 mm) dark pink immediate release film-coated tablet, debossed with “Pfizer” onone side and “LLN 100” on the other side.

Lorviqua as monotherapy is indicated for the treatment of adult patients with anaplastic lymphomakinase (ALK)-positive advanced non-small cell lung cancer (NSCLC) previously not treated with an

ALK inhibitor.

Lorviqua as monotherapy is indicated for the treatment of adult patients with ALK-positive advanced

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 TKI.

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

Detection of ALK-positive NSCLC is necessary for selection of patients for treatment with lorlatinibbecause 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 technologybeing utilised. Improper assay performance can lead to unreliable test results.

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

Treatment with lorlatinib should be continued until disease progression or unacceptable toxicity.

If a dose of Lorviqua is missed, then it should be taken as soon as the patient remembers unless it isless 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.

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 takenorally 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/dLor between ULN and 7.75 mmol/L)

OR

Moderate hypercholesterolaemia(cholesterol between 301 and 400 mg/dLor between 7.76 and 10.34 mmol/L) Introduce or modify lipid-lowering therapyb inaccordance with respective prescribing information;

OR continue lorlatinib at same dose.

Mild hypertriglyceridaemia(triglycerides between 150 and 300 mg/dLor 1.71 and 3.42 mmol/L)

OR

Moderate hypertriglyceridaemia

Table 1. Recommended lorlatinib dose modifications for adverse reactions

Adverse reactiona Lorlatinib dosing(triglycerides between 301 and 500 mg/dLor 3.43 and 5.7 mmol/L)

Severe hypercholesterolaemia(cholesterol between 401 and 500 mg/dL

Introduce the use of lipid-lowering therapy b; ifor between 10.35 and 12.92 mmol/L)currently on lipid-lowering therapy, increase the doseof this therapyb in accordance with respective

ORprescribing information; or change to a newlipid-lowering therapyb. Continue lorlatinib at the

Severe hypertriglyceridaemiasame dose without interruption.

(triglycerides between 501 and1,000 mg/dL or 5.71 and 11.4 mmol/L)

Introduce the use of lipid-lowering therapyb orincrease the dose of this therapyb in accordance withrespective prescribing information or change to a newlipid-lowering therapyb. Withhold lorlatinib until

Life-threatening hypercholesterolaemia recovery of hypercholesterolaemia and/or(cholesterol over 500 mg/dL or over hypertriglyceridaemia to moderate or mild severity12.92 mmol/L) grade.

OR Re-challenge at same lorlatinib dose while maximisinglipid-lowering therapyb in accordance with respective

Life-threatening hypertriglyceridaemia prescribing information.(triglycerides over 1,000 mg/dL or over11.4 mmol/L) If severe hypercholesterolaemia and/orhypertriglyceridaemia recur despite maximallipid-lowering therapyb in accordance with respectiveprescribing information, reduce lorlatinib by 1 doselevel.

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

Grade 2: Moderate

Withhold dose until toxicity is less than or equal to

OR Grade 1. Then resume lorlatinib at 1 reduced doselevel.

Grade 3: Severe

Grade 4: Life-threatening/Urgent

Permanently discontinue lorlatinib.intervention indicated

Lipase/Amylase increase

Grade 3: Severe

Withhold lorlatinib until lipase or amylase returns to

ORbaseline. Then resume lorlatinib at 1 reduced doselevel.

Grade 4: Life-threatening/Urgentintervention indicated

Withhold lorlatinib until symptoms have returned to

Grade 1: Mild baseline and consider initiating corticosteroids.

Resume lorlatinib at 1 reduced dose level.

OR

Permanently discontinue lorlatinib if ILD/pneumonitis

Grade 2: Moderate recurs or fails to recover after 6 weeks of lorlatinibhold and steroid treatment.

Grade 3: Severe

Permanently discontinue lorlatinib.

OR

Table 1. Recommended lorlatinib dose modifications for adverse reactions

Adverse reactiona Lorlatinib dosing

Grade 4: Life-threatening/Urgentintervention indicated

PR interval prolongation/Atrioventricular (AV) block

Continue lorlatinib at the same dose withoutinterruption. Consider effects of concomitant

First degree AV block: medicinal products, and assess and correct electrolyte

Asymptomatic imbalance that may prolong PR interval. Monitor

ECG/symptoms potentially related to AV blockclosely.

Withhold lorlatinib. Consider effects of concomitantmedicinal products, and assess and correct electrolyte

First degree AV block: imbalance that may prolong PR interval. Monitor

Symptomatic ECG/symptoms potentially related to AV blockclosely. If symptoms resolve, resume lorlatinib at1 reduced dose level.

Withhold lorlatinib. Consider effects of concomitantmedicinal products, and assess and correct electrolyteimbalance that may prolong PR interval. Monitor

Second degree AV block

ECG/symptoms potentially related to AV block

Asymptomaticclosely. If subsequent ECG does not show seconddegree AV block, resume lorlatinib at 1 reduced doselevel.

Withhold lorlatinib. Consider effects of concomitantmedicinal products, and assess and correct electrolyteimbalance that may prolong PR interval. Refer forcardiac observation and monitoring. Consider

Second degree AV blockpacemaker placement if symptomatic AV block

Symptomaticpersists. If symptoms and the second-degree AV blockresolve or if patients revert to asymptomaticfirst-degree AV block, resume lorlatinib at 1 reduceddose level.

Withhold lorlatinib. Consider effects of concomitantmedicinal products, and assess and correct electrolyteimbalance that may prolong PR interval. Refer forcardiac observation and monitoring. Pacemakerplacement may be indicated for severe symptomsassociated with AV block. If AV block does not

Complete AV block resolve, placement of a permanent pacemaker may beconsidered.

If pacemaker placed, resume lorlatinib at full dose. Ifno pacemaker placed, resume lorlatinib at 1 reduceddose level only when symptoms resolve, and

PR interval is less than 200 msec.

Table 1. Recommended lorlatinib dose modifications for adverse reactions

Adverse reactiona Lorlatinib dosing

Grade 3 (SBP greater than or equal to Withhold lorlatinib until hypertension has recovered to160 mmHg or DBP greater than or equal to Grade 1 or less (SBP less than 140 mmHg and DBP100 mmHg; medical intervention indicated; less than 90 mmHg), then resume lorlatinib at themore than one antihypertensive drug, or same dose.more intensive therapy than previously usedindicated) If Grade 3 hypertension recurs, withhold lorlatinibuntil recovery to Grade 1 or less, and resume at areduced dose.

If adequate hypertension control cannot be achievedwith optimal medical management, permanentlydiscontinue lorlatinib.

Grade 4 (Life-threatening consequences, Withhold lorlatinib until recovery to Grade 1 or less,urgent intervention indicated) and resume at a reduced dose or permanentlydiscontinue lorlatinib.

If Grade 4 hypertension recurs, permanentlydiscontinue lorlatinib.

Grade 3 Withhold lorlatinib until hyperglycaemia is adequatelycontrolled, then resume lorlatinib at the next lower

OR dosage.

Grade 4 (Persistent hyperglycaemia greater If adequate hyperglycaemic control cannot bethan 250 mg/dL despite optimal achieved with optimal medical management,anti-hyperglycaemic therapy) permanently discontinue lorlatinib.

Other adverse reactions

Grade 1: Mild

Consider no dose modification or reduce by 1 dose

ORlevel, as clinically indicated.

Grade 2: Moderate

Withhold lorlatinib until symptoms resolve to less than

Greater than or equal to Grade 3: Severe or equal to Grade 2 or baseline. Then resume lorlatinibat 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, orethyl 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 andgrapefruit juice products may increase lorlatinib plasma concentrations. An alternative concomitantmedicinal product with less potential to inhibit CYP3A4/5 should be considered (see section 4.5). If astrong CYP3A4/5 inhibitor must be co-administered, the starting lorlatinib dose of 100 mg once dailyshould 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 theinitiation of the strong CYP3A4/5 inhibitor and after a washout period of 3 to 5 half-lives of the strong

CYP3A4/5 inhibitor.

Due to the limited data on this population, no dose recommendation can be made for patients aged65 years and older (see section 5.2).

No dose adjustment is needed for patients with normal renal function and mild or moderate renalimpairment [absolute estimated glomerular filtration rate (eGFR): ≥ 30 mL/min]. A reduced dose oflorlatinib 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 forpatients on renal dialysis.

No dose adjustments are recommended for patients with mild hepatic impairment. No information isavailable for lorlatinib in patients with moderate or severe hepatic impairment. Therefore, lorlatinib isnot recommended in patients with moderate to severe hepatic impairment (see section 5.2).

The safety and efficacy of lorlatinib in paediatric patients below 18 years have not been established.

No data are available.

Lorviqua is for oral use.

Patients should be encouraged to take their dose of lorlatinib at approximately the same time each daywith or without food (see section 5.2). The tablets should be swallowed whole (tablets should not bechewed, crushed or split prior to swallowing). No tablet should be ingested if it is broken, cracked, orotherwise not intact.

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).

Hyperlipidaemia

The use of lorlatinib has been associated with increases in serum cholesterol and triglycerides (seesection 4.8). Median time of occurrence of severe increase in serum cholesterol and triglycerides is201 days (range: 29 to 729 days) and 127 days (range: 15 to 1367 days), respectively. Serumcholesterol and triglycerides should be monitored before initiation of lorlatinib; 2, 4 and 8 weeks afterinitiating lorlatinib; and regularly thereafter. Initiate or increase the dose of lipid-lowering medicinalproducts, if indicated (see section 4.2).

Central nervous system effects

Central nervous system (CNS) effects have been observed in patients receiving lorlatinib, includingpsychotic effects and changes in cognitive function, mood, mental status or speech (see section 4.8).

Dose modification or discontinuation may be required for those patients who develop CNS effects (seesection 4.2).

Atrioventricular block

Lorlatinib was studied in a population of patients that excluded those with second-degree orthird-degree AV block (unless paced) or any AV block with PR interval > 220 msec. PR intervalprolongation 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 inpatients with predisposing conditions to the occurrence of clinically significant cardiac events. Dosemodification may be required for those patients who develop AV block (see section 4.2).

Left ventricular ejection fraction decrease

Left ventricular ejection fraction (LVEF) decrease has been reported in patients receiving lorlatinibwho had baseline and at least one follow-up LVEF assessment. Based on the available clinical studydata, it is not possible to determine a causal relationship between effects on changes in cardiaccontractility and lorlatinib. In patients with cardiac risk factors and those with conditions that canaffect LVEF, cardiac monitoring, including LVEF assessment at baseline and during treatment, shouldbe considered. In patients who develop relevant cardiac signs/symptoms during treatment, cardiacmonitoring, including LVEF assessment, should be considered.

Lipase and amylase increase

Elevations of lipase and/or amylase have occurred in patients receiving lorlatinib (see section 4.8).

Median time of occurrence of increase in serum lipase and amylase is 169 days (range: 1 to 1755 days)and 158 days (range: 1 to 1932 days), respectively. Risk of pancreatitis should be considered inpatients receiving lorlatinib due to concomitant hypertriglyceridemia and/or a potential intrinsicmechanism. Patients should be monitored for lipase and amylase elevations prior to the start oflorlatinib 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 haveoccurred with lorlatinib (see section 4.8). Any patient who presents with worsening of respiratorysymptoms indicative of ILD/pneumonitis (e.g. dyspnoea, cough and fever) should be promptlyevaluated for ILD/pneumonitis. Lorlatinib should be withheld and/or permanently discontinued basedon severity (see section 4.2).

Hypertension has been reported in patients receiving lorlatinib (see section 4.8). Blood pressure shouldbe controlled prior to initiation of lorlatinib. Blood pressure should be monitored after 2 weeks and atleast monthly thereafter during treatment with lorlatinib. Lorlatinib should be withheld and resumed ata reduced dose or permanently discontinued based on severity (see section 4.2).

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

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 aspartateaminotransferase (AST) with no increase of total bilirubin and alkaline phosphatase (see section 4.5).

Concomitant use of a strong CYP3A4/5 inducer is contraindicated (see sections 4.3 and 4.5). Noclinically meaningful changes in liver function tests were seen in healthy subjects after receiving acombination of lorlatinib with the moderate CYP3A4/5 inducer modafinil (see section 4.5).

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

During treatment with lorlatinib and for at least 14 weeks after the final dose, male patients withfemale partners of childbearing potential must use effective contraception, including a condom, andmale patients with pregnant partners must use condoms (see section 4.6). Male fertility may becompromised during treatment with lorlatinib (see section 5.3). Men should seek advice on effectivefertility preservation before treatment. Women of childbearing potential should be advised to avoidbecoming pregnant while receiving lorlatinib. A highly effective non-hormonal method ofcontraception is required for female patients during treatment with lorlatinib, because lorlatinib canrender hormonal contraceptives ineffective (see sections 4.5 and 4.6). If a hormonal method ofcontraception 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 (seesection 4.6). It is not known whether lorlatinib affects female fertility.

This medicinal product contains lactose as an excipient. Patients with rare hereditary problems ofgalactose intolerance, total lactase deficiency, or glucose-galactose malabsorption should not take thismedicinal 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”.

In vitro data indicate that lorlatinib is primarily metabolised by CYP3A4 and uridinediphosphate-glucuronosyltransferase (UGT)1A4, with minor contributions from CYP2C8, CYP2C19,

CYP3A5 and UGT1A3.

Effect of medicinal products on lorlatinib

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 mgoral 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 lorlatinibplasma concentrations. The use of a strong CYP3A4/5 inducer with lorlatinib is contraindicated (seesections 4.3 and 4.4). No clinically meaningful changes in liver function test results were seen afteradministration 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 useof modafinil did not have a clinically meaningful effect on lorlatinib pharmacokinetics.

CYP3A4/5 inhibitors

Itraconazole, a strong inhibitor of CYP3A4/5, administered at oral doses of 200 mg once daily for5 days, increased the mean lorlatinib AUCinf by 42% and Cmax by 24% of a single 100 mg oral dose oflorlatinib in healthy volunteers. Concomitant administration of lorlatinib with strong CYP3A4/5inhibitors (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 increaselorlatinib plasma concentrations. Grapefruit products may also increase lorlatinib plasmaconcentrations and should be avoided. An alternative concomitant medicinal product with lesspotential to inhibit CYP3A4/5 should be considered. If a strong CYP3A4/5 inhibitor must beconcomitantly 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 oral2 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 CYP3A4/5substrates with narrow therapeutic indices, including but not limited to alfentanil, ciclosporin,dihydroergotamine, ergotamine, fentanyl, hormonal contraceptives, pimozide, quinidine, sirolimus andtacrolimus, should be avoided since the concentration of these medicinal products may be reduced bylorlatinib (see section 4.4).

Lorlatinib 100 mg once daily for 15 days decreased AUCinf and Cmax of a single oral 100 mg dose ofbupropion (a combined CYP2B6 and CYP3A4 substrate) by 49.5% and 53%, respectively. Thus,lorlatinib is a weak inducer of CYP2B6, and no dose adjustment is necessary when lorlatinib is used incombination with medicinal products that are mainly metabolised by CYP2B6.

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

UGT substrates

Lorlatinib 100 mg once daily for 15 days decreased AUCinf and Cmax of a single oral 500 mg dose ofacetaminophen (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 formedicinal products that are mainly metabolised by UGT. However, patients should be monitored incase 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 narrowtherapeutic indices (e.g. digoxin, dabigatran etexilate) should be used with caution in combinationwith 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. Lorlatinibshould 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 beruled out.

Women of childbearing potential should be advised to avoid becoming pregnant while receivinglorlatinib. A highly effective non-hormonal method of contraception is required for female patientsduring treatment with lorlatinib, because lorlatinib can render hormonal contraceptives ineffective (seesections 4.4 and 4.5). If a hormonal method of contraception is unavoidable, then a condom must beused in combination with the hormonal method. Effective contraception must be continued for at least35 days after completing therapy.

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

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

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

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

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

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

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

The most frequently reported adverse reactions were hypercholesterolaemia (79.0%),hypertriglyceridaemia (67.5%), oedema (55.4%), peripheral neuropathy (44.2%), fatigue (30.7%),weight increased (29.8%), arthralgia (27.8%), cognitive effects (27.4%), diarrhoea (22.7%) and moodeffects (21.4%).

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

Dose reductions due to adverse reactions occurred in 20.1% of patients receiving lorlatinib. The mostcommon adverse reactions that led to dose reductions were oedema, cognitive effects and peripheralneuropathy. Permanent treatment discontinuation associated with adverse reactions occurred in4.0% of patients receiving lorlatinib. The most frequent adverse reactions that led to permanentdiscontinuations were cognitive effects, peripheral neuropathy, pneumonitis and psychotic effects.

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

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 eachfrequency grouping, undesirable effects are presented in order of decreasing medical seriousness.

Table 2. Adverse reactions

System organ class and adverse Frequency category All Grades Grades 3-4reaction % %

Anaemia Very common 19.6 4.4

Hypercholesterolaemiaa Very common 79.0 19.2

Hypertriglyceridaemiab Very common 67.5 20.3

Hyperglycaemia Common 9.7 3.7

Mood effectsc Very common 21.4 1.3

Psychotic effectsd Common 6.9 0.9

Mental status changes Common 1.1 0.9

Cognitive effectse Very common 27.4 3.5

Peripheral neuropathyf Very common 44.2 2.6

Headache Very common 18.6 0.7

Speech effectsg Common 8.2 0.7

Vision disorderh Very common 16.1 0.2

Hypertension Very common 14.8 6.0

Respiratory, thoracic and mediastinaldisorders

Pneumonitisi Common 2.4 0.7

Diarrhoea Very common 22.7 1.8

Nausea Very common 17.6 0.9

Constipation Very common 16.8 0.2

Rashj Very common 14.6 0.2

Proteinuria Common 3.7 0.4

Musculoskeletal and connective tissuedisorders

Arthralgia Very common 27.8 0.7

Myalgiak Very common 15.0 0

General disorders and administration siteconditions

Oedemal Very common 55.4 2.9

Fatiguem Very common 30.7 1.1

Weight increased Very common 29.8 11

Lipase increased Very common 12.8 6.8

Amylase increased Very common 11.3 2.7

Electrocardiogram PR prolongation Uncommon 0.7 0

Adverse reactions that represent the same medical concept or condition were grouped together and reported asa single adverse reaction in the table above. Terms actually reported in the studies and contributing to therelevant 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, hallucination, visual hallucination).e Cognitive effects (including events from SOC Nervous system disorders: amnesia, cognitive disorder,dementia, disturbance in attention, memory impairment, mental impairment; and also including eventsfrom SOC Psychiatric disorders: attention deficit/hyperactivity disorder, confusional state, delirium,disorientation, reading disorder). Within these effects, terms from SOC Nervous system disorders weremore 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, sensorydisturbance).

g Speech effects (dysarthria, slow speech, speech disorder).h Vision disorder (including diplopia, photophobia, photopsia, vision blurred, visual acuity reduced, visualimpairment, 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).

Hypercholesterolaemia/hypertriglyceridaemia

Adverse reactions of increase in serum cholesterol or triglycerides were reported in 79.0% and 67.5%of patients, respectively. Of those, mild or moderate adverse reactions of hypercholesterolaemia orhypertriglyceridaemia occurred in 59.8% and 47.2% of patients, respectively (see section 4.4). Themedian time to onset for hypercholesterolaemia and hypertriglyceridaemia was 15 days (range: 1 to1921 days) and 16 days (range: 1 to 1921 days), respectively. The median duration ofhypercholesterolaemia and hypertriglyceridaemia was 526 and 519 days, 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%), and were generally mild, transient, and reversible spontaneouslyupon dose delay and/or dose reduction (see sections 4.2 and 4.4). The most frequent cognitive effect ofany grade was memory impairment (10.8%), and the most frequent Grade 3 or 4 reactions wereconfusional state and cognitive disorder (1.6% and 0.7%, respectively). The most frequent mood effectof any grade 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 frequentspeech effect of any grade 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 of any gradewas hallucination (2.7%), and the most frequent Grade 3 or 4 reactions were hallucination auditory,hallucination visual, delusion, acute psychosis and schizophrenic disorder (0.2% each). Median time toonset 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 84 days,respectively.

Adverse reactions of hypertension were reported in 14.8% of patients from Study A, CROWN(B7461006) and Study B (B7461027). Of those, mild or moderate adverse reactions of hypertensionoccurred in 8.8% of patients (see section 4.4). The median time to onset of hypertension was 295 days(range: 1 to 1990 days). The median duration of hypertension was 505 days.

Adverse reactions of hyperglycaemia were reported in 9.7% of patients from Study A, CROWN(B7461006) and Study B (B7461027). Of those, mild or moderate adverse reactions ofhyperglycaemia occurred in 6.0% of patients (see section 4.4). The median time to onset ofhyperglycaemia was 148 days (range: 1 to 1637 days). The median duration of hyperglycaemia was118 days.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Treatment of overdose with the medicinal product consists of general supportive measures. Given thedose-dependent effect on PR interval, ECG monitoring is recommended. There is no antidote forlorlatinib.

Pharmacotherapeutic group: anti-neoplastic agents, protein kinase inhibitors, ATC code: L01ED05

Lorlatinib is a selective, adenosine triphosphate (ATP)-competitive inhibitor of ALK and c-rosoncogene 1 (ROS1) tyrosine kinases.

In non-clinical studies, lorlatinib inhibited catalytic activities of non-mutated ALK and clinicallyrelevant ALK mutant kinases in recombinant enzyme and cell-based assays. Lorlatinib demonstratedmarked antitumour activity in mice bearing tumour xenografts that express echinodermmicrotubule-associated protein-like 4 (EML4) fusions with ALK variant 1 (v1), including ALKmutations L1196M, G1269A, G1202R, and I1171T. Two of these ALK mutants, G1202R and I1171T,are known to confer resistance to alectinib, brigatinib, ceritinib, and crizotinib. Lorlatinib was alsocapable of penetrating the blood-brain barrier. Lorlatinib demonstrated activity in mice bearingorthotopic EML4-ALK or EML4-ALKL1196M brain tumour implants.

Previously untreated ALK-positive advanced NSCLC (CROWN Study)

The efficacy of lorlatinib for the treatment of patients with ALK-positive NSCLC who had notreceived prior systemic therapy for metastatic disease was established in an open-label, randomised,active-controlled, multicentre Study B7461006 (CROWN study). Patients were required to have an

Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 and ALK-positive NSCLCas identified by the VENTANA ALK (D5F3) CDx assay. Neurologically stable patients with treatedor untreated asymptomatic CNS metastases, including leptomeningeal metastases, were eligible.

Patients were required to have finished radiation therapy, including stereotactic or partial brainirradiation within 2 weeks prior to randomisation; whole brain irradiation within 4 weeks prior torandomisation.

Patients were randomised 1:1 to receive lorlatinib 100 mg orally once daily or crizotinib 250 mg orallytwice daily. Randomisation was stratified by ethnic origin (Asian vs. non-Asian) and the presence orabsence of CNS metastases at baseline. Treatment on both arms was continued until diseaseprogression or unacceptable toxicity. The major efficacy outcome measure was progression-freesurvival (PFS) as determined by Blinded Independent Central Review (BICR) according to Response

Evaluation Criteria in Solid Tumours (RECIST) version 1.1 (v1.1). Additional efficacy outcomemeasures were overall survival (OS), PFS by investigator assessment, PFS2 and tumour assessmentrelated data by BICR, including objective response rate (ORR), duration of response (DOR) and timeto intracranial progression (IC-TTP). In patients with CNS metastases at baseline, additional outcomemeasures were intracranial objective response rate (IC-ORR) and intracranial duration of response(IC-DOR) all by BICR.

A total of 296 patients were randomised to lorlatinib (n=149) or crizotinib (n=147). The demographiccharacteristics of the overall study population were: median age 59 years (range: 26 to 90 years), age≥ 65 years (35%), 59% female, 49% White, 44% Asian and 0.3% Black. The majority of patients hadadenocarcinoma (95%) and never smoked (59%). Central nervous system metastases as determined by

BICR neuroradiologists were present in 26% (n=78) of patients: of these, 30 patients had measurable

CNS lesions.

Results from the CROWN study are summarised in Table 3. At the data cutoff point, OS and PFS2data were not mature.

Table 3. Overall efficacy results in CROWN study

Lorlatinib Crizotinib

Efficacy parameter N=149 N=147

Median duration of follow-up, months 18 15(95% CI)a (16, 20) (13, 18)

Progression-free survival by BICR

Number of patients with event, n (%) 41 (28%) 86 (59%)

Progressive disease, n (%) 32 (22%) 82 (56%)

Death, n (%) 9 (6%) 4 (3%)

Median, months (95% CI)a NE (NE, NE) 9 (8, 11)

Lorlatinib Crizotinib

Efficacy parameter N=149 N=147

Hazard ratio (95% CI)b 0.28 (0.19, 0.41)p-value* < 0.0001

Overall survival

Number of patients with event, n (%) 23 (15%) 28 (19%)

Median, months (95% CI)a NE (NE, NE) NE (NE, NE)

Hazard ratio (95% CI)b 0.72 (0.41, 1.25)

Progression-free survival by INV

Number of patients with event, n (%) 40 (27%) 104 (71%)

Progressive disease, n (%) 34 (23%) 99 (67%)

Death, n (%) 6 (4%) 5 (3%)

Median, months (95% CI)a NE (NE, NE) 9 (7, 11)

Hazard ratio (95% CI)b 0.21 (0.14, 0.31)p-value* < 0.0001

Overall response by BICR

Overall response rate, n (%) 113 (76%) 85 (58%)(95% CI)c (68, 83) (49, 66)

Time to intracranial progression

Median, months (95% CI)a NE (NE, NE) 16.6 (11, NE)

Hazard ratio (95% CI)b 0.07 (0.03, 0.17)

Duration of response

Number of responders 113 85

Median, months (95% CI)a NE (NE, NE) 11 (9, 13)

Intracranial overall response in patientswith measurable CNS lesions at baseline N=17 N=13

Intracranial response rate, n (%) 14 (82%) 3 (23%)(95% CI)c (57, 96) (5, 54)

Complete response rate 71% 8%

Duration of response

Number of responders 14 3

Median, months (95% CI)a NE (NE, NE) 10 (9, 11)

Intracranial overall response in patientswith any measurable or nonmeasurable

CNS lesions at baseline N=38 N=40

Intracranial response rate, n (%) 25 (66%) 8 (20%)(95% CI)c (49, 80) (9, 36)

Complete response rate 61% 15%

Duration of response

Number of responders 25 8

Median, months (95% CI)a NE (NE, NE) 9 (6, 11)

Abbreviations: BICR=blinded independent central review; CI=confidence interval; CNS=central nervous system;

INV=investigator assessment; N/n=number of patients; NE=not estimable.

* p-value based on 1-sided stratified log-rank test.a Based on the Brookmeyer and Crowley method.b Hazard ratio based on Cox proportional hazards model; under proportional hazards, hazard ratio < 1 indicates areduction in hazard rate in favour of lorlatinib.c Using exact method based on binomial distribution.

Figure 1. Kaplan-Meier plot of progression-free survival by blinded independent centralreview in CROWN study

Abbreviations: CI=confidence interval; N/No.=number of patients.

The benefit from lorlatinib treatment was comparable across subgroups of baseline patient and diseasecharacteristics, including patients with CNS metastases at baseline (n=38, HR=0.2, 95% CI: 0.10-0.43)and patients without CNS metastases at baseline (n=111, HR=0.32, 95% CI: 0.20-0.49).

ALK-positive advanced NSCLC previously treated with an ALK kinase inhibitor

The use of lorlatinib in the treatment of ALK-positive advanced NSCLC after treatment with at leastone second-generation ALK TKI was investigated in Study A, a single-arm, multicentre Phase 1/2study and in Study B, a single-arm, multicentre Phase 4 study. In Study A, a total of 139 patients with

ALK-positive advanced NSCLC after treatment with at least one second-generation ALK TKI wereenrolled in the Phase 2 portion of the study. In Study B, a total of 71 patients with ALK-positiveadvanced NSCLC after one prior ALK TKI treatment (alectinib or ceritinib) were enrolled. In bothstudies, patients received lorlatinib orally at the recommended dose of 100 mg oncedaily, continuously.

In Study A, the primary efficacy endpoint in the Phase 2 portion of the study was ORR, includingintracranial (IC)-ORR, as per Independent Central Review (ICR) according to modified RECIST v1.1.

Secondary endpoints included DOR, IC-DOR, time-to-tumour response (TTR) and PFS. In Study B,the primary efficacy endpoint was ORR, as per ICR according to RECIST v1.1. Secondary endpointsincluded IC-ORR, DOR, IC-DOR, time-to-tumour response (TTR), time-to-tumour progression (TTP)and PFS.

Patient demographics of the 139 ALK-positive advanced NSCLC patients after treatment with at leastone second-generation ALK TKI in Study A were 56% female, 48% White, 38% Asian, and themedian age was 53 years (range: 29-83 years) with 16% of patients ≥ 65 years of age. The ECOGperformance status at baseline was 0 or 1 in 96% patients. Brain metastases were present at baseline in67% of patients. Of the 139 patients, 20% received 1 prior ALK TKI, excluding crizotinib, 47%received 2 prior ALK TKIs and 33% received 3 or more prior ALK TKIs.

Patient demographics of the 71 ALK-positive advanced NSCLC patients who progressed aftertreatment with one prior ALK TKI (alectinib or ceritinib) with or without chemotherapy in Study Bwere 42% female, 76% White, 21% Asian, and the median age was 59 years (range: 26-87 years) with32% of patients ≥ 65 years of age. The ECOG performance status at baseline was 0 in 52% or 1 in48% of patients. Brain metastases were present at baseline in 42% of patients. Of the 71 patients, 84%received alectinib and 16% received ceritinib as their prior ALK TKIs.

The main efficacy results for Study A and Study B are included in Tables 4 and 5.

Table 4. Overall efficacy results in Study A and Study B by prior treatment

One prior ALK TKIa with Two or more prior ALKor without TKIs with or without prior

Efficacy parameterprior chemotherapy chemotherapy(N = 99)b (N = 111)c

Objective response rated 42.4% 39.6%(95% CI) (32.5, 52.8) (30.5, 49.4)

Complete response, n 5 2

Partial response, n 37 42

Duration of response

Median, months NE 9.9(95% CI) (7.8, NE) (5.7, 24.4)

Progression-free survival

Median, months 8.3 6.9(95% CI) (6.3, 16.5) (5.4, 9.5)

Abbreviations: ALK=anaplastic lymphoma kinase; CI=confidence interval; ICR=Independent Central

Review; N/n=number of patients; NE=not estimable; TKI=tyrosine kinase inhibitor.a Alectinib, brigatinib, or ceritinib.b Pooled efficacy results from Study A and Bc Efficacy results from Study A onlyd Per ICR.

Table 5. Intracranial* efficacy results in Study A and Study B by prior treatment

One prior ALK TKIa with Two or more prior ALKor without TKIs with or without prior

Efficacy parameterprior chemotherapy chemotherapy(N = 19)b (N = 48)c

Objective response rated 63.2% 52.1%(95% CI) (38.4, 83.7) (37.2, 66.7)

Complete response, n 4 10

Partial response, n 8 15

Duration of intra-cranialresponse

Median, months NE 12.4(95% CI) (4.2, NE) (6.0, NE)

Abbreviations: ALK=anaplastic lymphoma kinase; CI=confidence interval; ICR=Independent

Central Review; N/n=number of patients; NE=not estimable; TKI= tyrosine kinase inhibitor.

* In patients with at least one measurable brain metastasis at baseline.a Alectinib, brigatinib, or ceritinib.b Pooled efficacy results from Study A and Bc Efficacy results from Study A onlyd Per ICR.

In the overall efficacy population of 210 patients, 86 patients had a confirmed objective response by

ICR with a median TTR of 1.4 months (range: 1.2 to 16.6 months). The ORR for Asians was 48.5%(95% CI: 36.2, 61.0) and 35.7% for non-Asians (95% CI: 27.4, 44.6). Among the 37 patients with aconfirmed IC objective tumour response and at least one measurable brain metastasis at baseline by

ICR, the median IC-TTR was 1.4 months (range: 1.2 to 16.2 months). The IC-ORR was 58.3% for

Asians (95% CI: 36.6, 77.9) and 47.2% for non-Asians (95% CI: 30.4, 64.5).

The European Medicines Agency has waived the obligation to submit the results of studies withlorlatinib in all subsets of the paediatric population in lung carcinoma (small cell and non-small cellcarcinoma) (see section 4.2 for information on paediatric use).

Peak lorlatinib concentrations in plasma are rapidly reached with the median Tmax of 1.2 hoursfollowing a single 100 mg dose and 2.0 hours following multiple dosing of 100 mg once daily.

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 exposurecompared to fasted conditions. Lorlatinib may be administered with or without food.

At 100 mg once daily, the geometric mean (% coefficient of variation [CV]) peak plasmaconcentration was 577 (42) ng/mL and the AUC24 was 5,650 (39) ng h/mL in patients with cancer. Thegeometric mean (% CV) oral clearance was 17.7 (39) L/h.

In vitro binding of lorlatinib to human plasma proteins is 66% with moderate binding to albumin or toα1-acid glycoprotein.

In humans, lorlatinib undergoes oxidation and glucuronidation as the primary metabolic pathways.

In vitro data indicate that lorlatinib is metabolised primarily by CYP3A4 and UGT1A4, with minorcontribution from CYP2C8, CYP2C19, CYP3A5 and UGT1A3.

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

The plasma half-life of lorlatinib after a single 100 mg dose was 23.6 hours. The estimated lorlatinibeffective plasma half-life at steady-state following completion of autoinduction was 14.83 hours.

Following oral administration of a 100 mg radiolabelled dose of lorlatinib, a mean 47.7% of theradioactivity was recovered in urine and 40.9% of the radioactivity was recovered in faeces, withoverall mean total recovery of 88.6%.

Unchanged lorlatinib was the major component of human plasma and faeces, accounting for 44% and9.1% of total radioactivity, respectively. Less than 1% of unchanged lorlatinib was detected in urine.

Furthermore, lorlatinib is an inducer via human pregnane-X-receptor (PXR) and the humanconstitutive androstane receptor (CAR).

At single dose, lorlatinib systemic exposure (AUCinf and Cmax) increased in a dose-related manner overthe 10 to 200 mg dose range. Few data are available over the 10 to 200 mg dose range; however, nodeviation from linearity was observed for AUCinf and Cmax after single dose.

After multiple once daily dose administration, lorlatinib Cmax increased dose-proportionally and

AUCtau increased slightly less than proportionally over the dose range of 10 to 200 mg once daily.

Also, at steady-state lorlatinib plasma exposures are lower than those expected from single dosepharmacokinetics, indicative of a net time-dependent auto-induction effect.

As lorlatinib is metabolised in the liver, hepatic impairment is likely to increase lorlatinib plasmaconcentrations. 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. Populationpharmacokinetic analyses have shown that lorlatinib exposure was not clinically meaningfully alteredin patients with mild hepatic impairment (n = 50). No dose adjustments are recommended for patientswith mild hepatic impairment. No information is available for patients with moderate or severe hepaticimpairment.

Less than 1% of the administered dose is detected as unchanged lorlatinib in urine. Populationpharmacokinetic analyses have shown that lorlatinib steady-state plasma exposure and Cmax valuesslightly increase with worsening baseline renal function. Based on a renal impairment study, nostarting dose adjustments are recommended for patients with mild or moderate renal impairment[eGFR based on Modification of Diet in Renal Disease Study equation (MDRD)-derived eGFR (inmL/min/1.73 m2) × measured body surface area/1.73 ≥ 30 mL/min]. In this study, lorlatinib AUCinfincreased by 41% in subjects with severe renal impairment (absolute eGFR < 30 mL/min) compared tosubjects with normal renal function (absolute eGFR ≥ 90 mL/min). A reduced dose of lorlatinib isrecommended in patients with severe renal impairment, e.g., a once daily oral starting dose of 75 mg(see section 4.2). No information is available for patients on renal dialysis.

Age, gender, race, body weight and phenotype

Population pharmacokinetic analyses in patients with advanced NSCLC and healthy volunteersindicate that there are no clinically relevant effects of age, gender, race, body weight and phenotypesfor CYP3A5 and CYP2C19.

In Study A, 2 patients (0.7%) had absolute Fridericia’s correction QTc (QTcF) values > 500 msec and5 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 without200 mg once daily itraconazole was evaluated in a 2-way crossover study in 16 healthy volunteers. Noincreases in the mean QTc were observed at the mean observed lorlatinib concentrations in this study.

In 295 patients who received lorlatinib at the recommended dose of 100 mg once daily and had a ECGmeasurement in Study A, lorlatinib was studied in a population of patients that excluded those with

QTc interval > 470 msec. In the study population, the maximum mean change from baseline for

PR interval was 16.4 msec (2-sided 90% upper CI 19.4 msec) (see sections 4.2, pct. 4.4 and 4.8). Of these,7 patients had a baseline PR > 200 msec. Among the 284 patients with PR interval < 200 msec, 14%had PR interval prolongation ≥ 200 msec after starting lorlatinib. The prolongation of PR intervaloccurred 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 section 4.2).

The main toxicities observed were inflammation across multiple tissues (skin and cervix of rats andlung, trachea, skin, lymph nodes and/or the oral cavity including mandibular bone of dogs; associatedwith increases in white blood cells, fibrinogen and/or globulin and decreases in albumin) and changesin the pancreas (with increases in amylase and lipase), hepatobiliary system (with increases in liverenzymes), male reproductive system, cardiovascular system, kidneys and gastrointestinal tract,peripheral nerves and the CNS (potential for cognitive functional impairment) at dose equivalent tohuman clinical exposure at the recommended posology. Changes in blood pressure and heart rate, and

QRS complex and PR interval were also observed in animals after acute dosing (approximately2.6 times the human clinical exposure at 100 mg after a single dose based on Cmax). All target organfindings with the exception of hepatic bile duct hyperplasia were partially to fully reversible.

Lorlatinib is not mutagenic but is aneugenic in vitro and in vivo with a no observed effect level foraneugenicity approximately 16.5 times human clinical exposure at 100 mg based on AUC.

Carcinogenicity studies have not been conducted with lorlatinib.

Seminiferous tubular degeneration and/or atrophy in the testes, and epididymal changes (inflammationand/or vacuolation) were observed in the rat and dog. In the prostate, minimal to mild glandularatrophy was observed in dogs at dose equivalent to human clinical exposure at the recommendedposology). The effects on male reproductive organs were partially to fully reversible.

In embryo-foetal toxicity studies, conducted in rats and rabbits, respectively, increasedembryolethality and lower foetal body weights and malformations were observed. Foetal morphologicabnormalities included rotated limbs, supernumerary digits, gastroschisis, malformed kidneys, domedhead, high arched palate and dilation of ventricles of the brain. The exposure at the lowest doses withembryo-foetal effects in animals was equivalent to the human clinical exposure at 100 mg, based on

AUC.

Microcrystalline cellulose

Calcium hydrogen phosphate

Sodium starch glycolate

Magnesium stearate

Hypromellose

Lactose monohydrate

Macrogol

Triacetin

Titanium dioxide (E171)

Iron oxide black (E172)

Iron oxide red (E172)

Not applicable.

3 years.

This medicinal product does not require any special storage conditions.

OPA/Al/PVC blisters with aluminium foil backing containing 10 film-coated tablets.

Lorviqua 25 mg film-coated tablets

Each pack contains 90 film-coated tablets in 9 blisters.

Lorviqua 100 mg film-coated tablets

Each pack contains 30 film-coated tablets in 3 blisters.

Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Pfizer Europe MA EEIG

Boulevard de la Plaine 171050 Bruxelles

Belgium

EU/1/19/1355/002

EU/1/19/1355/003

Date of first authorisation: 6 May 2019

Date of latest renewal: 5 April 2024

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.