Lorviqua · 4.5 Interaction with other medicinal products and other forms of interaction · 1

HOS-098475 · has-adverse-reaction-information · PDF-Seite 12

Summary of the safety profile 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 mood effects (21.4%). Serious adverse 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 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 treated with lorlatinib 100 mg once daily 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 each frequency 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 3-4 reaction % % Blood and lymphatic system disorders Anaemia Very common 19.6 4.4 Metabolism and nutrition disorders Hypercholesterolaemiaa Very common 79.0 19.2 Hypertriglyceridaemiab Very common 67.5 20.3 Hyperglycaemia Common 9.7 3.7 Psychiatric disorders Mood effectsc Very common 21.4 1.3 Psychotic effectsd Common

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HOS-098471 · has-contraindication-information · PDF-Seite 7

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).

HOS-098470 · has-indication-information · PDF-Seite 2

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. 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. 2

HOS-098473 · has-interaction-information · PDF-Seite 9

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 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). 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 did not have a clinically meaningful effect on lorlatinib pharmacokinetics. 9 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 on

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HOS-098474 · has-pregnancy-information · PDF-Seite 11

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. 11

HOS-098472 · has-warning-information · PDF-Seite 7

Hyperlipidaemia The use of lorlatinib has been associated with increases in serum cholesterol and triglycerides (see section 4.8). Median time of occurrence of severe increase in serum cholesterol and triglycerides is 201 days (range: 29 to 729 days) and 127 days (range: 15 to 1367 days), respectively. 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 Central nervous system (CNS) effects have been observed in patients receiving lorlatinib, including psychotic 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 (see section 4.2). 7 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 Left ventricular ejection fraction (LVEF) decrease 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. 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

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