Source: European Medicines Agency (EU) Revision Year: 2020 Publisher: Pfizer Europe MA EEIG, Boulevard de la Plaine 17, 1050 Bruxelles, Belgium
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).
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: 42 to 518 days) and 127 days (range: 15 to 358 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 (CNS) effects have been observed in patients receiving lorlatinib, including changes in cognitive function, mood or speech (see section 4.8). Dose modification or discontinuation may be required for those patients who develop CNS effects (see section 4.2).
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 (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.
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 70 days (range: 7 to 696 days) and 41 days (range: 7 to 489 days), respectively. Risk of pancreatitis should be considered in patients receiving lorlatinib due to concomitant hypertriglyceridemia and/or a potential intrinsic mechanism. Patients should be monitored for lipase and amylase elevations prior to the start of lorlatinib treatment and regularly thereafter as clinically indicated (see section 4.2).
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).
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 (see sections 4.3 and 4.5).
Concomitant use with moderate CYP3A4/5 inducers should be avoided, if possible, as they may also reduce lorlatinib plasma concentrations (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, 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).
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.
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.
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 uridine diphosphate-glucuronosyltransferase (UGT)1A4, with minor contributions from CYP2C8, CYP2C19, CYP3A5 and UGT1A3.
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 (AUC) 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). Concomitant use with moderate CYP3A4/5 inducers should be avoided, if possible, as they may also reduce lorlatinib plasma concentrations (see section 4.4).
Itraconazole, a strong inhibitor of CYP3A4/5, administered at oral doses of 200 mg once daily for 5 days, increased the mean lorlatinib AUC by 42% and Cmax by 24% of a single 100 mg oral dose of lorlatinib in healthy volunteers. Concomitant administration of lorlatinib with strong 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).
In vitro studies indicated that lorlatinib is a time-dependent inhibitor as well as an inducer of CYP3A4/5 and it activates the human pregnane-X-receptor (PXR), with the net effect in vivo being induction. Concurrent administration of lorlatinib in patients resulted in decreased oral midazolam AUC when midazolam was administered alone, suggesting that lorlatinib is an inducer of CYP3A4/5. Lorlatinib 150 mg orally once daily for 15 days decreased AUC inf 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).
Lorlatinib may have the potential to inhibit CYP2C9.
In vitro studies also indicated that lorlatinib is an inducer of CYP2B6 and activates the human constitutive androstane receptor (CAR). Concomitant administration of lorlatinib with CYP2B6 substrates (e.g. bupropion, efavirenz) may result in reduced plasma concentrations of the CYP2B6 substrate. In vitro, lorlatinib has a low potential to cause drug-drug interactions by induction of CYP1A2.
In vitro studies indicated that lorlatinib may have the potential to inhibit UGT1A1. In vitro studies with drug transporters In vitro studies indicated that lorlatinib may have the potential to inhibit P-glycoprotein (P-gp, systemically and at the gastrointestinal [GI] tract), BCRP (GI tract), OATP1B1, OATP1B3, OCT1, MATE1 and OAT3 at clinically relevant concentrations.
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.
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.
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.
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.
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).
The most frequently reported adverse reactions were hypercholesterolaemia (84.4%), hypertriglyceridaemia (67.1%), oedema (54.6%), peripheral neuropathy (47.8%), cognitive effects (28.8%), fatigue (28.1%), weight increased (26.4%) and mood effects (22.7%).
Dose reductions due to adverse reactions occurred in 23.4% of patients receiving lorlatinib. The most common adverse reactions that led to dose reductions were oedema and peripheral neuropathy. Permanent treatment discontinuation associated with adverse reactions occurred in 3.1% of patients receiving lorlatinib. The most frequent adverse reaction that led to permanent discontinuations was cognitive effects.
Table 2 presents adverse reactions occurring in 295 adult patients treated with lorlatinib 100 mg once daily with advanced NSCLC from Study A.
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:
Adverse reactions of increase in serum cholesterol or triglycerides were reported in 84.4% and 67.1% of patients, respectively. Of those, mild or moderate adverse reactions of hypercholesterolaemia or hypertriglyceridaemia occurred in 67.8% and 50.5% of patients, respectively (see section 4.4). The median time to onset for both hypercholesterolaemia and hypertriglyceridaemia was 15 days (range: 1 to 399 days). The median duration of hypercholesterolaemia and hypertriglyceridaemia was 381 and 405 days, respectively.
CNS adverse reactions were primarily cognitive effects (28.8%), mood effects (22.7%), and speech effects (9.8%), and were generally mild, transient, and reversible spontaneously upon dose delay and/or dose reduction (see sections 4.2 and 4.4). The most common cognitive effect of any grade was memory impairment (11.5%), and the most common Grade 3 or 4 reactions were cognitive effect and confusional state (0.7% each). The most common mood effect of any grade was irritability (6.1%), which was also the most common Grade 3 or 4 reaction (1.0%). The most common speech effect of any grade was dysarthria (4.1%), and the most common Grade 3 or 4 reaction was slow speech (0.3%). Median time to onset for cognitive, mood and speech effects was 92, 44 and 42 days, respectively. Median duration of cognitive, mood and speech effects was 224, 83 and 106 days, respectively.
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 national reporting system listed in Appendix V.
Not applicable.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
