LORVIQUA Film-coated tablet Ref.[7603] Active ingredients: Lorlatinib

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 104 days (range: 29 to 518 days) and 120 days (range: 15 to 780 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).

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 141 days (range: 1 to 1091 days) and 138 days (range: 1 to 1112 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).

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).

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 according to national guidelines. Lorlatinib should be withheld and resumed at a reduced dose or permanently discontinued based on severity (see section 4.2).

Drug-drug interactions

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). 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).

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

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”.

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 (AUC_inf) by 85% and C_max 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.

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 AUC_inf by 42% and C_max 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 AUC_inf and C_max 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 AUC_inf and C_max of a single oral 100 mg dose of bupropion (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 in combination with medicinal products that are mainly metabolised by CYP2B6.

CYP2C9 substrates

Lorlatinib 100 mg once daily for 15 days decreased AUC_inf and C_max 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 AUC_inf and C_max 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 AUC_inf and C_max of a single oral dose of 60 mg fexofenadine [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.

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.

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).

Summary of the safety profile

The most frequently reported adverse reactions were hypercholesterolaemia (81.1%), hypertriglyceridaemia (67.2%), oedema (55.7%), peripheral neuropathy (43.7%), weight increased (30.9%), cognitive effects (27.7%), fatigue (27.3%), arthralgia (23.5%), diarrhoea (22.9%) and mood effects (21.0%).

Serious adverse reactions were reported in 7.4% of patients receiving lorlatinib. The most frequent serious adverse drug reactions were cognitive effects and pneumonitis.

Dose reductions due to adverse reactions occurred in 20.0% 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 3.2% 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 476 adult patients treated with lorlatinib 100 mg once daily with advanced NSCLC from Study A (N=327) and CROWN study (N=149).

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 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, 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 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 81.1% and 67.2% of patients, respectively. Of those, mild or moderate adverse reactions of hypercholesterolaemia or hypertriglyceridaemia occurred in 62.8% and 47.9% of patients, respectively (see section 4.4). The median time to onset for both hypercholesterolaemia and hypertriglyceridaemia was 15 days (hypercholesterolaemia range: 1 to 784 days; hypertriglyceridaemia range: 1 to 796 days). The median duration of hypercholesterolaemia and hypertriglyceridaemia was 451 and 427 days, respectively.

Central nervous system effects

CNS adverse reactions were primarily cognitive effects (27.7%), mood effects (21.0%), speech effects (8.2%) and psychotic effects (6.5%), and were generally mild, transient, and reversible spontaneously upon dose delay and/or dose reduction (see sections 4.2 and 4.4). The most frequent cognitive effect of any grade was memory impairment (11.3%), and the most frequent Grade 3 or 4 reactions were confusional state and cognitive disorder (1.7% and 0.8%, respectively). The most frequent mood effect of any grade was anxiety (6.5%), and the most frequent Grade 3 and 4 reactions were irritability and depression (0.8% and 0.4%, respectively). The most frequent speech effect of any grade was dysarthria (4.0%), and the Grade 3 or 4 reactions were dysarthria, slow speech and speech disorder (0.2% each). The most frequent psychotic effect of any grade was hallucination (3.7%) and the most frequent Grade 3 or 4 reactions were hallucination, hallucination auditory and hallucination visual (0.3% each). Median time to onset for cognitive, mood, speech and psychotic effects was 109, 43, 49 and 23 days, respectively. Median duration of cognitive, mood, speech and psychotic effects was 223, 143, 147 and 74 days, respectively.

Hypertension

Adverse reactions of hypertension were reported in 13% of patients from Study A and CROWN (B7461006). Of those, mild or moderate adverse reactions of hypertension occurred in 6.9% of patients (see section 4.4). The median time to onset of hypertension was 208 days (range: 1 to 1028 days). The median duration of hypertension was 219 days.

Hyperglycaemia

Adverse reactions of hyperglycaemia were reported in 9.2% of patients from Study A and CROWN (B7461006). Of those, mild or moderate adverse reactions of hyperglycaemia occurred in 6.1% of patients (see section 4.4). The median time to onset of hyperglycaemia was 145 days (range: 1 to 1058 days). The median duration of hyperglycaemia was 113 days.

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 national reporting system listed in Appendix V.

Not applicable.