LORVIQUA

Treatment with lorlatinib should be initiated and supervised by a physician experienced in the use of anticancer medicinal products. Detection of ALK positive NSCLC is necessary for selection of patients for treatment with lorlatinib because these are the only patients for whom benefit has been shown.

Assessment for ALK positive NSCLC should be performed by laboratories with demonstrated proficiency in the specific technology being utilized. Improper assay performance can lead to unreliable test results. Posology The recommended dose is 100 mg lorlatinib taken orally once daily.

Duration of treatment Treatment with lorlatinib is recommended as long as the patient is deriving clinical benefit from therapy without unacceptable toxicity. Delayed or missed doses If a dose of Lorviqua is missed, then it should be taken as soon as the patient remembers unless it is less than 4 hours before the next dose, in which case the patient should not take the missed dose.

Patients should not take 2 doses at the same time to make up for a missed dose. Dose modifications Dosing interruption or dose reduction may be required based on individual safety and tolerability. Lorlatinib dose reduction levels are summarised below: • First dose reduction: 75 mg taken orally once daily • Second dose reduction: 50 mg taken orally once daily Lorlatinib should be permanently discontinued if the patient is unable to tolerate the 50 mg dose taken orally once daily.

Dose modification recommendations for toxicities and for patients who develop atrioventricular (AV) block are provided in Table 1. Table 1. 7 mmol/L) Introduce or modify lipid-lowering therapyb in accordance with respective prescribing information; continue lorlatinib at same dose.

Table 1. 4 mmol/L) Introduce the use of lipid-lowering therapyb; if currently on lipid-lowering therapy, increase the dose of this therapyb in accordance with respective prescribing information; or change to a new lipid-lowering therapyb.

Continue lorlatinib at the same dose without interruption. 4 mmol/L) Introduce the use of lipid-lowering therapyb or increase the dose of this therapyb in accordance with respective prescribing information or change to a new lipid-lowering therapyb.

Withhold lorlatinib until recovery of hypercholesterolaemia and/or hypertriglyceridaemia to moderate or mild severity grade. Re-challenge at same lorlatinib dose while maximising lipid-lowering therapyb in accordance with respective prescribing information.

Summary of the safety profile The frequencies of adverse reactions are based on all-cause adverse events. 4%). 1% of patients receiving lorlatinib. The most frequent serious adverse drug reactions were cognitive effects and pneumonitis.

1% of patients receiving lorlatinib. The most common adverse reactions that led to dose reductions were oedema, cognitive effects and peripheral neuropathy. 0% of patients receiving lorlatinib. The most frequent adverse reactions that led to permanent discontinuations were cognitive effects, peripheral neuropathy, pneumonitis and psychotic effects.

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

The adverse reactions listed in Table 2 are presented by system organ class and frequency categories, defined using the following convention: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000).

Within each frequency grouping, undesirable effects are presented in order of decreasing medical seriousness. Table 2. 4 11 0 Adverse reactions that represent the same medical concept or condition were grouped together and reported as a single adverse reaction in the table above.

Terms actually reported in the studies and contributing to the relevant adverse reaction are indicated in parentheses, as listed below. a Hypercholesterolaemia (including blood cholesterol increased, hypercholesterolaemia). b Hypertriglyceridaemia (including blood triglycerides increased, hypertriglyceridaemia).

c Mood effects (including affective disorder, affect lability, aggression, agitation, anger, anxiety, bipolar I disorder, depressed mood, depression, depressive symptom, euphoric mood, irritability, mania, mood altered, mood swings, panic attack, personality change, stress).

8). Serum cholesterol and triglycerides should be monitored before initiation of lorlatinib; 2, 4 and 8 weeks after initiating lorlatinib; and regularly thereafter. 2). 8). 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.

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. 2). Left ventricular ejection fraction decrease A decrease in left ventricular ejection fraction (LVEF) has been reported in patients receiving lorlatinib who had baseline and at least one follow-up LVEF assessment.

Based on the available clinical study data, it is not possible to determine a causal relationship between effects on changes in cardiac contractility and lorlatinib. In patients with cardiac risk factors and those with conditions that can affect LVEF, cardiac monitoring, including LVEF assessment at baseline and during treatment, should be considered.

In patients who develop relevant cardiac signs/symptoms during treatment, cardiac monitoring, including LVEF assessment, should be considered. Dosing interruption, dose reduction, or discontinuation should be considered as appropriate if such symptoms are observed.

8). Lorlatinib was studied in a population of patients that excluded, at the discretion of the investigator, those with risk factors for pancreatitis, such as uncontrolled hyperglycaemia or gallstone disease. Risk of pancreatitis should be considered in patients receiving lorlatinib due to concomitant hypertriglyceridemia and/or a potential intrinsic mechanism.

2). 8). g. dyspnoea, cough and fever) should be promptly evaluated for ILD/pneumonitis. 2). 8). Patients should be advised to report any visual symptoms. 2). 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.

1. 5).