Lorviqua

Lorlatinib.

Each 25 mg film-coated tablet contains 25 mg of lorlatinib.
Each 100 mg film-coated tablet contains 100 mg of lorlatinib.
Excipients/Inactive Ingredients: Tablet core contains: Microcrystalline Cellulose, Dibasic Calcium Phosphate Anhydrous, Sodium Starch Glycolate, Magnesium Stearate.
Film-coating contains: HPMC 2910/Hypromellose, Lactose Monohydrate, Macrogol 4000/PEG 3350, Triacetin, Titanium Dioxide, Ferrosoferric Oxide/Black Iron Oxide, Iron Oxide Red.

Pharmacology: Pharmacodynamics: Lorlatinib is a selective, adenosine triphosphate (ATP)-competitive, brain-penetrant, small molecule inhibitor of ALK and ROS1 tyrosine kinases that addresses mechanisms of resistance following previous treatment with ALK inhibitor therapy.
In nonclinical studies, lorlatinib potently inhibited catalytic activities of non-mutated ALK and a broad range of clinically relevant ALK mutant kinases in recombinant enzyme and cell-based assays. The ALK mutations analyzed included those conferring resistance to other ALK inhibitors, including alectinib, brigatinib, ceritinib, and crizotinib.
Lorlatinib demonstrated marked antitumor activity at low nanomolar free plasma concentrations in mice bearing tumor xenografts that express echinoderm microtubule-associated protein-like 4 (EML4) fusions with ALK variant 1 (v1), including ALK mutations L1196M, G1269A, G1202R, and I1171T. Two of these ALK mutants, G1202R and I1171T, are known to confer resistance to first and second generation ALK inhibitors. Lorlatinib is also capable of penetrating the blood-brain barrier and achieved efficacious brain exposure in mice and rat. In mice bearing orthotopic EML4-ALK or EML4-ALK^L1196M brain tumor implants, lorlatinib caused tumor shrinkage and prolonged survival. The overall antitumor efficacy of lorlatinib was dose-dependent and strongly correlated with inhibition of ALK phosphorylation.
Clinical studies: Previously untreated ALK-positive advanced NSCLC (CROWN Study): The efficacy of lorlatinib for the treatment of patients with ALK-positive NSCLC who had not received prior systemic therapy for metastatic disease was established in an open-label, randomized, active-controlled, multicenter Study B7461006 (CROWN Study). Patients were required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 and ALK-positive NSCLC as identified by the VENTANA ALK (D5F3) CDx assay. Neurologically stable patients with treated or untreated asymptomatic CNS metastases, including leptomeningeal metastases, were eligible. Patients were required to have finished radiation therapy, including stereotactic or partial brain irradiation within 2 weeks prior to randomization; whole brain irradiation within 4 weeks prior to randomization.
Patients were randomized 1:1 to receive lorlatinib 100 mg orally once daily or crizotinib 250 mg orally twice daily. Randomization was stratified by ethnic origin (Asian vs. non-Asian) and the presence or absence of CNS metastases at baseline. Treatment on both arms was continued until disease progression or unacceptable toxicity. The major efficacy outcome measure was progression-free survival (PFS) as determined by Blinded Independent Central Review (BICR) according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (v1.1). Additional efficacy outcome measures were overall survival (OS), PFS by investigator assessment, PFS2 and tumour assessment related data by BICR, including objective response rate (ORR), duration of response (DOR) and time to intracranial progression (IC-TTP). In patients with measurable CNS metastases at baseline, additional outcome measures were intracranial objective response rate (IC-ORR) and intracranial duration of response (IC-DOR) all by BICR.
A total of 296 patients were randomized to lorlatinib (n=149) or crizotinib (n=147). The demographic characteristics 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 had adenocarcinoma (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 are summarized in Table 1. At the data cutoff point OS and PFS2 data were not mature. (See Table 1 and Figure 1.)

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The benefit from lorlatinib treatment was comparable across subgroups of baseline patient and disease characteristics, 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 LORVIQUA in the treatment of ALK-positive advanced NSCLC previously treated with 1 or more ALK TKIs was investigated in Study B7461001, a single-arm, multicenter Phase 1/2 study. A total of 197 patients with ALK-positive advanced NSCLC previously treated with 1 or more ALK TKIs were enrolled in the Phase 2 portion of the study. Patients received LORVIQUA orally at the recommended dose of 100 mg once daily, continuously.
The primary efficacy endpoint in the Phase 2 portion of the study was ORR, including intracranial ORR, as per Independent Central Review (ICR) according to modified Response Evaluation Criteria in Solid Tumors (modified RECIST 1.1). Secondary endpoints included DOR, intracranial DOR, time-to-tumor response (TTR), and progression-free survival (PFS).
Patient demographics of the 197 ALK-positive advanced NSCLC patients previously treated with 1 or more ALK TKIs, were 59% female, 49% Caucasian, 36% Asian and the mean age was 53 years (range: 29 to 85 years) with 19% ≥65 years of age. The Eastern Cooperative Oncology Group (ECOG) performance status at baseline was 0 or 1 in 97% of patients and 2 in 4% of patients. Brain metastases were present at baseline in 62% of patients. All 197 patients had received prior systemic therapy, 20% received 1, 28% received 2, 19% received 3, and 34% received 4 or more prior systemic therapies. Of the 197 patients, 44% received 1 prior ALK TKI, 33% received 2 prior ALK TKIs, and 23% received 3 or more prior ALK TKIs.
The main efficacy results for Study B7461001 are included in Tables 2 and 3. (See Tables 2 and 3.)

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Among the 93 patients with a confirmed objective response by ICR, the median TTR was 1.4 months (range: 1.1 to 11.0 months). Among the 70 patients with a confirmed objective tumor response by ICR, the median intracranial-TTR was 1.4 months (range: 1.1 to 6.2 months).
Pharmacokinetics: Absorption: Peak lorlatinib concentrations in plasma are rapidly reached with the median T_max of 1.2 hours following a single 100 mg dose and 2.0 hours following 100 mg once daily multiple dosing.
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 exposure compared to overnight fasting (AUC_inf ratio of 104.7%; 90% CI for the ratio: 101.3%, 108.3%). Lorlatinib may be administered with or without food. The proton-pump inhibitor rabeprazole had a minimal effect on lorlatinib plasma exposure (AUC_inf ratio of 100.9%; 90% CI for the ratio: 97.6%, 104.3%). No dose adjustment is recommended when lorlatinib is taken with proton-pump inhibitors, H₂-receptor antagonists or locally-acting antacids.
After multiple once daily dose administration, lorlatinib C_max increased dose-proportionally and AUC_tau increased slightly less than proportionally over the dose range of 10 to 200 mg once daily. At the 100 mg once daily lorlatinib dose, the geometric mean peak plasma concentration was 577 ng/mL and the AUC₂₄ 5650 ng·h/mL in patients with cancer. The geometric mean oral clearance was 17.7 L/h. Lorlatinib oral clearance increased at steady-state compared to single dose, indicating autoinduction.
Distribution: In vitro binding of lorlatinib to human plasma proteins is 66% with moderate binding to albumin to α₁-acid glycoprotein.
Metabolism: In humans, lorlatinib undergoes oxidation and glucuronidation as the primary metabolic pathways. In vitro data indicate that lorlatinib is metabolized primarily by CYP3A4 and UGT1A4, with minor contribution from CYP2C8, CYP2C19, CYP3A5, and UGT1A3.
In plasma, a benzoic acid metabolite of lorlatinib resulting from the oxidative cleavage of the amide and aromatic ether bonds of lorlatinib was observed as a major metabolite, accounting for 21% of the circulating radioactivity. The oxidative cleavage metabolite is pharmacologically inactive.
Elimination: The plasma half-life of lorlatinib after a single 100 mg dose was 23.6 hours. Following oral administration of a 100 mg radiolabeled dose of lorlatinib, a mean 47.7% of the radioactivity was recovered in urine and 40.9% of the radioactivity was recovered in feces, with overall mean total recovery of 88.6%.
Unchanged lorlatinib was the major component of human plasma and feces, accounting for 44% and 9.1% of total radioactivity in plasma and feces, respectively. Less than 1% of unchanged lorlatinib was detected in urine.
Cardiac electrophysiology: QT interval: In Study B7461001, 2 patients (0.7%) had absolute Fridericia's correction QTc (QTcF) values >500 msec, and 5 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 without 200 mg once daily itraconazole was evaluated in a 2-way crossover study in 16 healthy volunteers. No increases in the mean QTc interval 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 in Study B7461001, no large mean increases from baseline in the QTcF interval (i.e., >20 ms) were detected.
PR interval: In 295 patients who received lorlatinib at the recommended dose of 100 mg once daily and had a ECG measurement in Study B7461001, the maximum mean change from baseline for PR interval was 16.4 ms (2-sided 90% upper CI: 19.4 ms). Among the 284 patients with PR interval <200 ms, 14% had PR interval prolongation ≥200 ms after starting lorlatinib. The prolongation of PR interval occurred 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 Dosage & Administration).
Special populations: Hepatic impairment: As lorlatinib is metabolized in the liver, hepatic impairment is likely to increase lorlatinib plasma concentrations. Clinical studies that were conducted excluded patients with AST or ALT >2.5 x ULN, or if due to underlying malignancy, >5.0 x ULN or with total bilirubin >1.5 x ULN. Population pharmacokinetic analyses have shown that lorlatinib exposure was not clinically meaningfully altered in patients with mild hepatic impairment (n=50). No dose adjustments are recommended for patients with mild hepatic impairment (see Dosage & Administration). Lorlatinib has not been studied in patients with moderate or severe hepatic impairment.
Renal impairment: Less than 1% of the administered dose is detected as unchanged lorlatinib in urine. Clinical studies excluded patients with serum creatinine >1.5 x ULN or estimated CL_cr <60 mL/min. Population pharmacokinetic analyses have shown that lorlatinib exposure was not clinically meaningfully altered in patients with mild (n=103) or moderate (n=41) renal impairment (CL_cr ≥30 mL/min). Based on a renal impairment study, no dose adjustments are recommended for patients with mild or moderate renal impairment [absolute eGFR based on Modification of Diet in Renal Disease Study equation (MDRD) derived eGFR (in mL/min/1.73 m²) x measured body surface area/1.73 ≥30 mL/min]. In this study, lorlatinib AUC_inf increased by 41% in subjects with severe renal impairment (absolute eGFR <30 mL/min) compared to subjects with normal renal function (absolute eGFR ≥90 mL/min). A reduced dose of LORVIQUA is recommended in patients with severe renal impairment, e.g. a starting dose of 75 mg taken orally once daily (see Dosage & Administration).
Elderly (≥65 years): Out of the 476 patients who received lorlatinib 100 mg orally once daily in Study B7461001(N=327) and Study B7461006 (N=149), 25% of patients were aged 65 years or older. Of the 215 patients in the efficacy population in Study B7461001, 17.7% of patients were aged 65 years or older, and of the 149 patients in the lorlatinib arm of the CROWN Study, 40% were aged 65 years or older. No clinically relevant differences in safety or efficacy were observed between patients aged greater than or equal to 65 years of age and younger patients; no dose adjustments are recommended in elderly patients (see Dosage & Administration).
Gender, race, body weight, and phenotype: Population pharmacokinetic analyses in patients with advanced NSCLC and healthy volunteers indicate that there are no clinically relevant effects of age, gender, race, body weight, or phenotypes for CYP3A5 and CYP2C19.
Toxicology: Preclinical Safety Data: Repeat-dose toxicity: The main toxicities observed were inflammation across multiple tissues (with increases in white blood cells), and changes in the pancreas (with increases in amylase and lipase), hepatobiliary system (with increases in liver enzymes), male reproductive system, cardiovascular system, kidneys and gastrointestinal tract, and peripheral nerves and the CNS (potential for cognitive functional impairment) (approximately 4.6 to 21 times the human clinical exposure at 100 mg based on AUC for all toxicities). Changes in blood pressure and heart rate, and QRS and PR interval prolongation were also observed in animals after acute dosing (approximately 2.6 times the human clinical exposure at 100 mg after a single dose based on C_max). All target organ findings with the exception of the hepatic bile duct hyperplasia (approximately 7.1 to 21 times the human clinical exposure at 100 mg based on AUC) were partially to fully reversible.
Genotoxicity: Lorlatinib was not mutagenic in a bacterial reverse mutation (Ames) assay. Lorlatinib induced micronuclei via an aneugenic mechanism in human lymphoblastoid TK6 cells in vitro and in the bone marrow of rats. The exposure of animals at the no observed effect level for aneugenicity was approximately 16.5 times human clinical exposure at 100 mg based on AUC.
Carcinogenicity: Carcinogenicity studies have not been conducted with lorlatinib.
Reproductive toxicity: Effects on male reproductive organs (testis, epididymis, and prostate) were observed in animals (approximately 3.9 to 1.6 times the human clinical exposure at 100 mg based on AUC). The effects on male reproductive organs were fully or partially reversible.
In embryo-fetal toxicity studies increased embryo lethality, and lower fetal body weights were observed. Fetal morphologic abnormalities included rotated limbs, supernumerary digits, gastroschisis, malformed kidneys, domed head, high arched palate, and dilation of ventricles of the brain. The lowest doses with embryo-fetal effects in animals correlated with 0.6 to 1.1 times the human clinical exposure at 100 mg, based on AUC.

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.

Treatment with lorlatinib should be initiated and supervised by a physician experienced in the use of anticancer medicinal products.
ALK testing: 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.
Recommended dosing: The recommended dose schedule of LORVIQUA is 100 mg taken orally once daily continuously. Continue treatment as long as the patient is deriving clinical benefit from therapy.
LORVIQUA may be taken with or without food (see Pharmacology: Pharmacokinetics under Actions).
Patients should be encouraged to take their dose of lorlatinib at approximately the same time each day. Tablets should be swallowed whole (tablets should not be chewed, crushed or split prior to swallowing). No tablet should be ingested if it is broken, cracked, or otherwise not intact.
If a dose of lorlatinib 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 and/or dose reduction may be required based on individual safety and tolerability. Dose reduction levels are summarized as follows.
First dose reduction: LORVIQUA 75 mg taken orally once daily.
Second dose reduction: LORVIQUA 50 mg taken orally once daily.
LORVIQUA should be permanently discontinued if the patient is unable to tolerate LORVIQUA 50 mg taken orally once daily.
Dose modification recommendations for toxicities and for patients who develop first-degree, second-degree, or complete atrioventricular (AV) block are provided in Table 4. (See Tables 4A and 4B.)

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Strong cytochrome P-450 (CYP)3A inhibitors: Concurrent use of LORVIQUA with strong CYP3A inhibitors may increase lorlatinib plasma concentrations. An alternative concomitant medicinal product with less potential to inhibit CYP3A should be considered (see Interactions and Pharmacology: Pharmacokinetics under Actions). If a strong CYP3A inhibitor must be administered concomitantly, the starting LORVIQUA dose of 100 mg once daily should be reduced to once daily 75 mg dose. If concurrent use of a strong CYP3A inhibitor is discontinued, LORVIQUA should be resumed at the dose used prior to the initiation of the strong CYP3A inhibitor and after a washout period of 3 to 5 half-lives of the strong CYP3A inhibitor.
Hepatic impairment: No dose adjustments are recommended for patients with mild hepatic impairment. Limited information is available for lorlatinib in patients with moderate or severe hepatic impairment. Therefore, LORVIQUA is not recommended in patients with moderate to severe hepatic impairment (see Pharmacology: Pharmacokinetics under Actions).
Renal impairment: No dose adjustment is needed for patients with mild or moderate renal impairment [absolute estimated glomerular filtration rate (eGFR): ≥30 mL/min]. A reduced dose of LORVIQUA is recommended in patients with severe renal impairment (absolute eGFR <30 mL/min), e.g., a starting dose of 75 mg taken orally once daily (see Pharmacology: Pharmacokinetics under Actions).
Elderly (≥65 years): The limited data on the safety and efficacy of lorlatinib in patients aged 65 years and older do not suggest that a dose adjustment is required in elderly patients (see Pharmacology: Pharmacokinetics under Actions).
Pediatric patients: The safety and efficacy of lorlatinib in pediatric patients has not been established.

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

Hypersensitivity to lorlatinib or to any of the excipients listed in Description.
Concomitant use of strong CYP3A inducers with lorlatinib is contraindicated due to the potential for serious hepatotoxicity (aspartate aminotransferase [AST] and alanine aminotransferase [ALT] elevations) (see Precautions and Interactions).

Hyperlipidemia: The use of lorlatinib has been associated with increases in serum cholesterol and triglycerides (see Adverse Reactions). Serum cholesterol and triglycerides should be monitored before initiation of lorlatinib; 2, 4, and 8 weeks after initiating lorlatinib; and periodically thereafter. Initiation, or increase in the dose, of lipid-lowering agents is required (see Dosage & Administration).
Central nervous system effects: Central nervous system (CNS) effects have been observed in patients receiving lorlatinib including psychotic effects, changes in cognitive function, mood, speech, and mental status changes, (see Adverse Reactions). Dose modification or discontinuation may be required for those patients who develop CNS effects (see Dosage & Administration).
Atrioventricular block: PR interval prolongation and atrioventricular (AV) block events have been reported in patients receiving LORVIQUA. 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 Dosage & Administration).
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 Adverse Reactions). 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 Dosage & Administration).
Pneumonitis: Severe or life-threatening pulmonary adverse drug reactions consistent with pneumonitis have occurred with lorlatinib (see Adverse Reactions). Any patient who presents with worsening of respiratory symptoms indicative of pneumonitis (e.g. dyspnea, cough, and fever) should be promptly evaluated for pneumonitis. Lorlatinib should be withheld and/or permanently discontinued based on severity (see Dosage & Administration).
Hypertension: Hypertension has been reported in patients receiving lorlatinib (see Adverse Reactions).
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 Dosage & Administration).
Hyperglycemia: Hyperglycemia has occurred in patients receiving lorlatinib (see Adverse Reactions).
Fasting serum glucose should be assessed prior to initiation of lorlatinib and monitored periodically thereafter. Lorlatinib should be withheld and resumed at a reduced dose or permanently discontinued based on severity (see Dosage & Administration).
Drug-drug interactions: In a study conducted in healthy volunteers, the concomitant use of lorlatinib and rifampin, a strong CYP3A inducer was associated with increases of ALT and AST with no increase of total bilirubin and alkaline phosphatase (see Interactions). Concomitant use of any strong CYP3A inducer is contraindicated (see Contraindications and Interactions). Any strong CYP3A inducers have to be discontinued for at least 3 plasma half-lives of the strong CYP3A inducer before lorlatinib treatment is started. No clinically meaningful changes in liver function tests were seen in healthy subjects after receiving a combination of lorlatinib with the moderate CYP3A inducer modafinil (see Interactions).
Effects on Ability to Drive and Use Machines: 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 Adverse Reactions).
Use in Pregnancy: Fertility and pregnancy: Based on animal data and mechanism of action, there is a risk of fetal harm if exposed to LORVIQUA (see Pharmacology: Pharmacodynamics and Pharmacology: Toxicology: Preclinical Safety Data under Actions). Women of childbearing potential should be advised to avoid becoming pregnant while receiving LORVIQUA. A highly effective non-hormonal method of contraception is required for female patients during treatment with LORVIQUA, because lorlatinib can render hormonal contraceptives ineffective (see Interactions and Use in Pregnancy & Lactation). 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 21 days after completing therapy.
During treatment with LORVIQUA and for at least 97 days after the final dose, male patients with female partners of reproductive potential must use effective contraception, including a condom, and male patients with pregnant partners must use condoms (see Use in Pregnancy & Lactation). Male fertility may be compromised during treatment with lorlatinib (see Pharmacology: Toxicology: Preclinical Safety Data under Actions). Men should seek advice on effective fertility preservation before treatment.

Women of childbearing potential/Contraception in females and males: Women of childbearing potential should be advised to avoid becoming pregnant while receiving LORVIQUA. A highly effective nonhormonal method of contraception is required for female patients during treatment with LORVIQUA, because lorlatinib can render hormonal contraceptives ineffective (see Precautions and Interactions). 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 21 days after completing therapy.
During treatment with LORVIQUA and for at least 97 days after the final dose, advise male patients with female partners of reproductive potential to use effective contraception, including a condom, and advise male patients with pregnant partners to use condoms.
Pregnancy: Studies in animals have shown embryo-fetal toxicity (see Pharmacology: Toxicology: Preclinical Safety Data under Actions). There are no data in pregnant women using LORVIQUA. LORVIQUA may cause fetal harm when administered to a pregnant woman.
LORVIQUA is not recommended during pregnancy or for women of childbearing potential not using contraception.
Breastfeeding: It is not known whether lorlatinib and its metabolites are excreted in human milk. A risk to the new born child cannot be excluded.
LORVIQUA should not be used during breastfeeding. Breastfeeding should be discontinued during treatment with LORVIQUA and for 7 days after the last dose.
Fertility: Based on nonclinical safety findings, male fertility may be compromised during treatment with LORVIQUA (see Pharmacology: Toxicology: Preclinical Safety Data under Actions). It is not known whether LORVIQUA affects female fertility. Men should seek advice on effective fertility preservation before treatment.

Summary of safety profile: The data described as follows reflect exposure to LORVIQUA in 476 adult patients with ALK-positive or c-ros oncogene 1 (ROS1)-positive metastatic NSCLC who received LORVIQUA 100 mg orally once daily in single-arm Study B7461001 or randomized, open label, active controlled Phase 3 Study B7461006.
The median duration of treatment was 16.3 months (range: 0 day to 55 months), the median age was 55 years (range: 19 to 90 years), and 25% of patients were older than 65 years. A total of 57% of patients were female, 50% of patients were White, 39% of patients were Asian, and 1% were Black.
The most frequently reported adverse drug 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 drug 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 drug reactions occurred in 20.0% of patients receiving lorlatinib. The most common adverse drug reactions that led to dose reductions were oedema and peripheral neuropathy. Permanent treatment discontinuation associated with adverse drug reactions occurred in 3.2% of patients receiving lorlatinib. The most frequent adverse drug reactions that led to a permanent discontinuation were cognitive effects, peripheral neuropathy, and pneumonitis.
The adverse reactions listed in Table 5 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. (See Table 5.)

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Description of selected adverse drug reactions: Hypercholesterolaemia/Hypertriglyceridaemia: In clinical trials of patients with ALK-positive or c-ros oncogene 1 (ROS1) positive metastatic NSCLC, adverse drug reactions of increase in serum cholesterol or triglycerides were reported in 81.1% and 67.2% of patients, respectively. Mild or moderate adverse drug reactions of hypercholesterolaemia or hypertriglyceridaemia occurred in 62.8% and 47.9% of patients, respectively. No patient was discontinued from treatment with lorlatinib due to hypercholesterolaemia or hypertriglyceridaemia (see Dosage & Administration and Precautions). The median time to onset for both hypercholesterolaemia and hypertriglyceridaemia was 15 days. The median duration of hypercholesterolaemia and hypertriglyceridaemia was 451 and 427 days, respectively.
Central nervous system effects: In clinical trials of patients with ALK-positive or c-ros oncogene 1 (ROS1) positive metastatic NSCLC, CNS adverse drug reactions were primarily cognitive effects (27.7%), mood effects (21.0%), speech effects (8.2%), and psychotic effects (6.9%) and were generally mild, transient, and reversible upon dose delay and/or dose reduction (see Dosage & Administration and Precautions). The most frequent cognitive effect of any grade was memory impairment (11.3%), and the most frequent Grade 3 or 4 reactions were cognitive disorder and confusional state (0.8% and 1.7%, respectively). The most frequent mood effect of any grade was anxiety (6.5%), and the most frequent Grade 3 or 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 (2.9%), and the most frequent Grade 3 or 4 reactions were hallucination auditory and hallucination visual (0.2% 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 78 days, respectively.

In vitro data indicate that lorlatinib is primarily metabolized by CYP3A4 and uridine diphosphate-glucuronosyltransferase (UGT) 1A4, with minor contributions from CYP2C8, CYP2C19, CYP3A5, and UGT1A3.
CYP3A inhibitors: Itraconazole, a strong inhibitor of CYP3A, administered at a dose of 200 mg once daily for 5 days, increased the mean area under the curve (AUC) 42% and C_max 24% of a single 100 mg oral dose of lorlatinib in healthy volunteers. Concomitant administration of lorlatinib with strong CYP3A inhibitors (e.g., boceprevir, cobicistat, conivaptan, itraconazole, ketoconazole, posaconazole, telaprevir, troleandomycin, voriconazole, ritonavir, paritaprevir in combination with ritonavir and ombitasvir and/or dasabuvir, and ritonavir in combination with either danoprevir, elvitegravir, indinavir, lopinavir, saquinavir, or tipranavir) may increase lorlatinib plasma concentrations. Grapefruit products may also increase lorlatinib plasma concentrations. An alternative concomitant medicinal product with less potential to inhibit CYP3A should be considered. If a strong CYP3A inhibitor must be concomitantly administered, a dose reduction of lorlatinib is recommended (see Dosage & Administration).
CYP3A inducers: Rifampin, a strong inducer of CYP3A, administered at a dose of 600 mg once daily for 9 days, reduced the mean lorlatinib AUC by 85% and C_max by 76% of a single 100 mg dose of lorlatinib in healthy volunteers; increases in liver function tests (AST and ALT) were also observed. Concomitant administration of lorlatinib with strong CYP3A inducers (e.g., rifampin, carbamazepine, enzalutamide, mitotane, phenytoin, and St. John's wort) may decrease lorlatinib plasma concentrations. The use of a strong CYP3A inducer with lorlatinib is contraindicated (see Contraindications and Precautions). Any strong CYP3A inducers have to be discontinued for at least 3 plasma half-lives of the strong CYP3A inducer before lorlatinib treatment is started. 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 CYP3A 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.
Proton-pump inhibitors, H₂-receptor antagonists, or locally-acting antacids: The proton-pump inhibitor rabeprazole had a minimal effect on lorlatinib plasma exposure (90% confidence interval [CI] for the AUC_inf ratio, expressed as a percentage: 97.6%, 104.3%). No dose adjustment is required when lorlatinib is taken with proton-pump inhibitors, H₂-receptor antagonists, or locally-acting antacids.
Drugs whose plasma concentrations may be altered by lorlatinib: CYP3A substrates: Lorlatinib has a net induction effect on CYP3A both in vitro and in vivo. Lorlatinib 150 mg orally once daily for 15 days decreased AUC_inf by 64% and C_max by 50% of a single oral 2 mg dose of midazolam (a sensitive CYP3A substrate). Thus, concurrent administration of lorlatinib with CYP3A substrates with narrow therapeutic indices, including but not limited to hormonal contraceptives, alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus, should be avoided since the concentration of these drugs may be reduced by lorlatinib.
In vitro studies of other CYP inhibition and induction: In vitro studies indicated that clinical drug-drug interactions as a result of lorlatinib-mediated inhibition of the metabolism of substrates for CYP1A2, CYP2B6, CYP2C8, CYP2C19, and CYP2D6 are unlikely to occur.
In vitro studies indicated that lorlatinib is an inhibitor of CYP2C9 and that it activates the human pregnane-X-receptor (PXR), with the net effect in vivo being weak CYP2C9 induction. In vitro studies also indicated that lorlatinib is a time-dependent inhibitor as well as an inducer of CYP3A, with the net effect in vivo being induction. In vitro studies also indicated that lorlatinib is an inducer of CYP2B6 and activates the human constitutive androstane receptor (CAR) and in vivo lorlatinib is a weak inducer of CYP2B6. In vitro, lorlatinib has a low potential to cause drug-drug interactions by induction of CYP1A2.
In vitro, the major circulating metabolite for lorlatinib showed a low potential to cause drug-drug interaction by inhibiting CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A, or by inducing CYP1A2, CYP2B6, and CYP3A.
In vitro studies of UDP-glucuronosyltransferase (UGT) inhibition: In vitro studies indicated that clinical drug-drug interactions as a result of lorlatinib-mediated inhibition of the metabolism of substrates for UGT1A4, UGT1A6, UGT1A9, UGT2B7, and UGT2B15 are unlikely to occur. In vitro studies indicated that lorlatinib is an inhibitor of UGT1A1 and that it activates PXR, with the net effect in vivo being weak UGT induction.
In vitro studies indicated that clinical drug-drug interactions as a result of inhibition by the major lorlatinib circulating metabolite of substrates for UGT1A1, UGT1A4, UGT1A6, UGT1A9, UGT2B7, and UGT2B15 are unlikely to occur.
In vitro studies with drug transporters: In vitro studies indicated that clinical drug-drug interactions as a result of lorlatinib-mediated inhibition of breast cancer resistance protein (BCRP, systemically), multidrug and toxin extrusion protein (MATE)2K, organic anion transporter (OAT)1, and organic cation transporter (OCT)2 are unlikely. In vitro studies indicated that lorlatinib is an inhibitor of P-glycoprotein (P-gp) and that it activates PXR, with the net effect in vivo being moderate induction. Lorlatinib may have the potential to inhibit BCRP (GI tract), OATP1B1, OATP1B3, OCT1, MATE1, and OAT3 at clinically relevant concentrations.
In vitro studies indicated that clinical drug-drug interactions as a result of inhibition by the major lorlatinib circulating metabolite of substrates for P-gp, BCRP, OATP1B1, OATP1B3, OAT1, OAT3, OCT1, OCT2, MATE1, and MATE2K are unlikely to occur.
In vivo studies with drug transporters: A drug interaction study conducted in NSCLC patients indicated that lorlatinib is a moderate inducer of P-gp. P-gp substrates with narrow therapeutic index (e.g., digoxin) should be used with caution in combination with lorlatinib due to the likelihood of reduced plasma concentrations of these substrates.

Incompatibilities: Not applicable.
Special Precautions for Disposal and Other Handling: Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Store below 30°C.

Targeted Cancer Therapy

L01ED05 - lorlatinib ; Belongs to the class of anaplastic lymphoma kinase (ALK) inhibitors. Used in the treatment of cancer.

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