Lorviqua

25 mg: Round light pink immediate release film-coated tablet, debossed with "Pfizer" on one side and "25" and "LLN" on the other.
Each 25 mg film-coated tablet contains 25 mg of lorlatinib.
100 mg: Oval dark pink immediate release film-coated tablet, debossed with "Pfizer" on one side and "LLN 100" on the other.
Each 100 mg film-coated tablet contains 100 mg of lorlatinib.
Excipients/Inactive Ingredients: Tablet core contains: Microcrystalline cellulose, Calcium hydrogen phosphate, Sodium starch glycolate, Magnesium stearate.
Film-coating contains: Hypromellose, Lactose monohydrate, Macrogol, Triacetin, Titanium dioxide (E171), Iron oxide black (E172), Iron oxide red (E172).

Pharmacotherapeutic group: Anti neoplastic agents, protein kinase inhibitors. ATC code: L01ED05.
Pharmacology: Pharmacodynamics: Mechanism of action: Lorlatinib is a selective, adenosine triphosphate (ATP)-competitive inhibitor of ALK and c-ros oncogene 1 (ROS1) tyrosine kinases.
In non-clinical studies, lorlatinib inhibited catalytic activities of non-mutated ALK and clinically relevant ALK mutant kinases in recombinant enzyme and cell-based assays.
Lorlatinib demonstrated marked antitumour activity in mice bearing tumour 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 alectinib, brigatinib, ceritinib, and crizotinib. Lorlatinib was also capable of penetrating the blood-brain barrier. Lorlatinib demonstrated activity in mice bearing orthotopic EML4-ALK or EML4-ALK^L1196M brain tumour implants.
Clinical efficacy: 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, multicentre 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 randomisation; whole brain irradiation within 4 weeks prior to randomization.
Patients were randomised 1:1 to receive lorlatinib 100 mg orally once daily or crizotinib 250 mg orally twice daily. Randomisation 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 Tumours (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 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 randomised 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 study are summarised in Table 1. At the data cutoff point, OS and PFS2 data were not mature. (See Table 1 and figure.)

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Click on icon to see table/diagram/image

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 lorlatinib in the treatment of ALK-positive advanced NSCLC after treatment with at least one second-generation ALK TKI was investigated in Study A, a single-arm, multicentre Phase 1/2 study. A total of 139 patients with ALK-positive advanced NSCLC after treatment with at least one second-generation ALK TKI were enrolled in the Phase 2 portion of the study. Patients received lorlatinib 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 (IC)-ORR, as per Independent Central Review (ICR) according to modified RECIST v1.1. Secondary endpoints included DOR, IC-DOR, time-to-tumour response (TTR), and PFS.
Patient demographics of the 139 ALK-positive advanced NSCLC patients after treatment with at least one second-generation ALK TKI, were 56% female, 48% White, 38% Asian and the median age was 53 years (range: 29 to 83 years) with 16% of patients ≥65 years of age. The Eastern Cooperative Oncology Group (ECOG) performance status at baseline was 0 or 1 in 96% patients. Brain metastases were present at baseline in 67% of patients. Of the 139 patients, 20% received 1 prior ALK TKI, excluding crizotinib, 47% received 2 prior ALK TKIs, and 33% received 3 or more prior ALK TKIs.
The main efficacy results for Study A are included in Tables 2 and 3. (See Tables 2 and 3.)

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Click on icon to see table/diagram/image

In the overall efficacy population of 139 patients, 56 patients had a confirmed objective response by ICR with a median TTR of 1.4 months (range: 1.2 to 16.6 months). The ORR for Asians was 49.1% (95% CI: 35.1, 63.2) and 31.5% for non-Asians (95% CI: 21.1, 43.4). Among the 31 patients with a confirmed IC objective tumour response and at least one measurable brain metastasis at baseline by ICR, the median IC-TTR was 1.4 months (range: 1.2 to 16.2 months). The IC ORR was 54.5% for Asians (95% CI: 32.2, 75.6) and 46.4% for non-Asians (95% CI: 27.5, 66.1).
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 multiple dosing of 100 mg once daily.
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 fasted conditions. Lorlatinib may be administered with or without food.
At 100 mg once daily, the geometric mean (% coefficient of variation [CV]) peak plasma concentration was 577 (42) ng/mL and the AUC₂₄ was 5,650 (39) ng·h/mL in patients with cancer. The geometric mean (% CV) oral clearance was 17.7 (39) L/h.
Distribution: In vitro binding of lorlatinib to human plasma proteins is 66% with moderate binding to albumin or to α₁-acid glycoprotein.
Biotransformation: In humans, lorlatinib undergoes oxidation and glucuronidation as the primary metabolic pathways.
In vitro data indicate that lorlatinib is metabolised 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. The estimated lorlatinib effective plasma half-life at steady-state following completion of autoinduction was 14.83 hours. Following oral administration of a 100 mg radiolabelled dose of lorlatinib, a mean 47.7% of the radioactivity was recovered in urine and 40.9% of the radioactivity was recovered in faeces, with overall mean total recovery of 88.6%.
Unchanged lorlatinib was the major component of human plasma and faeces, accounting for 44% and 9.1% of total radioactivity, respectively. Less than 1% of unchanged lorlatinib was detected in urine.
Furthermore, lorlatinib is an inducer via human pregnane-X-receptor (PXR) and the human constitutive androstane receptor (CAR).
Linearity/non-linearity: At single dose, lorlatinib systemic exposure (AUC_inf and C_max) increased in a dose-related manner over the 10 to 200 mg dose range. Few data are available over the 10 to 200 mg dose range; however, no deviation from linearity was observed for AUC_inf and C_max after single dose.
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.
Also, at steady-state lorlatinib plasma exposures are lower than those expected from single dose pharmacokinetics, indicative of a net time-dependent auto-induction effect.
Cardiac electrophysiology: In Study A, 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 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 and had a ECG measurement in Study A, lorlatinib was studied in a population of patients that excluded those with QTc interval >470 msec. In the study population, the maximum mean change from baseline for PR interval was 16.4 msec (2-sided 90% upper CI 19.4 msec) (see Dosage & Administration, Precautions and Adverse Reactions). Of these, 7 patients had a baseline PR >200 msec. Among the 284 patients with PR interval <200 msec, 14% had PR interval prolongation ≥200 msec 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 metabolised 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 × ULN, or if due to underlying malignancy, >5.0 × ULN or with total bilirubin >1.5 × 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. No information is available for patients with moderate or severe hepatic impairment.
Renal impairment: Less than 1% of the administered dose is detected as unchanged lorlatinib in urine. Population pharmacokinetic analyses have shown that lorlatinib steady-state plasma exposure and C_max values slightly increase with worsening baseline renal function. Based on a renal impairment study, no starting dose adjustments are recommended for patients with mild or moderate renal impairment [eGFR based on Modification of Diet in Renal Disease Study equation (MDRD)-derived eGFR (in mL/min/1.73 m²) × 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 lorlatinib is recommended in patients with severe renal impairment, e.g., a once daily oral starting dose of 75 mg (see Dosage & Administration). No information is available for patients on renal dialysis.
Age, 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, and phenotypes for CYP3A5 and CYP2C19.
Toxicology: Preclinical safety data: Repeat-dose toxicity: The main toxicities observed were inflammation across multiple tissues (skin and cervix of rats and lung, trachea, skin, lymph nodes and/or the oral cavity including mandibular bone of dogs; associated with increases in white blood cells, fibrinogen, and/or globulin and decreases in albumin), 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, peripheral nerves and the CNS (potential for cognitive functional impairment) at dose equivalent to human clinical exposure at the recommended posology.
Changes in blood pressure and heart rate, and QRS complex and PR interval 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 hepatic bile duct hyperplasia were partially to fully reversible.
Genotoxicity: Lorlatinib is not mutagenic but is aneugenic in vitro and in vivo with a no observed effect level for aneugenicity approximately 16.5 times human clinical exposure at 100 mg based on AUC.
Carcinogenicity: Carcinogenicity studies have not been conducted with lorlatinib.
Reproductive toxicity: Seminiferous tubular degeneration and/or atrophy in the testes, and epididymal changes (inflammation and/or vacuolation) were observed in the rat and dog. In the prostate, minimal to mild glandular atrophy was observed in dogs at dose equivalent to human clinical exposure at the recommended posology). The effects on male reproductive organs were partially to fully reversible.
In embryo-foetal toxicity studies, conducted in rats and rabbits, respectively, increased embryolethality, and lower foetal body weights and malformations were observed. Foetal morphologic abnormalities included rotated limbs, supernumerary digits, gastroschisis, malformed kidneys, domed head, high arched palate, and dilation of ventricles of the brain. The exposure at the lowest doses with embryo-foetal effects in animals was equivalent to 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.
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 thespecific technology being utilised. 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 should be continued until disease progression or unacceptable toxicity.
Delayed or missed doses: 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 or dose reduction may be required based on individual safety and tolerability. Lorlatinib dose reduction levels are summarised as follows: 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 4. (See Tables 4a and 4b.)

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Click on icon to see table/diagram/image

Strong cytochrome P-450 (CYP) 3A4/5 inhibitors: Concurrent use of lorlatinib with medicinal products that are strong CYP3A4/5 inhibitors and grapefruit juice products may increase lorlatinib plasma concentrations. An alternative concomitant medicinal product with less potential to inhibit CYP3A4/5 should be considered (see Interactions). If a strong CYP3A4/5 inhibitor must be co-administered, the starting lorlatinib dose of 100 mg once daily should be reduced to once daily 75 mg dose (see Interactions and Pharmacology: Pharmacokinetics under Actions). If concurrent use of the strong CYP3A4/5 inhibitor is discontinued, lorlatinib should be resumed at the dose used prior to the initiation of the strong CYP3A4/5 inhibitor and after a washout period of 3 to 5 half-lives of the strong CYP3A4/5 inhibitor.
Special populations: Hepatic impairment: No dose adjustments are recommended for patients with mild hepatic impairment. No information is available for lorlatinib in patients with moderate or severe hepatic impairment. Therefore, lorlatinib 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 normal renal function and mild or moderate renal impairment [absolute estimated glomerular filtration rate (eGFR): ≥30 mL/min]. A reduced dose of lorlatinib is recommended in patients with severe renal impairment (absolute eGFR <30 mL/min), e.g. a once daily starting dose of 75 mg taken orally (see Pharmacology: Pharmacokinetics under Actions). No information is available for patients on renal dialysis.
Elderly (≥65 years): Due to the limited data on this population, no dose recommendation can be made for patients aged 65 years and older (see Pharmacology: Pharmacokinetics under Actions).
Paediatric population: The safety and efficacy of lorlatinib in paediatric patients below 18 years have not been established. No data are available.
Method of administration: Lorviqua is for oral use.
Patients should be encouraged to take their dose of lorlatinib at approximately the same time each day with or without food (see Pharmacology: Pharmacokinetics under Actions). The 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.

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 CYP3A4/5 inducers (see Precautions and Interactions).

Warning (based on the Ministry of Public Health's Announcement): This drug may cause serious harm, should be used under the supervision of a physician.

Hyperlipidaemia: The use of lorlatinib has been associated with increases in serum cholesterol and triglycerides (see Adverse Reactions). 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 Dosage & Administration).
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 Adverse Reactions). Dose modification or discontinuation may be required for those patients who develop CNS effects (see Dosage & Administration).
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 Pharmacology: Pharmacokinetics under Actions). 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 1,112 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).
Interstitial lung disease/Pneumonitis: Severe or life-threatening pulmonary adverse reactions consistent with ILD/pneumonitis have occurred with lorlatinib (see Adverse Reactions). 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 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).
Hyperglycaemia: Hyperglycaemia has occurred in patients receiving lorlatinib (see Adverse Reactions). 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 Dosage & Administration).
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 Interactions). Concomitant use of a strong CYP3A4/5 inducer is contraindicated (see Contraindications and Interactions). 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 Interactions).
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 Interactions).
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''.
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: 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 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 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 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 35 days after completing therapy (see Use in Pregnancy & Lactation). It is not known whether lorlatinib affects female fertility.

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 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 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 Pharmacology: Toxicology: Preclinical safety data under Actions). 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 Pharmacology: Toxicology: Preclinical safety data under Actions). It is not known whether lorlatinib affects female fertility. Men should seek advice on effective fertility preservation before treatment.

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 5 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 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 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 Precautions). 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%), and 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 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 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, and 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 Precautions). 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 Precautions). 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.

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 Contraindications and Precautions). 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 Dosage & Administration).
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 Precautions).
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.

Incompatibilities: Not applicable.

Shelf life: 36 months.
Special precautions for storage: The medicinal product does not require any special storage conditions.

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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