Source: European Medicines Agency (EU) Revision Year: 2024 Publisher: Pfizer Europe MA EEIG, Boulevard de la Plaine 17, 1050 Bruxelles, Belgium
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:
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 utilised. Improper assay performance can lead to unreliable test results.
The recommended dose is 100 mg lorlatinib taken orally once daily.
Treatment with lorlatinib should be continued until disease progression or unacceptable toxicity.
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.
Dosing interruption or dose reduction may be required based on individual safety and tolerability.
Lorlatinib dose reduction levels are summarised below:
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. Recommended lorlatinib dose modifications for adverse reactions:
| Adverse reactiona | Lorlatinib dosing |
|---|---|
| Hypercholesterolaemia or hypertriglyceridaemia | |
| Mild hypercholesterolaemia (cholesterol between ULN and 300 mg/dL or between ULN and 7.75 mmol/L) OR Moderate hypercholesterolaemia (cholesterol between 301 and 400 mg/dL or between 7.76 and 10.34 mmol/L) OR Mild hypertriglyceridaemia (triglycerides between 150 and 300 mg/dL or 1.71 and 3.42 mmol/L) OR Moderate hypertriglyceridaemia (triglycerides between 301 and 500 mg/dL or 3.43 and 5.7 mmol/L) | Introduce or modify lipid-lowering therapyb in accordance with respective prescribing information; continue lorlatinib at same dose. |
| Severe hypercholesterolaemia (cholesterol between 401 and 500 mg/dL or between 10.35 and 12.92 mmol/L) OR Severe hypertriglyceridaemia (triglycerides between 501 and 1,000 mg/dL or 5.71 and 11.4 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. |
| Life-threatening hypercholesterolaemia (cholesterol over 500 mg/dL or over 12.92 mmol/L) OR Life-threatening hypertriglyceridaemia (triglycerides over 1,000 mg dL or over 11.4 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. If severe hypercholesterolaemia and/or hypertriglyceridaemia recur despite maximal lipid-lowering therapyb in accordance with respective prescribing information, reduce lorlatinib by 1 dose level. |
| Central nervous system (CNS) effects (comprises psychotic effects and changes in cognition, mood, mental status or speech) | |
| Grade 2: Moderate OR Grade 3: Severe | Withhold dose until toxicity is less than or equal to Grade 1. Then resume lorlatinib at 1 reduced dose level. |
| Grade 4: Life-threatening/Urgent intervention indicated | Permanently discontinue lorlatinib. |
| Lipase/Amylase increase | |
| Grade 3: Severe OR Grade 4: Life-threatening/Urgent intervention indicated | Withhold lorlatinib until lipase or amylase returns to baseline. Then resume lorlatinib at 1 reduced dose level. |
| Interstitial lung disease (ILD)/Pneumonitis | |
| Grade 1: Mild OR Grade 2: Moderate | Withhold lorlatinib until symptoms have returned to baseline and consider initiating corticosteroids. Resume lorlatinib at 1 reduced dose level. Permanently discontinue lorlatinib if ILD/pneumonitis recurs or fails to recover after 6 weeks of lorlatinib hold and steroid treatment. |
| Grade 3: Severe OR Grade 4: Life-threatening/Urgent intervention indicated | Permanently discontinue lorlatinib. |
| PR interval prolongation/Atrioventricular (AV) block | |
| First degree AV block: Asymptomatic | Continue lorlatinib at the same dose without interruption. Consider effects of concomitant medicinal products, and assess and correct electrolyte imbalance that may prolong PR interval. Monitor ECG/symptoms potentially related to AV block closely. |
| First degree AV block: Symptomatic | Withhold lorlatinib. Consider effects of concomitant medicinal products, and assess and correct electrolyte imbalance that may prolong PR interval. Monitor ECG/symptoms potentially related to AV block closely. If symptoms resolve, resume lorlatinib at 1 reduced dose level. |
| Second degree AV block Asymptomatic | Withhold lorlatinib. Consider effects of concomitant medicinal products, and assess and correct electrolyte imbalance that may prolong PR interval. Monitor ECG/symptoms potentially related to AV block closely. If subsequent ECG does not show second degree AV block, resume lorlatinib at 1 reduced dose level. |
| Second degree AV block Symptomatic | Withhold lorlatinib. Consider effects of concomitant medicinal products, and assess and correct electrolyte imbalance that may prolong PR interval. Refer for cardiac observation and monitoring. Consider pacemaker placement if symptomatic AV block persists. If symptoms and the second-degree AV block resolve or if patients revert to asymptomatic first-degree AV block, resume lorlatinib at 1 reduced dose level. |
| Complete AV block | Withhold lorlatinib. Consider effects of concomitant medicinal products, and assess and correct electrolyte imbalance that may prolong PR interval. Refer for cardiac observation and monitoring. Pacemaker placement may be indicated for severe symptoms associated with AV block. If AV block does not resolve, placement of a permanent pacemaker may be considered. If pacemaker placed, resume lorlatinib at full dose. If no pacemaker placed, resume lorlatinib at 1 reduced dose level only when symptoms resolve, and PR interval is less than 200 msec. |
| Hypertension | |
| Grade 3 (SBP greater than or equal to 160 mmHg or DBP greater than or equal to 100 mmHg; medical intervention indicated; more than one antihypertensive drug, or more intensive therapy than previously used indicated) | Withhold lorlatinib until hypertension has recovered to Grade 1 or less (SBP less than 140 mmHg and DBP less than 90 mmHg), then resume lorlatinib at the same dose. If Grade 3 hypertension recurs, withhold lorlatinib until recovery to Grade 1 or less, and resume at a reduced dose. If adequate hypertension control cannot be achieved with optimal medical management, permanently discontinue lorlatinib. |
| Grade 4 (Life-threatening consequences, urgent intervention indicated) | Withhold lorlatinib until recovery to Grade 1 or less, and resume at a reduced dose or permanently discontinue lorlatinib. If Grade 4 hypertension recurs, permanently discontinue lorlatinib. |
| Hyperglycaemia | |
| Grade 3 OR Grade 4 (Persistent hyperglycaemia greater than 250 mg/dL despite optimal anti-hyperglycaemic therapy) | Withhold lorlatinib until hyperglycaemia is adequately controlled, then resume lorlatinib at the next lower dosage. If adequate hyperglycaemic control cannot be achieved with optimal medical management, permanently discontinue lorlatinib. |
| Other adverse reactions | |
| Grade 1: Mild OR Grade 2: Moderate | Consider no dose modification or reduce by 1 dose level, as clinically indicated. |
| Greater than or equal to Grade 3: Severe | Withhold lorlatinib until symptoms resolve to less than or equal to Grade 2 or baseline. Then resume lorlatinib at 1 reduced dose level. |
Abbreviations: CNS = central nervous system; CTCAE = Common Terminology Criteria for Adverse Events; DBP = diastolic blood pressure; ECG = electrocardiogram; HMG CoA = 3-hydroxy-3-methylglutaryl coenzyme A; NCI = National Cancer Institute; SBP = systolic blood pressure; ULN = upper limit of normal.
a Grade categories are based on NCI CTCAE classifications.
b Lipid-lowering therapy may include: HMG CoA reductase inhibitor, nicotinic acid, fibric acid derivatives, or ethyl esters of omega-3 fatty acids.
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 section 4.5). 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 sections 4.5 and 5.2). 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.
Due to the limited data on this population, no dose recommendation can be made for patients aged 65 years and older (see section 5.2).
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 section 5.2). No information is available for patients on renal dialysis.
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 section 5.2).
The safety and efficacy of lorlatinib in paediatric patients below 18 years have not been established. No data are available.
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 section 5.2). 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.
3 years.
This medicinal product does not require any special storage conditions.
OPA/Al/PVC blisters with aluminium foil backing containing 10 film-coated tablets.
Lorviqua 25 mg film-coated tablets: Each pack contains 90 film-coated tablets in 9 blisters.
Lorviqua 100 mg film-coated tablets: Each pack contains 30 film-coated tablets in 3 blisters.
Not all pack sizes may be marketed.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
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