Chemical formula: C₂₁H₁₉FN₆O₂ Molecular mass: 406.421 g/mol PubChem compound: 71731823
Lorlatinib interacts in the following cases:
In vitro studies indicated that lorlatinib may have the potential to inhibit UGT1A1.
In vitro, lorlatinib has a low potential to cause drug-drug interactions by induction of CYP1A2.
Lorlatinib may have the potential to inhibit CYP2C9.
In vitro studies indicated that lorlatinib is a time-dependent inhibitor as well as an inducer of CYP3A4/5 and it activates the human pregnane-X-receptor (PXR), with the net effect in vivo being induction. Concurrent administration of lorlatinib in patients resulted in decreased oral midazolam AUC when midazolam was administered alone, suggesting that lorlatinib is an inducer of CYP3A4/5. Lorlatinib 150 mg orally once daily for 15 days decreased AUC inf and Cmax 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.
In vitro studies also indicated that lorlatinib is an inducer of CYP2B6 and activates the human constitutive androstane receptor (CAR). Concomitant administration of lorlatinib with CYP2B6 substrates (e.g. bupropion, efavirenz) may result in reduced plasma concentrations of the CYP2B6 substrate.
In vitro studies indicated that lorlatinib may have the potential to inhibit UGT1A1. In vitro studies with drug transporters. In vitro studies indicated that lorlatinib may have the potential to inhibit P-glycoprotein (P-gp, systemically and at the gastrointestinal [GI] tract), BCRP (GI tract), OATP1B1, OATP1B3, OCT1, MATE1 and OAT3 at clinically relevant concentrations.
In vitro data indicate that lorlatinib is primarily metabolised by CYP3A4.
Itraconazole, a strong inhibitor of CYP3A4/5, administered at oral doses of 200 mg once daily for 5 days, increased the mean lorlatinib AUC by 42% and Cmax 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.
In vitro data indicate that lorlatinib is primarily metabolised by CYP3A4.
Concomitant use with moderate CYP3A4/5 inducers should be avoided, if possible, as they may also reduce lorlatinib plasma concentrations.
Information for lorlatinib use in patients with severe (CLcr: <30 mL/min) renal impairment is very limited. Therefore, lorlatinib is not recommended in patients with severe renal 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.
Based on non-clinical safety findings, male fertility may be compromised during treatment with lorlatinib. It is not known whether lorlatinib affects female fertility. Men should seek advice on effective fertility preservation before treatment.
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.
Severe or life-threatening pulmonary adverse reactions consistent with ILD/pneumonitis have occurred with lorlatinib. 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.
Recommended lorlatinib dose modifications for adverse reactions:
| Adverse reactiona | Lorlatinib dosing |
|---|---|
| Grade 1: Mild OR Grade 2: Moderate | Withhold lorlatinib until symptoms have returned to |
Abbreviations: CTCAE = Common Terminology Criteria for Adverse Events; NCI = National Cancer Institute
a Grade categories are based on NCI CTCAE classifications
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. 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.
Recommended lorlatinib dose modifications for adverse reactions:
| Adverse reactioa | Lorlatinib dosing |
|---|---|
| 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 |
| 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. |
Abbreviations: CTCAE=Common Terminology Criteria for Adverse Events; ECG=electrocardiogram; HMGCoA=3-hydroxy-3-methylglutarylcoenzyme A; NCI=National Cancer Institute; ULN=upper limit of normal.
a Grade categories are based on NCI CTCAE classifications.
The use of lorlatinib has been associated with increases in serum cholesterol and triglycerides. Median time of occurrence of severe increase in serum cholesterol and triglycerides is 201 days (range: 42 to 518 days) and 127 days (range: 15 to 358 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.
Recommended lorlatinib dose modifications for adverse reactions:
| Adverse reactiona | Lorlatinib dosing |
|---|---|
| Mild hypercholesterolaemia (cholesterol between ULN and 300 mg/dL or between ULN and 7.75 mmol/L) | Introduce or modify lipid-lowering therapyb in accordance with respective prescribing information; continue lorlatinib at same dose. |
| 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) | |
| Severe hypercholesterolaemia (cholesterol between 401 and 500 mg/dL or between 10.35 and 12.92 mmol/L) | Introduce the use of lipid-lowering therapy;b 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. |
| OR Severe hypertriglyceridaemia (triglycerides between 501 and 1,000 mg/dL or 5.71 and 11.4 mmol/L) | |
| 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. |
Abbreviations: CTCAE=Common Terminology Criteria for Adverse Events; ECG=electrocardiogram; HMGCoA=3-hydroxy-3-methylglutarylcoenzyme A; NCI=National Cancer Institute; ULN=upper limit of normal.
a Grade categories are based on NCI CTCAE classifications.
b Lipid-lowering therapy may include: HMGCoA reductase inhibitor, nicotinic acid, fibric acid derivatives, or ethyl esters of omega-3 fatty acids.
Central nervous system (CNS) effects have been observed in patients receiving lorlatinib, including changes in cognitive function, mood or speech. Dose modification or discontinuation may be required for those patients who develop CNS effects.
Recommended lorlatinib dose modifications for adverse reactions:
| Adverse reactiona | Lorlatinib dosing |
|---|---|
| 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. |
Abbreviations: CTCAE = Common Terminology Criteria for Adverse Events; NCI = National Cancer Institute
a Grade categories are based on NCI CTCAE classifications
Elevations of lipase and/or amylase have occurred in patients receiving lorlatinib. Median time of occurrence of increase in serum lipase and amylase is 70 days (range: 7 to 696 days) and 41 days (range: 7 to 489 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.
Recommended lorlatinib dose modifications for adverse reactions:
| Adverse reactiona | Lorlatinib dosing |
|---|---|
| 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. |
Abbreviations: CTCAE = Common Terminology Criteria for Adverse Events; NCI = National Cancer Institute
a Grade categories are based on NCI CTCAE classifications.
Studies in animals have shown embryo-foetal toxicity. 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.
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.
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. 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.
Based on non-clinical safety findings, male fertility may be compromised during treatment with lorlatinib. It is not known whether lorlatinib affects female fertility. Men should seek advice on effective fertility preservation before treatment.
Lorlatinib has moderate influence on the ability to drive and use machines. Caution should be exercised when driving or operating machines as patients may experience CNS effects.
The most frequently reported adverse reactions were hypercholesterolaemia (84.4%), hypertriglyceridaemia (67.1%), oedema (54.6%), peripheral neuropathy (47.8%), cognitive effects (28.8%), fatigue (28.1%), weight increased (26.4%) and mood effects (22.7%).
Dose reductions due to adverse reactions occurred in 23.4% 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 3.1% of patients receiving lorlatinib. The most frequent adverse reaction that led to permanent discontinuations was cognitive effects.
The following table presents adverse reactions occurring in 295 adult patients treated with lorlatinib 100 mg once daily with advanced NSCLC from Study A.
The adverse reactions 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.
Adverse reactions of increase in serum cholesterol or triglycerides were reported in 84.4% and 67.1% of patients, respectively. Of those, mild or moderate adverse reactions of hypercholesterolaemia or hypertriglyceridaemia occurred in 67.8% and 50.5% of patients, respectively. The median time to onset for both hypercholesterolaemia and hypertriglyceridaemia was 15 days (range: 1 to 399 days). The median duration of hypercholesterolaemia and hypertriglyceridaemia was 381 and 405 days, respectively.
CNS adverse reactions were primarily cognitive effects (28.8%), mood effects (22.7%), and speech effects (9.8%), and were generally mild, transient, and reversible spontaneously upon dose delay and/or dose reduction. The most common cognitive effect of any grade was memory impairment (11.5%), and the most common Grade 3 or 4 reactions were cognitive effect and confusional state (0.7% each). The most common mood effect of any grade was irritability (6.1%), which was also the most common Grade 3 or 4 reaction (1.0%). The most common speech effect of any grade was dysarthria (4.1%), and the most common Grade 3 or 4 reaction was slow speech (0.3%). Median time to onset for cognitive, mood and speech effects was 92, 44 and 42 days, respectively. Median duration of cognitive, mood and speech effects was 224, 83 and 106 days, respectively.
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