Summary of Prescribing Information

Brand name of product: LORBRIQUA^®

Generic name of product: Lorlatinib tablets

Presentation: Lorlatinib Tablets 25 mg and 100 mg, 25 mg

Indication: Lorlatinib is indicated for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors are anaplastic lymphoma kinase (ALK)-positive.

Dosage: Recommended dosage is 100 mg orally once daily, with or without food

Method of Administration: Oral

Contraindications: Lorlatinib is contraindicated in patients taking strong CYP3A inducers, due to the potential for serious hepatotoxicity

Warnings and Precautions: 1. Risk of serious hepatotoxicity with concomitant Use of Strong CYP3A inducers. discontinue strong CYP3A inducers for 3 plasma half-lives of the strong CYP3A inducer prior to initiating lorlatinib. 2. Central nervous system (CNS)effects: A broad spectrum of central nervous system (CNS) effects can occur in patients receiving lorlatinib. These include seizures, hallucinations, and changes in cognitive function, mood (including suicidal ideation), speech, mental status, and sleep. Withhold and resume at the same dose or at a reduced dose or permanently discontinue lorlatinib based on severity. 3. Hyperlipidemia: Increases in serum cholesterol and triglycerides can occur in patients receiving lorlatinib. Initiate or increase the dose of lipid-lowering agents in patients with hyperlipidemia. Monitor serum cholesterol and triglycerides before initiating lorlatinib, 1 and 2 months after initiating lorlatinib, and periodically thereafter. Withhold and resume at the same dose for the first occurrence; resume at the same or a reduced dose of lorlatinib for recurrence based on severity. 4. Atrioventricular Block: PR interval prolongation and atrioventricular (AV) block can occur in patients receiving lorlatinib. Monitor ECG prior to initiating lorlatinib and periodically thereafter. Withhold and resume at a reduced dose or at the same dose in patients who undergo pacemaker placement. Permanently discontinue for recurrence in patients without a pacemaker. 5. Interstitial Lung Disease/Pneumonitis: Severe or life-threatening pulmonary adverse reactions consistent with interstitial lung disease (ILD)/pneumonitis can occur with lorlatinib. Promptly investigate for ILD/pneumonitis in any patient who presents with worsening of respiratory symptoms indicative of ILD/pneumonitis (e.g., dyspnea, cough, and fever). Immediately withhold lorlatinib in patients with suspected ILD/pneumonitis. Permanently discontinue lorlatinib for treatment related ILD/pneumonitis of any severity. 6. Hypertension can occur in patients receiving Lorlatinib. Control blood pressure prior to initiation of Lorlatinib. Monitor blood pressure after 2 weeks and at least monthly thereafter during treatment with Lorlatinib. Withhold and resume at a reduced dose or permanently discontinue Lorlatinib based on severity. 7. Hyperglycemia can occur in patients receiving Lorlatinib. Assess fasting serum glucose prior to initiation of Lorlatinib and monitor periodically thereafter. Withhold and resume at a reduced dose or permanently discontinue Lorlatinib based on severity. 8. Embryo-Fetal Toxicity: Based on findings from animal studies and its mechanism of action, lorlatinib can cause fetal harm when administered to a pregnant woman.

Use in Special population: Pregnancy: There are no available data on Lorlatinib use in pregnant women. Advise a pregnant woman of the potential risk to a fetus.

Lactation: There are no data on the presence of Lorlatinib or its metabolites in either human or animal milk or its effects on the breastfed infant or on milk production. Because of the potential for serious adverse reactions in breastfed infants, instruct women not to breastfeed during treatment with Lorlatinib and for 7 days after the final dose.

Females and Males of Reproductive Potential: Verify pregnancy status in females of reproductive potential prior to initiating lorlatinib. Advise females of reproductive potential to use an effective non-hormonal method of contraception, since Lorlatinib can render hormonal contraceptives ineffective, during treatment with Lorlatinib and for at least 6 months after the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with Lorlatinib and for 3 months after the final dose. Based on findings from animal studies, Lorlatinib may transiently impair male fertility.

Pediatric Use: The safety and effectiveness of Lorlatinib in pediatric patients have not been established.

Geriatric Use: Although data are limited, no clinically important differences in safety or efficacy were observed between patients aged 65 years or older and younger patients.

Hepatic Impairment: No dose adjustment is recommended for patients with mild hepatic impairment (total bilirubin ≤ upper limit of normal [ULN] with AST > ULN or total bilirubin >1 to 1.5 × ULN with any AST). The recommended dose of Lorlatinib has not been established for patients with moderate or severe hepatic impairment.

Renal Impairment: Reduce the dose when administering Lorlatinib to patients with severe (CLcr 15 to <30 mL/min, estimated by Cockcroft Gault) renal impairment. No dose adjustment is recommended for patients with mild or moderate renal impairment (creatinine clearance [CLcr] 30 to 89 mL/min estimated by Cockcroft-Gault). There is no data on effects on ability to drive and use machines.

Adverse reactions (Very common and common): Adverse Reactions Occurring in ≥10% of Patients- Psychiatric: Mood effects. Nervous system: Peripheral neuropathy, Cognitive effects, Headache, Dizziness, Sleep effects, Speech effect. Respiratory: Dyspnea, Cough. Respiratory failure. Vascular disorders: Hypertension. Ocular: Vision disorder. Gastrointestinal: Diarrhea, Nausea, Constipation, Vomiting. Musculoskeletal and connective tissue: Arthralgia, Myalgia, Back pain, Pain in extremity. General: Edema, Weight gain, Fatigue, Pyrexia, Chest pain. Infections: Upper respiratory tract infection, Pneumonia, Bronchitis. Skin: Rash. Laboratory abnormalities worsening from baseline in >20% of patients- Chemistry: Hypertriglyceridemia, Hypercholesterolemia, Increased creatinine, Increased GGT, Increased AST, Hyperglycemia, Increased ALT, Increased CPK, Hypoalbuminemia, Increased lipase, Increased alkaline phosphatase, Hyperkalemia, Hypophosphatemia, Hypomagnesemia, Increased amylase. Hematology: Anemia, Activated PTT, Lymphopenia, Thrombocytopenia. Additional clinically significant adverse reactions occurring at an incidence between 1% and 10% were speech effects, psychotic effects and hallucinations. 

Drug interactions: Concomitant use of lorlatinib with a strong CYP3A inducer decreased lorlatinib plasma concentrations, which may decrease the efficacy of lorlatinib. Discontinue strong CYP3A inducers for 3 plasma half-lives of the strong CYP3A inducer prior to initiating lorlatinib. Concomitant use of Lorlatinib with a moderate CYP3A inducer decreased lorlatinib plasma concentrations, which may decrease the efficacy of Lorlatinib. Avoid concomitant use of moderate CYP3A inducers with Lorlatinib. If concomitant use is unavoidable, increase the Lorlatinib dose. Concomitant use with a strong CYP3A inhibitor increased lorlatinib plasma concentrations, which may increase the incidence and severity of adverse reactions of lorlatinib. Avoid the concomitant use of Lorlatinib with a strong CYP3A inhibitor. If concomitant use cannot be avoided, reduce the Lorlatinib dosage. Avoid concomitant use of Lorlatinib with fluconazole. If concomitant use cannot be avoided, reduce the Lorlatinib dosage. Lorlatinib is a moderate CYP3A inducer. Concomitant use of Lorlatinib decreases the concentration of CYP3A substrates, which may reduce the efficacy of these substrates. Avoid concomitant use of lorlatinib with CYP3A substrates, where minimal concentration changes may lead to serious therapeutic failures. If concomitant use is unavoidable, increase the CYP3A substrate dosage in accordance with approved product labeling. Concomitant use of Lorlatinib decreases the concentration of P-gp substrates, which may reduce the efficacy of these substrates. Lorlatinib is considered a moderate P-gp inducer. Avoid concomitant use of Lorlatinib with P-gp substrates for which minimal concentration changes may lead to serious therapeutic failures. If concomitant use is unavoidable, increase the P-gp substrate dosage in accordance with approved product labeling.

Overdose: No data

Storage Condition: Store below 30°C. Keep out of reach of children

Pharmacokinetics: Steady-state lorlatinib maximum plasma concentration (Cmax) increases proportionally and AUC increased slightly less than proportionally over the dose range of 10 mg to 200 mg orally once daily (0.1 to 2 times the recommended dosage). At the recommended dosage, the mean (coefficient of variation [CV] %) Cmax was 577 ng/mL (42%) and the AUC0-24h was 5650 ng h/mL (39%) in patients with cancer. Lorlatinib oral clearance increased at steady state compared to single dose, indicating autoinduction. The median lorlatinib Tmax was 1.2 hours (0.5 to 4 hours) following a single oral 100 mg dose and 2 hours (0.5 to 23 hours) following 100 mg orally once daily at steady-state. The mean plasma half-life (t½) of lorlatinib was 24 hours (40%) after a single oral 100 mg dose of Lorlatinib. The mean oral clearance (CL/F) was 11 L/h (35%) following a single oral 100 mg dose and increased to 18 L/h (39%) at steady state, suggesting autoinduction. No clinically significant differences in lorlatinib pharmacokinetics were observed based on age (19 to 85 years), sex, race/ethnicity, body weight, mild to moderate renal impairment, mild hepatic impairment or metabolizer phenotypes for CYP3A5 and CYP2C19.

Pharmacodynamic: The overall antitumor activity of lorlatinib in in vivo models was dose-dependent and correlated with inhibition of ALK phosphorylation.

Reference: LPD version 7.0, LPDLOR102022
Date of this document: 8th December 2022.

ALK+, anaplastic lymphoma kinase-positive; NSCLC, non-small cell lung cancer.

Reference:

​​​​​1. Lorbriqua. Local product document. Pfizer; 2021. LPD Version 7.0 LPDLOR102022.