Lorlatinib
FDA Drug Information • Also known as: Lorbrena
- Brand Names
- Lorbrena
- Drug Class
- Kinase Inhibitor [EPC]
- Route
- ORAL
- Dosage Form
- TABLET, FILM COATED
- Product Type
- HUMAN PRESCRIPTION DRUG
Description
11 DESCRIPTION LORBRENA (lorlatinib) is a kinase inhibitor for oral administration. The molecular formula is C 21 H 19 FN 6 O 2 (anhydrous form) and the molecular weight is 406.41 Daltons. The chemical name is (10 R )-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2 H -4,8-methenopyrazolo[4,3- h ][2,5,11] benzoxadiazacyclotetradecine-3-carbonitrile. The chemical structure is shown below: Lorlatinib is a white to off-white powder with a pKa of 4.92. The solubility of lorlatinib in aqueous media decreases over the range pH 2.55 to pH 8.02 from 32.38 mg/mL to 0.17 mg/mL. The log of the distribution coefficient (octanol/water) at pH 9 is 2.45. LORBRENA is supplied as tablets containing 25 mg or 100 mg of lorlatinib with the following inactive ingredients: microcrystalline cellulose, dibasic calcium phosphate anhydrous, sodium starch glycolate, and magnesium stearate. The film-coating contains hydroxypropyl methylcellulose (HPMC) 2910/hypromellose, lactose monohydrate, macrogol/polyethylene glycol (PEG) 3350, triacetin, titanium dioxide, ferrosoferric oxide/black iron oxide, and iron oxide red. Chemical Structure
What Is Lorlatinib Used For?
1 INDICATIONS AND USAGE LORBRENA ® is indicated for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors are anaplastic lymphoma kinase (ALK)-positive as detected by an FDA-approved test. LORBRENA is a kinase inhibitor indicated for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors are anaplastic lymphoma kinase (ALK)-positive as detected by an FDA-approved test. ( 1 , 2.1 )
Dosage and Administration
2 DOSAGE AND ADMINISTRATION Recommended dosage : 100 mg orally once daily. ( 2.2 ) Severe Hepatic Impairment : 50 mg orally once daily. ( 2.5 , 8.6 , 12.3 ) Renal Impairment : 75 mg orally once daily. ( 2.6 , 8.7 , 12.3 ) 2.1 Patient Selection Select patients for the treatment of metastatic NSCLC with LORBRENA based on the presence of ALK positivity in tumor specimens [see Indications and Usage (1) and Clinical Studies (14) ] . Information on FDA-approved tests for the detection of ALK rearrangements in NSCLC is available at http://www.fda.gov/CompanionDiagnostics . 2.2 Recommended Dosage The recommended dosage of LORBRENA is 100 mg orally once daily, with or without food, until disease progression or unacceptable toxicity [see Clinical Pharmacology (12.3) ] . Swallow tablets whole. Do not chew, crush or split tablets. Do not ingest if tablets are broken, cracked, or otherwise not intact. Take LORBRENA at the same time each day. If a dose is missed, then take the missed dose unless the next dose is due within 4 hours. Do not take 2 doses at the same time to make up for a missed dose. Do not take an additional dose if vomiting occurs after LORBRENA but continue with the next scheduled dose. 2.3 Dosage Modifications for Adverse Reactions The recommended dose reductions are:
First dose reduction: LORBRENA 75 mg orally once daily Second dose reduction: LORBRENA 50 mg orally once daily Permanently discontinue LORBRENA in patients who are unable to tolerate 50 mg orally once daily. Dosage modifications for adverse reactions of LORBRENA are provided in Table 1. Table 1 Recommended LORBRENA Dosage Modifications for Adverse Reactions Adverse Reaction Grade based on National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Dosage Modifications Abbreviation: AV=atrioventricular; DBP=diastolic blood pressure; SBP=systolic blood pressure. Central Nervous System Effects [see Warnings and Precautions (5.2) ] Grade 1 Continue at the same dose or withhold the dose until recovery to baseline. Resume LORBRENA at the same dose or at a reduced dose. Grade 2 OR Grade 3 Withhold dose until Grade 0 or 1. Resume LORBRENA at a reduced dose. Grade 4 Permanently discontinue LORBRENA. Hyperlipidemia [see Warnings and Precautions (5.3) ] Grade 4 hypercholesterolemia OR Grade 4 hypertriglyceridemia Withhold LORBRENA until recovery of hypercholesterolemia and/or hypertriglyceridemia to less than or equal to Grade 2. Resume LORBRENA at the same dose. If severe hypercholesterolemia and/or hypertriglyceridemia recurs, resume LORBRENA at a reduced dose. Atrioventricular (AV) Block [see Warnings and Precautions (5.4) ] Second-degree AV block Withhold LORBRENA until PR interval is less than 200 ms. Resume LORBRENA at a reduced dose. First occurrence of complete AV block Withhold LORBRENA until pacemaker placed OR PR interval less than 200 ms. If a pacemaker is placed, resume LORBRENA at the same dose. If no pacemaker is placed,...Side Effects (Adverse Reactions)
6 ADVERSE REACTIONS The following adverse reactions are described elsewhere in the labeling:
Risk of Serious Hepatotoxicity with Concomitant Use of Strong CYP3A Inducers [see Warnings and Precautions (5.1) ] Central Nervous System Effects [see Warnings and Precautions (5.2) ] Hyperlipidemia [see Warnings and Precautions (5.3) ] Atrioventricular Block [see Warnings and Precautions (5.4) ] Interstitial Lung Disease/Pneumonitis [see Warnings and Precautions (5.5) ] Hypertension [see Warnings and Precautions (5.6) ] Hyperglycemia [see Warnings and Precautions (5.7) ] Most common (incidence ≥20%) adverse reactions and Grade 3–4 laboratory abnormalities are edema, peripheral neuropathy, weight gain, cognitive effects, fatigue, dyspnea, arthralgia, diarrhea, mood effects, hypercholesterolemia, hypertriglyceridemia, and cough. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at 1-800-438-1985 or www.pfizer.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The pooled safety population described in the Warnings and Precautions section reflects exposure to LORBRENA in 476 patients who received 100 mg LORBRENA once daily in Study B7461001 (N=327) and Study B7461006 (N=149). Among 476 patients who received LORBRENA, 75% were exposed for 6 months or longer and 61% were exposed for greater than 1 year. In this pooled safety population, the most frequent adverse reactions in ≥ 20% of 476 patients who received LORBRENA were edema (56%), peripheral neuropathy (44%), weight gain (31%), cognitive effects (28%), fatigue (27%), dyspnea (27%), arthralgia (24%), diarrhea (23%), mood effects (21%), and cough (21%). The most frequent Grade 3–4 laboratory abnormalities in ≥ 20% of 476 patients who received LORBRENA were hypercholesterolemia (21%) and hypertriglyceridemia (21%). Previously Untreated ALK-Positive Metastatic NSCLC (CROWN Study) The safety of LORBRENA was evaluated in 149 patients with ALK-positive NSCLC in a randomized, open-label, active-controlled trial for the treatment of patients with ALK-positive, locally advanced or metastatic, NSCLC who had not received previous systemic treatment for advanced disease [see Clinical Studies (14) ]. The median duration of exposure to LORBRENA was 16.7 months (4 days to 34.3 months) and 76% received LORBRENA for at least 12 months. Serious adverse reactions occurred in 34% of patients treated with LORBRENA; the most frequently reported serious adverse reactions were pneumonia (4.7%), dyspnea (2.7%), respiratory failure (2.7%), cognitive effects (2.0%), and pyrexia (2.0%). Fatal adverse reactions occurred in 3.4% of patients treated with LORBRENA and included pneumonia (0.7%), respiratory failure (0.7%), cardiac failure acute (0.7%), pulmonary embolism (0.7%), and sudden death (0.7%). Permanent discontinuation of LORBRENA due to adverse reactions occurred in 6.7% of patients. The most frequent adverse reaction that led to permanent discontinuation of LORBRENA was cognitive effects (1.3%). Adverse reactions leading to dose interruptions occurred in 49% of patients treated with LORBRENA. The most frequent adverse reactions that led to dose interruptions of LORBRENA were hypertriglyceridemia (7%), edema (5%), pneumonia (4.7%) cognitive effects (4.0%), mood effects (4.0%), and hypercholesterolemia (3.4%). Adverse reactions leading to dose reductions occurred in 21% of patients treated with LORBRENA. The most frequent adverse reactions that led to dose reductions were edema (5%), hypertriglyceridemia (4.0%), and peripheral neuropathy (3.4%). Tables 2 and 3 summarize most frequent adverse reactions and laboratory abnormalities, respectively, in patients treated with LORBRENA in...Drug Interactions
7 DRUG INTERACTIONS
Strong CYP3A Inducers : Contraindicated. ( 2.4 , 7.1 ) Moderate CYP3A Inducers : Avoid concomitant use. If concomitant use cannot be avoided, increase the LORBRENA dose. ( 2.4 , 7.1 ) Strong CYP3A Inhibitors : Avoid concomitant use; reduce LORBRENA dose if concomitant use cannot be avoided. ( 2.4 , 7.1 ) Fluconazole : Avoid concomitant use; reduce LORBRENA dose if concomitant use cannot be avoided. ( 2.4 , 7.1 ) Certain CYP3A Substrates : Avoid concomitant use with CYP3A substrates for which minimal concentration changes may lead to serious therapeutic failures. ( 7.2 ) Certain P-gp Substrates : Avoid concomitant use with P-gp substrates for which minimal concentration changes may lead to serious therapeutic failures. ( 7.2 ) 7.1 Effect of Other Drugs on LORBRENA Strong CYP3A Inducers LORBRENA is contraindicated in patients taking strong CYP3A inducers [see Contraindication (4) ] . Discontinue strong CYP3A inducers for 3 plasma half-lives of the strong CYP3A inducer prior to initiating LORBRENA [see Dosage and Administration (2.3) ] . Concomitant use of LORBRENA with a strong CYP3A inducer decreased lorlatinib plasma concentrations [see Clinical Pharmacology (12.3) ] , which may decrease the efficacy of LORBRENA. Severe hepatotoxicity occurred in healthy subjects receiving LORBRENA with rifampin, a strong CYP3A inducer. In 12 healthy subjects receiving a single 100 mg dose of LORBRENA with multiple daily doses of rifampin, Grade 3 or 4 increases in ALT or AST occurred in 83% of subjects and Grade 2 increases in ALT or AST occurred in 8%. A possible mechanism for hepatotoxicity is through activation of the pregnane X receptor (PXR) by LORBRENA and rifampin, which are both PXR agonists. Moderate CYP3A Inducers Avoid concomitant use of moderate CYP3A inducers with LORBRENA. If concomitant use is unavoidable, increase the LORBRENA dose [see Dosage and Administration (2.4) ] . Concomitant use of LORBRENA with a moderate CYP3A inducer decreased lorlatinib plasma concentrations, which may decrease the efficacy of LORBRENA [see Clinical Pharmacology (12.3) ] . Strong CYP3A Inhibitors Avoid concomitant use of LORBRENA with a strong CYP3A inhibitor. If concomitant use cannot be avoided, reduce the LORBRENA dosage [see Dosage and Administration (2.4) ] . Concomitant use with a strong CYP3A inhibitor increased lorlatinib plasma concentrations [see Clinical Pharmacology (12.3) ] , which may increase the incidence and severity of adverse reactions of LORBRENA. Fluconazole Avoid concomitant use of LORBRENA with fluconazole. If concomitant use cannot be avoided, reduce the LORBRENA dosage [see Dosage and Administration (2.4) ] . Concomitant use of LORBRENA with fluconazole may increase lorlatinib plasma concentrations [see Clinical Pharmacology (12.3) ] , which may increase the incidence and severity of adverse reactions of LORBRENA. 7.2 Effect of LORBRENA on Other Drugs Certain CYP3A Substrates Avoid concomitant use of LORBRENA...Contraindications
4 CONTRAINDICATIONS LORBRENA is contraindicated in patients taking strong CYP3A inducers, due to the potential for serious hepatotoxicity [see Warnings and Precautions (5.1) ] . Concomitant use with strong CYP3A inducers. ( 4 )
Pregnancy and Breastfeeding
8.1 Pregnancy Risk Summary Based on findings from animal studies and its mechanism of action [see Clinical Pharmacology (12.1) ] , LORBRENA can cause embryo-fetal harm when administered to a pregnant woman. There are no available data on LORBRENA use in pregnant women. Administration of lorlatinib to pregnant rats and rabbits by oral gavage during the period of organogenesis resulted in malformations, increased post-implantation loss, and abortion at maternal exposures that were equal to or less than the human exposure at the recommended dose of 100 mg once daily based on AUC (see Data ) . Advise a pregnant woman of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies are 2 to 4% and 15 to 20%, respectively. Data Animal Data Preliminary embryo-fetal development studies investigating the administration of lorlatinib during the period of organogenesis were conducted in rats and rabbits. In rabbits, lorlatinib administration resulted in abortion and total loss of pregnancy at doses of 15 mg/kg (approximately 3 times the human exposure at the recommended dose of 100 mg) or greater. At a dose of 4 mg/kg (approximately 0.6 times the human exposure at the recommended dose of 100 mg) toxicities included increased post-implantation loss and malformations including rotated limbs, malformed kidneys, domed head, high arched palate, and dilation of the cerebral ventricles. In rats, administration of lorlatinib resulted in total loss of pregnancy at doses of 4 mg/kg (approximately 5 times the human exposure at the recommended dose of 100 mg) or greater. At a dose of 1 mg/kg (approximately equal to the human exposure at the recommended dose of 100 mg) there was increased post-implantation loss, decreased fetal body weight, and malformations including gastroschisis, rotated limbs, supernumerary digits, and vessel abnormalities.
How Supplied
16 HOW SUPPLIED/STORAGE AND HANDLING Table 11 describes the available strengths and package configurations for LORBRENA: Table 11 LORBRENA Tablets Strength (mg) Package Configuration NDC Description 25 30 tablets bottle with a child-resistant closure 0069-0227-01 8 mm round, tan, immediate release film‑coated tablet, debossed with “Pfizer” on one side and “25” and “LLN” on the other side 25 120 tablets bottle with a child-resistant closure 0069-0227-03 8 mm round, tan, immediate release film‑coated tablet, debossed with “Pfizer” on one side and “25” and “LLN” on the other side 100 30 tablets bottle with a child-resistant closure 0069-0231-01 8.5 mm × 17 mm oval, lavender, immediate release, film‑coated tablet, debossed with “Pfizer” on one side and “LLN 100” on the other side Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].
About This Information
This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.
What are side effects?
Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.
What are drug interactions?
Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.