Lorbrena

Lorbrena (lorlatinib) is a prescription medicine that is used to treat people with non-small cell lung cancer (NSCLC)

• that is caused by an abnormal anaplastic lymphoma kinase (ALK) gene and,
• that has spread to other parts of your body and,
• who have taken the medicine alectinib or ceritinib or who have taken both the medicine crizotinib and at least 1 other medicine to treat NSCLC that is caused by the ALK gene, and
• their NSCLC is no longer responding to these treatments. It is not known if Lorbrena is safe and effective in children.

The most common side effects of Lorbrena include:

• swelling in your arms, legs, hands and feet (edema)
• numbness and tingling feeling in your joints or arms and legs (peripheral neuropathy)
• difficulty thinking or confusion
• difficulty breathing
• tiredness (fatigue)
• weight gain
• pain in your joints
• changes in mood, feeling sad or anxious
• diarrhea

Lorbrena may cause decreased fertility in males. In males, this could affect your ability to father a child. Talk to your healthcare provider if you have concerns about fertility.

These are not all of the possible side effects of Lorbrena. For more information, ask your healthcare provider or pharmacist.

Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Patient Selection

• Select patients for the treatment of metastatic NSCLC with Lorbrena based on the presence of ALK positivity in tumor specimens.
• Information on FDA-approved tests for the detection of ALK rearrangements in NSCLC is available at http://www.fda.gov/CompanionDiagnostics.

Recommended Dosage

• The recommended dosage of Lorbrena is 100 mg orally once daily, with or without food, until disease progression or unacceptable toxicity.
• 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.

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

Concomitant Use of Strong CYP3A Inducers

• Lorbrena is contraindicated in patients taking strong CYP3A inducers. Discontinue strong CYP3A inducers for 3 plasma half-lives of the strong CYP3A inducer prior to initiating Lorbrena.

Concomitant Use of Moderate CYP3A Inducers

• Avoid concomitant use of moderate CYP3A inducers with Lorbrena. If concomitant use with moderate CYP3A inducers is unavoidable, increase the Lorbrena dose to 125 mg once daily.

Dosage Modification for Strong CYP3A Inhibitors

• Avoid concomitant use of Lorbrena with strong CYP3A inhibitors. If concomitant use with a strong CYP3A inhibitor is unavoidable, reduce the starting dose of Lorbrena from 100 mg orally once daily to 75 mg orally once daily.
• In patients who have had a dose reduction to 75 mg orally once daily due to adverse reactions and who initiate a strong CYP3A inhibitor, reduce the Lorbrena dose to 50 mg orally once daily.
• If concomitant use of a strong CYP3A inhibitor is discontinued, increase the Lorbrena dose (after 3 plasma half-lives of the strong CYP3A inhibitor) to the dose that was used before starting the strong inhibitor.

Dosage Modification for Fluconazole

• Avoid concomitant use of Lorbrena with fluconazole. If concomitant use is unavoidable, reduce the starting dose of Lorbrena from 100 mg orally once daily to 75 mg orally once daily.

Dosage Modification for Severe Renal Impairment

• Reduce the recommended dosage of Lorbrena for patients with severe renal impairment (creatinine clearance [CLcr] 15 to < 30 mL/min, estimated by Cockcroft-Gault) from 100 mg to 75 mg orally once daily.

Effect of Other Drugs on Lorbrena

Strong CYP3A Inducers

• Concomitant use of Lorbrena with a strong CYP3A inducer decreased lorlatinib plasma concentrations, 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.
• Lorbrena is contraindicated in patients taking strong CYP3A inducers. Discontinue strong CYP3A inducers for 3 plasma half-lives of the strong CYP3A inducer prior to initiating Lorbrena.

Moderate CYP3A Inducers

• Concomitant use of Lorbrena with a moderate CYP3A inducer decreased lorlatinib plasma concentrations, which may decrease the efficacy of Lorbrena.
• Avoid concomitant use of moderate CYP3A inducers with Lorbrena. If concomitant use is unavoidable, increase the Lorbrena dose.

Strong CYP3A Inhibitors

• Concomitant use with a strong CYP3A inhibitor increased lorlatinib plasma concentrations, which may increase the incidence and severity of adverse reactions of Lorbrena. Avoid concomitant use of Lorbrena with a strong CYP3A inhibitor. If concomitant use cannot be avoided, reduce the Lorbrena dosage.

Fluconazole

• Concomitant use of Lorbrena with fluconazole may increase lorlatinib plasma concentrations, which may increase the incidence and severity of adverse reactions of Lorbrena. Avoid concomitant use of Lorbrena with fluconazole. If concomitant use cannot be avoided, reduce the Lorbrena dosage.

Effect of Lorbrena on Other Drugs

Certain CYP3A Substrates

• Lorbrena is a moderate CYP3A inducer. Concomitant use of Lorbrena decreases the concentration of CYP3A substrates, which may reduce the efficacy of these substrates.
• Avoid concomitant use of Lorbrena with certain CYP3A substrates, for which 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.

Certain P-glycoprotein (P-gp) Substrates

• Lorbrena is a moderate P-gp inducer. Concomitant use of Lorbrena decreases the concentration of P-gp substrates, which may reduce the efficacy of these substrates.
• Avoid concomitant use of Lorbrena with certain 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.

• There are no available data on Lorbrena use in pregnant women.
• 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 Lorbrena and for 7 days after the final dose.