Lorbrena (lorlatinib): Lung Cancer Drug Side Effects & Warnings

Generic drug: lorlatinib

Brand name: Lorbrena

What is Lorbrena (lorlatinib), and how does it work?

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.

What are the side effects of Lorbrena?

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.

What is the dosage for Lorbrena?

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

Adverse Reaction^a
Dosage Modifications

Central Nervous System Effects

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

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

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, resume Lorbrena at a reduced dose.

Recurrent complete AV block
Place pacemaker or permanently discontinue Lorbrena.

Interstitial Lung Disease (ILD)/Pneumonitis

Any Grade treatment-related ILD/Pneumoniti s
Permanently discontinue Lorbrena.

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 Lorbrena until hypertension has recovered to Grade 1 or less (SBP less than 140 mmHg and DBP less than 90 mmHg), then resume
Lorbrena at the same dose. If Grade 3 hypertension recurs, withhold
Lorbrena 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
Lorbrena.

Grade 4 (life-threatening consequences, urgent intervention indicated)
Withhold Lorbrena until recovery to Grade 1 or less, and resume at a reduced dose or permanently discontinue
Lorbrena. If Grade 4 hypertension recurs, permanently discontinue
Lorbrena.

Hyperglycemia

Grade 3 ((greater than 250 mg/dL) despite optimal anti-hyperglycemic therapy OR Grade 4
Withhold Lorbrena until hyperglycemia is adequately controlled, then resume
Lorbrena at the next lower dosage. If adequate hyperglycemic control cannot be achieved with optimal medical management, permanently discontinue
Lorbrena.

Other Adverse Reactions

Grade 1 OR Grade 2
Continue Lorbrena at same dose or reduced dose.

Grade 3 OR Grade 4
Withhold Lorbrena until symptoms resolve to less than or equal to Grade 2 or baseline. Resume
Lorbrena at reduced dose.

Abbreviation: AV=atrioventricular; DBP=diastolic blood pressure; SBP=systolic blood pressure.
^a Grade based on National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.

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.

What drugs interact with Lorbrena?

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.

Is Lorbrena safe to use while pregnant or breastfeeding?

• 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.