Recommendations for Therapy Management

Therapy Management for Specific Adverse Reactions

THERAPY MANAGEMENT GUIDANCE FOR HYPERLIPIDEMIA

  • Hyperlipidemia was generally managed with lipid-lowering agents and dose interruptions, and in more severe (Grade ≥3) cases, dose modification2
    • 80% of patients required initiation of lipid-lowering medications
    • Median time to start of lipid-lowering therapy: 21 days
    • Pitavastatin, pravastatin, or rosuvastatin should initially be considered based on their low involvement with specific CYP450 enzymes which can interact with LORBRENA (eg, CYP3A4)2
  • Monitor serum cholesterol and triglycerides before initiating LORBRENA, 1 and 2 months after initiating LORBRENA, and periodically thereafter
  • In the clinical trial, dose interruption was required in 3.4% of patients due to hypercholesterolemia and 6% of patients due to hypertriglyceridemia
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A broad spectrum of CNS effects can occur in patients receiving LORBRENA

  • These include seizures, hallucinations, and changes in cognitive function, mood (including suicidal ideation), speech, mental status, and sleep
  • In the clinical trial, 1.5% of patients required permanent discontinuation of LORBRENA for a CNS effect; 9% required temporary discontinuation, and 8% required dose reduction

DOSAGE MODIFICATION GUIDANCE FOR CNS EFFECTS

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  • The most commonly reported cognitive effects were memory impairment, cognitive disorder, and amnesia2
  • Patients and their caregivers should be instructed to report any changes in cognitive function to the patient’s healthcare professional2
  • In the clinical trial, dose interruption (4.4%), reduction (4.1%), or permanent discontinuation (0.7%) was required due to cognitive effects

DOSAGE MODIFICATION GUIDANCE FOR COGNITIVE EFFECTS

  • Cognitive effects were generally Grades 1-2 and reversible after dose modification2
  • The possibility of cognitive-related adverse reactions should be discussed with patients and caregivers prior to initiating LORBRENA treatment, along with advice on how to minimize the impact on daily activities (eg, setting reminders)2
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  • The most commonly reported mood effects were irritability, anxiety, depression, and affect lability2
  • In the clinical trial, dose interruption (3.1%), reduction (3.1%), or permanent discontinuation (0.7%) was required due to mood effects

DOSAGE MODIFICATION GUIDANCE FOR MOOD EFFECTS

  • Mood effects were generally Grades 1-2, temporary, and reversible after dose modification2
  • Effects on mood should be discussed with patients prior to treatment initiation, particularly in those with preexisting psychiatric conditions2
  • Patients and their caregivers should be instructed to report any changes in mood to the patient’s healthcare professional2
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  • Speech effects have been reported by patients as a perception of slowed speech or difficulty in word finding2
  • Patients and their caregivers should be instructed to report any changes in speech to the patient's healthcare professional2

DOSAGE MODIFICATION GUIDANCE FOR SPEECH EFFECTS

  • Speech effects were generally mild in severity and reversible upon dose modification or discontinuation, if needed2
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  • Patients should be advised of likely weight gain of some degree2

THERAPY MANAGEMENT GUIDANCE FOR WEIGHT GAIN

  • Dose modifications may help manage more severe cases of weight gain2
  • An increase in appetite has been reported by some patients, suggesting that body weight increase may potentially be associated with increased caloric intake and a heightened desire to eat; however, causality has not been determined2
  • Counseling on food intake, dietary advice from a nutritionist, and exercise may be effective weight management strategies for some patients2
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  • Edema was the most common cause of dose interruptions (7%) and reductions (6%) in the clinical trial

THERAPY MANAGEMENT GUIDANCE FOR EDEMA

  • Prior to LORBRENA dose modification, consider the following to manage low-grade edema in LORBRENA-treated patients2:
    • Compression stockings
    • Leg elevations
    • Lifestyle modifications (increased exercise and limiting dietary salt)
    • Diuretics (usually furosemide)
  • If edema persists or worsens, dose modification guidance of LORBRENA is recommended until edema resolves to Grade ≤2 (if not a safety risk) or to baseline and rechallenged at a reduced dose2
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THERAPY MANAGEMENT GUIDANCE FOR PERIPHERAL NEUROPATHY

  • Most reports of peripheral neuropathy were mild (Grades 1-2) and generally reversible following standard medical therapy or dose modification2
  • In the clinical trial, dose interruption (5%) or reduction (4.7%) was required due to peripheral neuropathy
  • Treatment with vitamin B1 and vitamin B6 and medications for pain associated with peripheral neuropathy may provide symptom relief for some patients2
  • For carpal tunnel syndrome, the use of a night splint may provide improvement2
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DOSAGE MODIFICATION GUIDANCE FOR INCREASED LIPASE

  • In the clinical trial, dose interruption was required in 3.7% of patients due to increased lipase
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  • GI effects were generally mild in severity2
  • Dose modifications due to GI effects were rare2

THERAPY MANAGEMENT GUIDANCE FOR GI EFFECTS

  • Constipation and diarrhea may be managed with standard medical therapy2
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  • In 295 patients who received LORBRENA at a dose of 100 mg orally once daily in Study B7461001 and who had a baseline electrocardiography (ECG)
    • 1% experienced AV block
    • 0.3% experienced Grade 3 AV block and underwent pacemaker placement
  • Before starting LORBRENA, patients should be2
    • Informed about potential risks of AV block
    • Advised to contact their healthcare professional immediately if they experience new chest pain or discomfort, heartbeat changes, palpitations, dizziness, lightheadedness, fainting, or changes in or new use of heart or blood pressure medication
  • Monitor ECG prior to initiating LORBRENA and periodically thereafter
  • For patients with preexisting PR prolongation, ECG monitoring should be conducted throughout treatment2

DOSAGE MODIFICATION GUIDANCE FOR AV BLOCK

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  • One patient (0.3%) discontinued LORBRENA for ILD/pneumonitis
  • Promptly investigate for ILD/pneumonitis in any patient who presents with worsening of respiratory symptoms indicative of ILD/pneumonitis (eg, dyspnea, cough, and fever)

DOSAGE MODIFICATION GUIDANCE FOR ILD/PNEUMONITIS

  • Immediately withhold LORBRENA in patients with suspected ILD/pneumonitis
  • Permanently discontinue LORBRENA for treatment-related ILD/pneumonitis of any severity
The data in Warnings and Precautions reflect exposure to LORBRENA in 332 patients with ALK-positive or ROS1-positive, metastatic NSCLC enrolled in a multi-cohort, multinational, non-comparative, dose-finding, and activity-estimating trial (Study B7461001) who received LORBRENA at doses ranging from 10 mg to 200 mg daily in single or divided doses.

DOSAGE MODIFICATION GUIDANCE FOR OTHER ADVERSE REACTIONS

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