. 2022 Nov 11;7(6):100612. doi: 10.1016/j.esmoop.2022.100612

Table 4.

Guidance for physicians on the management of AEs in patients receiving alectinib

	Guidance for physicians
Myalgia	• Inform patients of the possibility of myalgia occurring when initiating alectinib treatment and reassure them that it can be easily managed • Advise patients to report any unexplained muscle pain, tenderness or weakness¹⁵^,¹⁶ • Follow up with patients regularly to assess the impact of myalgia on their daily life, as patients may need to reduce their daily activity, which could be more difficult for younger patients • Assess CPK levels every 2 weeks for the first month of treatment and as clinically indicated in patients reporting symptoms¹⁵^,¹⁶ • When CPK is elevated to >5 times ULN, temporarily withhold alectinib until recovery to baseline, or to ≤2.5 times ULN, then resume at the same dose¹⁵^,¹⁶ • When CPK is elevated to >10 times ULN or it is the second occurrence of CPK elevation of >5 times ULN, temporarily withhold alectinib until recovery to baseline or to ≤2.5 times ULN, then resume at a reduced dose¹⁵^,¹⁶
Peripheral oedema	• Advise patients to use pressure stockings to reduce fatigue in the legs • Exclude other sources of peripheral oedema (cardiac, liver and renal) • Consider prescribing diuretics as a short-term treatment • If severe, reduce the dose of alectinib
Bradycardia	• Inform patients of the possibility of bradycardia occurring when initiating alectinib treatment and reassure them to not worry about it • Patients with bradycardia while on alectinib treatment are not typically at risk for sudden death but may experience dizziness or syncope • Advise patients that their GP or cardiologist should seek input from their oncologist before reducing the dose of alectinib • Avoid co-medications, such as beta blockers, which may cause bradycardia • Dose modification is not required in case of asymptomatic bradycardia¹⁵^,¹⁶ • If patients experience symptomatic bradycardia (grade 2/3) or life-threatening (grade 4) events, concomitant medicinal products known to cause bradycardia, as well as antihypertensive medicinal products should be evaluated and the alectinib dose should be adjusted¹⁵^,¹⁶ ○ Refer to cardiologist; perform ECG every 1-3 months or refer for Holter monitoring and exclude other possible underlying conditions if patient is symptomatic • Resume alectinib at a reduced dose upon recovery to asymptomatic bradycardia or to a heart rate of ≥60 bpm, with frequent monitoring as clinically indicated¹⁵^,¹⁶ • Permanently discontinue alectinib if no contributing concomitant medicinal product is identified or in case of recurrence¹⁵^,¹⁶ • If bradycardia continues, a pacemaker may need to be fitted
Liver function abnormalities	• Review the patient’s co-medications and dietary habits • Monitor liver function, including ALT, AST and total bilirubin at baseline, then every 2 weeks during the first 3 months of treatment¹⁵^,¹⁶ ○ Thereafter, monitoring should be carried out periodically, since events may occur later than 3 months, with more frequent testing in patients who develop aminotransferase and bilirubin elevations¹⁵^,¹⁶ • If severe (grade 3/4), withhold and resume at a reduced dose of alectinib, or permanently discontinue¹⁵^,¹⁶ • If severe, conduct further investigations for the presence of liver metastases
Anaemia	• Exclude other sources of anaemia, in particular, abundant menstrual bleeding and iron metabolism disturbances • If severe, reduce the dose of alectinib, consider a blood transfusion when clinically indicated³⁷ and screen for haemolysis • Advise patients to report if they develop any signs or symptoms of haemolytic anaemia, such as jaundice, weakness or dizziness, or shortness of breath¹⁶ • Alectinib SmPC¹⁵ ○ If haemoglobin concentration is <10 g/dl and haemolytic anaemia is suspected, withhold alectinib and appropriate laboratory testing should be initiated ○ If haemolytic anaemia is confirmed, resume alectinib at a reduced dose upon resolution • Alectinib prescribing information¹⁶ ○ If haemolytic anaemia is suspected, withhold alectinib ○ If haemolytic anaemia is confirmed, consider resuming alectinib at a reduced dose upon resolution or permanently discontinue
Fatigue	• Exclude other sources of fatigue, such as low iron metabolism as a predisposing factor for anaemia or monitor weight • If severe, reduce the dose of alectinib
Constipation	• Follow current ESMO Clinical Practice guidelines on constipation in advanced cancer³⁸ • Consider dietary recommendations or laxative treatment
Renal toxicity	• Check if patients are drinking enough fluids • Carefully assess concomitant medications for their effects on renal function, such as nonsteroidal anti-inflammatory drugs • Consider carrying out CT without contrast for efficacy assessments • Alectinib SmPC¹⁵ ○ No dose adjustment of alectinib is required in patients with mild or moderate renal impairment ○ Alectinib has not been studied in patients with severe renal impairment; since alectinib elimination via the kidney is negligible, no dose adjustment is required in patients with severe renal impairment • Alectinib prescribing information¹⁶ ○ Withhold alectinib for grade 3 renal toxicity until recovery to ≤1.5 times ULN, then resume at a reduced dose ○ Permanently discontinue alectinib for grade 4 renal toxicity
Rash	• Advise patients to avoid direct or prolonged sun exposure while taking alectinib and for ≥7 days after discontinuation of treatment¹⁵^,¹⁶ • Advise patients to also use a broad-spectrum UVA/UVB sunscreen and lip balm (SPF ≥50) to help protect against potential sunburn¹⁵^,¹⁶

AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; bpm, beats per minute; CPK, creatine phosphokinase; CT, computed tomography; ECG, electrocardiogram; ESMO, European Society of Medical Oncology; GP, general practitioner; SmPC, summary of product characteristics; SPF, sun protection factor; ULN, upper limit of normal.