Alectinib is a highly selective and potent inhibitor of the ALK and RET tyrosine kinases. Alectinib is indicated as first-line monotherapy for adults with ALK-positive advanced non-small cell lung cancer (NSCLC). As monotherapy, the medicinal product is also indicated for the treatment of adults with ALK-positive advanced NSCLC who have previously been treated with crizotinib. The EU package leaflet contains information on severe myalgia and elevated creatine phosphokinase (CPK) levels. In the pivotal clinical trials of Alectinib, cases of myalgia and musculoskeletal pain were reported, including those of grade 3 severity. Cases of elevated CPK levels, including those of grade 3 severity, were also observed in the pivotal clinical trials. The median time to onset of grade 3 CPK elevation in clinical trials (NP28761, NP28673, BO28984) was 14 days.
Myalgia and elevated blood CPK levels are listed in the instructions for medical use of medicinal products containing Alectinib in the EU and the US. However, no information on rhabdomyolysis is provided.
As of May 19, 2019, the WHO Global Database VigiBase contained 8 reports on Alectinib and the adverse reaction of rhabdomyolysis. The reports indicate a relationship between Alectinib and rhabdomyolysis. In 6 cases Alectinib is the only suspected drug.
Currently, the instructions for medical use of Alectinib do not contain sufficient precautions and warnings to inform healthcare professionals and patients about the adverse reaction – rhabdomyolysis.
Tyrosine kinases, such as anaplastic lymphoma kinase (ALK), are major areas of interest for the development of new chemotherapy agents. ALK plays an important role in brain development; it also drives the progression of several cancers, including anaplastic large cell lymphoma, neuroblastoma and non-small cell lung cancer (NSCLC). Alectinib is a highly selective and potent inhibitor of ALK and RET tyrosine kinases.
Alectinib received accelerated approval in the USA from the FDA in December 2015 for the treatment of patients with ALK-positive advanced NSCLC whose disease worsened after crizotinib or who were intolerant to crizotinib. Full approval followed in November 2017. The medicinal product was conditionally approved by the EMA in February 2017 for the same indications and was extended in October 2017 with an indication for first-line therapy in adult patients with ALK-positive advanced NSCLC.
Alectinib is available as capsules (150 mg). The recommended dose is 4 capsules 2 times/day with food (1200 mg per day in total). For patients with severe hepatic impairment, the recommended dose is 3 capsules 2 times/day with food (900 mg). If adverse effects occur, the physician may reduce the dose or temporarily discontinue treatment. Most of the adverse effects caused by ALK inhibitors can be managed effectively by dose modification or treatment interruption.
Drug-related myotoxicity, in the form of rhabdomyolysis or myoglobinuria, is the most serious medical emergency. Rhabdomyolysis is an acute fulminant necrotizing myopathy that can cause severe myalgia, muscle swelling and weakness, as well as an increase in CPK levels to 2000 times above the upper limit of normal. This is associated with myoglobinuria (dark brown or pink urine due to the presence of pigmented myoglobin), which can cause acute renal failure and death. If the suspected drug is discontinued and patients are actively treated, the muscles, as a rule, recover well.
The combination Alectinib – rhabdomyolysis was first identified in 2016 during VigiBase screening focused on new medicinal products and serious adverse drug reactions.
As of May 2019, out of more than 20 million reports in VigiBase, 1993 reports named Alectinib as the suspected medicinal product. A total of 8 reports (0,4%) concerned the combination of Alectinib with rhabdomyolysis; all of these reports were classified as serious. The reports came from Germany (2), Portugal (2), Austria, Canada, the USA, and Australia (one each, respectively).
Discussion and conclusion
Besides hepatotoxicity, the next category of adverse reactions to be monitored is myalgia and elevated CPK levels. Among ALK inhibitors, this is characteristic only of Alectinib and, to a lesser extent, Brigatinib (43% and 30% for CPK elevation of any grade). Since patients are poorly informed about the signs of myalgia and CPK elevation, before starting treatment they should be informed about potential symptoms such as muscle pain or weakness. As with adverse liver reactions, CPK elevation also has an early onset. The median time to CPK elevation to grade 3 occurs by approximately day 14, so CPK levels should be monitored every two weeks during the first month of treatment, and then as often as clinically required. If severe myalgia or CPK elevation occurs, it is advisable to discontinue treatment with Alectinib until the CPK elevation decreases to at least grade 1.
Currently, rhabdomyolysis is not listed in the instruction for medical use of Alectinib, only myalgia and increased CPK levels. However, the existing reports in VigiBase indicate an association between Alectinib and rhabdomyolysis. In 6 cases, Alectinib was reported as the only suspected drug. In 6 cases, regression of rhabdomyolysis symptoms after drug withdrawal was reported. In 2 cases, the adverse reaction recurred after the drug was resumed. The time to onset of the adverse reaction was 12-14 days. At present, the instruction for medical use of Alectinib does not inform patients and healthcare professionals about the potential interaction with statins and their synergistic effect on rhabdomyolysis.
More detailed information on the mechanisms of action of Alectinib, cases of rhabdomyolysis and their analysis is provided in the document Uppsala Monitoring Centre “Alectinib– Rhabdomyolysis”. (504 KB) (Downloaded: 25.01.2021 08:42:49) List of medicinal products containing Alectinib that are authorized for medical use in Ukraine (according to the State Register of Medicinal Products as of 31.03.2020). (2.8 MB) (Downloaded: 25.01.2021 08:42:49)
