A new drug safety signal- “Rhabdomyolysis association with Alectinib” identified by the UMC (Uppsala Monitoring Center), from the VigiBase, a global drug safety database maintained by UMC on behalf of WHO. UMC is a WHO Collaborating Centre present in in Sweden for international service and scientific research within the field of pharmacovigilance.
Alectinib is an anti-cancer medication used in the treatment of non-small cell lung cancer (NSCLC) patients who are tested positive for anaplastic lymphoma kinase (ALK) gene and not responding to crizotinib (a medicine used to treat NSCLC). It belongs to the drug-therapeutic class of “ALK-Tyrosine kinase inhibitor (TKI)” which acts by inhibiting the ALK-TKI enzyme involved in the growth of cells and development of blood vessels. Alectinib initially developed in Japan, gained accelerated approval from US-FDA for marketing in United States and gained a conditional approval from European medicine agency (EMA) for marketing in Europe region.
Rhabdomyolysis is a serious and complex medical situation which involves the breakdown and rapid dissolution of damaged or injured skeletal muscle tissue into blood. This could severely affect the functioning of kidneys.
On 19-May-2019, UMC identified 8 case reports from the VigiBase database pertaining to the drug-event combination: “Alectinib – Rhabdomyolysis” which is not consistent with the expected number of case reports (3). All these 8 case reports were considered as ‘serious’ and are originated from six different countries.
Listedness of Rhabdomyolysis in Alectinib product labels:
Rhabdomyolysis is not well documented in both European Summary of Product Characteristics (Eu-SmPC) and United States Prescribing information (USPI) documents. However, there are other two similar adverse drug reactions- “myalgia and increased blood CPK” which are documented in the Alectinib product labels.
Analysis of case reports supporting causal relationship for ‘Alectinib – Rhabdomyolysis’ pair
Temporal relationship: 12 to 14 days for the onset of symptoms (Time to onset of signs & symptoms was not reported in 4 cases).
Dechallenge: Positive for 6 cases (Rhabdomyolysis event resolved w.r.t alectinib dose interruption).
Rechallenge: Positive for 2 cases (reoccurrence of symptoms of rhabdomyolysis after alectinib reintroduction in two patients).
Abnormal laboratory investigations: Elevated CPK (creatine phosphokinase) levels after alectinib administration reported in the Index case.
A single suspected medicine: In 6 cases, Alectinib is reported as the only suspected medicinal product.
A glimpse on Roche response for this new drug-event combination:
With respect to UMC’s signal report, marketing authorization holder for alectinib-Roche concluded that causal association for ‘Alectinib – Rhabdomyolysis’ pair cannot be confirmed with the below responses-
Rhabdomyolysis Diagnosis: Roche stated that only one case report comprises the criteria for the diagnosis of rhabdomyolysis. In the remaining case reports, the specified abnormal laboratory investigations (elevated CPK levels) does not met the criteria required for rhabdomyolysis diagnosis, (as specified by Health Canada and USA MedWatch definitions) and due to lack of adequate elements from cases pertaining to rhabdomyolysis definition.
Strong Alternative explanations: Roche emphasized other contributing factors for myalgia and elevated levels of CPK which included concurrent medical conditions like retroperitoneal bleeding, brain metastasis and cachexia. In one case report, strenuous physical exercise is highlighted as confounding factor for muscle pain and CPK increase. Concomitant medications which are considered as confounding factors included mirtazapine, levetiracetam and statins for which myalgia, elevated CPK and rhabdomyolysis are labelled adverse drug reactions.