EU Safety Updates For Lenalidomide, Pegfilgrastim & Pembrolizumab
Executive Summary
The labeling of several major medicines marketed in the EU is to be updated to reflect cases of serious adverse events. The European Medicines Agency’s pharmacovigilance committee has also recommended a new warning on drug-drug interactions, and asked for additional information on several other products.
A European Medicines Agency committee has recommended changes to the labeling of a number of medicines as a result of safety signals received through the EU’s pharmacovigilance system and other sources, including reports of progressive multifocal leukoencephalopathy (PML) associated with lenalidomide, aseptic meningitis with pembrolizumab, and rare cases of pulmonary hemorrhage with lenograstim, pegfilgrastim and lipegfilgrastim.
The EMA's Pharmacovigilance Risk Assessment Committee has also asked manufacturers to submit supplementary information on a range of other drugs for which safety signals have been detected.
Lenalidomide And Pembrolizumab
Lenalidomide (Celgene Corp.'s Revlimid) is authorized for multiple myeloma, myelodysplastic syndromes and mantle cell lymphoma. The company has been asked to change the labeling to warn that cases of PML have been reported with the drug several months to several years after starting treatment, generally in patients who were also taking dexamethasone or who had prior treatment with other immunosuppressive chemotherapy.
The labeling should also say that patients should be monitored at regular intervals and that doctors should “consider PML in the differential diagnosis in patients with new or worsening neurological symptoms, cognitive or behavioural signs or symptoms, the PRAC says. It should state that the evaluation for PML should be based on neurological examination, MRI imaging of the brain, and cerebrospinal fluid analysis for JC virus (JCV) DNA by polymerase chain reaction or a brain biopsy with testing for JCV. “If PML is suspected, further dosing must be suspended until PML has been excluded. If PML is confirmed, lenalidomide must be permanently discontinued.” In the case of Merck & Co. Inc.'s pembrolizumab (Keytruda), the PRAC cites rare cases of aseptic meningitis reported on the basis of evidence in EudraVigilance and the literature, and says the side-effects section of the labeling should be updated to reflect this. Aseptic meningitis is characterized by inflammation of the membrane around the spinal cord and brain that may present as neck stiffness, headache, fever, eye sensitivity to light, and nausea and vomiting.
G-CSF Products
Having considered evidence from the EudraVigilance database, the possibility of a class effect, and responses from marketing authorization holders (MAHs), the PRAC has recommended that the labeling of the G-CSF products for neutropenia, pegfilgrastim (Amgen Inc.’s Neulasta), lipegfilgrastim (Teva Pharmaceutical Industries Ltd.’s Lonquex) and lenograstim (Chugai Pharmaceutical Co. Ltd. ’s Granocyte) should be updated to reflect the products’ potential to cause hemoptysis (coughing up blood) and pulmonary hemorrhage. For pegfilgrastim, the two adverse events are described by the PRAC as “uncommon” and “rare” respectively, while the frequencies for the other two drugs are to be calculated by the MAHs, the PRAC says.
Applicants with pegfilgrastim products under evaluation are advised to update their product information accordingly during the assessment process, according to the committee. Eight biosimilar versions of the product are currently being evaluated for approval by the EMA’s drug assessment committee, the CHMP. (Also see "Pfizer’s Dacomitinib And More Biosimilar Hopefuls Among New EMA Filings " - Pink Sheet, 12 Mar, 2018.)
Apixaban & Edoxaban Interactions
On the basis of evidence from EudraVigilance and the literature, “including the response from Bristol-Myers Squibb Co. and Daiichi Sankyo Europe GmBH," the PRAC has asked the companies to update the labeling of their respective anticoagulant products, apixaban (Eliquis) and edoxaban (Lixiana/Roteas). The list of products that could increase the risk of bleeding when used concomitantly with apixaban and edoxaban is now to include selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs).
The label currently warns of a risk of increased bleeding when either apixaban or edoxaban is used together with medicines affecting hemostasis, such as acetylsalicylic acid, P2Y12 platelet inhibitors, other thrombolytic agents, fibrinolytic therapy, and NSAIDs.
The updated label will say: “As with other anticoagulants the possibility may exist that patients are at increased risk of bleeding in case of concomitant use with SSRIs or SNRIs due to their reported effect on platelets.”
Information Requests
The PRAC has requested supplementary information from companies on a number of products and product classes, including the following (safety signals in parentheses):
- apixaban (neutropenia);
- direct acting antivirals for hepatitis C (dysglycemia);
- dolutegravir (birth outcomes in HIV-infected women);
- hormonal contraceptives (suicidality);
- ipilimumab (cytomegalovirus GI infection);
- niraparid (potential occurrence of embolic and thrombolic events);
- tocilizumab (non-infectious encephalitis); and
- pertuzumab/trastuzumab/trastuzumab emtansine (multiple sclerosis relapse).
From the editors of Scrip Regulatory Affairs.