Ketoacidosis in a Patient with Type 2 Diabetes Requiring Alpelisib: Learnings and Observations Regarding Alpelisib Initiation and Rechallenge.

Background: Diabetic ketoacidosis (DKA) is a rare complication of alpelisib, but cases of DKA are reported. Alpelisib's safety in patients with long-standing, suboptimally controlled diabetes is unclear since clinical trials of alpelisib did not include them. Case: A case is presented on a patient with metastatic breast cancer and type 2 diabetes admitted for DKA eleven days after starting alpelisib. Since DKA is implicated in antihyperglycemics that inhibit sodium-glucose cotransporter-2 (SGLT2) inhibitors, her empagliflozin was discontinued. Alpelisib was also held since it was recently initiated. After the DKA resolved, she was discharged and restarted alpelisib. Within 4 hours of taking the first dose, the patient developed a second episode of DKA, and alpelisib treatment was stopped permanently. Conclusion: Patients with long-standing type 2 diabetes are at high risk of alpelisib-induced Grade 3 and 4 hyperglycemia, including DKA. It is essential to communicate with non-oncology stakeholders about the risk of DKA with alpelisib as it can be overlooked for more common causes. Restarting alpelisib can result in severe hyperglycemia or DKA within 24 hours of the first dose. In this population, the risks associated with rechallenging alpelisib must be heavily weighed against its benefits. Before restarting alpelisib, a thorough evaluation of the appropriateness of the patient's antihyperglycemics and diet must occur to anticipate and mitigate a second event. Antihyperglycemics independent of the PI3K/AKT/mTOR pathway may be preferred agents. A plan should be in place to quickly respond to rising glycemia and early referral to a diabetologist or endocrinologist is recommended. Continuous glucose monitoring and hospital admission are recommended during rechallenge. A better understanding of alpelisib-induced hyperglycemia, especially in patients with diabetes, is required to navigate alpelisib treatment safely. Emphasis should be placed on patient education of symptoms and monitoring parameters.

Developing recommendations for the safe handling of oral anti-cancer drugs in community pharmacies: A pan-Canadian consensus approach.

PURPOSE: To create a set of consensus-based and evidence-informed recommendations to provide guidance around the safe dispensing and handling of oral anti-cancer drugs in low-volume settings unique to the community pharmacy setting. METHODS: A review of published and grey literature (published in non-commercial domains such as national organizations and associations) documents and nine key informant interviews were conducted and a modified Delphi approach was taken to achieve consensus. The final list of 47 candidate recommendations was reviewed by a task force and validated by multi-disciplinary stakeholders. A draft of the statements was circulated broadly within the community pharmacy community in an effort to assess relevance and implementation feasibility. RESULTS: The final report included 44 recommendations that addressed 11 key areas germane to the safe handling of oral anti-cancer drugs in community pharmacies. Mean agreement increased from 70% to 95%. Early feedback from community pharmacy leaders during the external review suggests that many of the proposed recommendations can be feasibly implemented within a reasonable timeframe when released with appropriate education and resource materials. CONCLUSIONS: A modified-Delphi approach supplemented by key informant interviews and a comprehensive external review resulted in a set of evidence-informed, community-driven recommendations for community pharmacies. The recommendations address a gap in existing literature to improve understanding of the risks associated with handling and dispensing oral anti-cancer drugs for both community pharmacy staff and management and offer mitigating strategies to reduce those risks. Incorporating feasibility assessment actions early (through the key informant interviews) and late (through the external review) ensures recommendations are grounded in practicality and support broad and early knowledge translation strategies.

A modified filgrastim regimen does not reduce pain burden compared to pegfilgrastim in women receiving chemotherapy for non-metastatic breast cancer.

PURPOSE: The short half-life of filgrastim allows for modification in the dose or duration of prophylaxis to limit inconvenience, adverse effects, and cost. The objectives of this study were to characterize and compare pain and neutropenic events between filgrastim and pegfilgrastim. METHODS: A prospective, observational study was performed. Eligible patients had non-metastatic breast cancer and were to receive adjuvant or neo-adjuvant chemotherapy with prophylaxis for febrile neutropenia. The prophylaxis used was a fixed-dose regimen of filgrastim 300 µg subcutaneously once daily for 7 days or pegfilgrastim 6 mg subcutaneously for 1 day. Participants completed a pain diary once a day for 14 days commencing the evening of the patient's first chemotherapy. Telephone interviews occurred at two instances within 2 weeks after their first treatment. The primary endpoints of this study were the difference in pain and incidences of neutropenia. Muscle pain, pain burden, and potential risk factors for pain were also explored. RESULTS: A total of 142 women were enrolled, 94 with pegfilgrastim and 48 with filgrastim. Filgrastim was associated with worse joint and muscle pain compared to pegfilgrastim. Joint pain was present in 38 and 26 % of diary entries for filgrastim and pegfilgrastim, respectively (p = 0.009). The mean AUC for joint pain score across 14 days, normalized to 100, were 6.0 for pegfilgrastim and 8.6 for filgrastim in patients receiving non-docetaxel chemotherapy and 14.6 for pegfilgrastim and 21.5 for filgrastim in patients receiving docetaxel-based chemotherapy (p = 0.037). Muscle pain patterns and frequencies were similar to joint pain. There were no statistical differences in febrile neutropenia and neutropenic events. CONCLUSIONS: Both filgrastim and pegfilgrastim caused significant pain burden. A fixed-dose regimen of filgrastim may be effective, but offers no advantage to minimize muscle or joint pain and, in fact, appears to cause greater and more frequent pain.

Should the concomitant use of erlotinib and acid-reducing agents be avoided? The drug interaction between erlotinib and acid-reducing agents.

CONTEXT: Erlotinib, an epidermal growth factor receptor tyrosine kinase inhibitor, exhibits a drug interaction with proton pump inhibitors (PPIs) and histamine-2 receptor antagonists (H2RAs). The manufacturer recommends avoidance of the combination however, the extent of the drug interaction is not clearly understood. Evidence acquisition. A literature search was performed and the pharmacokinetics and pharmacology of acid-reducing agents were reviewed. RESULTS: Acid-reducing agents reduce the solubility, and subsequent absorption, of erlotinib by raising gastric pH. Our literature search was unable to identify any published studies or case reports that address this issue. Until more information is available, the clinical relevance of this interaction, and whether it actually leads to failure of therapy, is unknown. PPIs would all be expected to exhibit a similar effect on erlotinib. Of the H2RAs, co-administration appears to have a greater impact than administering them separately. Ranitidine, famotidine, and nizatidine should likely have similar effects on erlotinib absorption. Cimetidine has a shorter duration of action, but should be used with caution because of its effects on cytochrome P450 3A4, a pathway also utilized by erlotinib. Antacids are not expected to have a significant effect. CONCLUSIONS: The clinical relevance of this drug interaction is unknown. Until more information is available, decision making regarding this interaction should be on a patient-by-patient basis. The indication for acid-reducing therapy should be reevaluated and stopping therapy or changing therapy can be considered. However, there may be occasions where any benefit of such actions will be exceeded by its risks.