Drug Interactions between acetaminophen / butalbital / caffeine / codeine and pembrolizumab

GENERALLY AVOID: Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants (e.g., nonbenzodiazepine sedatives/hypnotics, anxiolytics, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol) may result in profound sedation, respiratory depression, coma, and death. The risk of hypotension may also be increased with some CNS depressants (e.g., alcohol, benzodiazepines, phenothiazines).

MANAGEMENT: The use of opioids in conjunction with benzodiazepines or other CNS depressants should generally be avoided unless alternative treatment options are inadequate. If coadministration is necessary, the dosage and duration of each drug should be limited to the minimum required to achieve desired clinical effect, with cautious titration and dosage adjustments when needed. Patients should be monitored closely for signs and symptoms of respiratory depression and sedation, and advised to avoid driving or operating hazardous machinery until they know how these medications affect them. Cough medications containing opioids (e.g., codeine, hydrocodone) should not be prescribed to patients using benzodiazepines or other CNS depressants including alcohol. For patients who have been receiving extended therapy with both an opioid and a benzodiazepine and require discontinuation of either medication, a gradual tapering of dose is advised, since abrupt withdrawal may lead to withdrawal symptoms. Severe cases of benzodiazepine withdrawal, primarily in patients who have received excessive doses over a prolonged period, may result in numbness and tingling of extremities, hypersensitivity to light and noise, hallucinations, and epileptic seizures.

MONITOR: Opioid analgesics may reduce the efficacy of immune checkpoint inhibitors (ICIs) such as anti-cytotoxic T-lymphocyte-associated protein (CTLA)-4 monoclonal antibodies and/or inhibitors of programmed cell death-1 (PD-1)/programmed death ligand-1 (PD-L1). The mechanism of this interaction has not been fully elucidated, but may involve the ability of opioids to modify cellular functions of the immune system (T-cells), potentially affecting tumor growth. Additionally, ICIs can suppress the efficacy of opioids leading to an increase in opioid use via inhibition of the PD-1/PD-L1 signaling pathway. In a meta-analysis review of 7 studies (531 studies screened), it was observed that the use of opioids in patients treated with ICIs was negatively associated with overall survival (OS) and significantly reduced progression-free survival (PFS). Similarly, an observational, retrospective study including 375 patients with recurrent or metastatic cancer treated with anti-PD-1 or anti-PD-L1 monoclonal antibodies noted that patients who were not treated with opioid analgesics had significantly longer median PFS (6.83 vs. 4.30 months) and median OS (17.05 vs 7.68 months) compared to patients who were treated with opioid analgesics. Furthermore, a retrospective, single-center, observational cohort study observed that the median amount of change in opioid dose from baseline was significantly higher in patients who were treated with ICIs as compared to patients who were treated with non-ICI anticancer therapies (22.5 vs. 15.0 morphine mg equivalents). Multiple regression analysis and propensity score matching identified ICI administration as an independent factor associated with the amount of increase in opioid dose.

MANAGEMENT: Until more information is available, caution and clinical monitoring for reduced efficacy of immune checkpoint inhibitors (ICIs) and opioid analgesics are advised if concomitant therapy is required. Opioid analgesic use should be limited to clinically appropriate indications and durations. Clinicians should consult relevant literature, local and national treatment guidelines, and package labeling for further guidance.

MONITOR: Barbiturates may increase the hepatotoxic potential of acetaminophen and decrease its therapeutic effects. The mechanism may be related to accelerated CYP450 metabolism of acetaminophen with consequent increase in hepatotoxic metabolites. This interaction is of greatest concern in cases of acetaminophen overdose.

MANAGEMENT: Monitoring for altered efficacy and safety is recommended. Prolonged use or high doses of acetaminophen should be avoided by patients on barbiturate therapy.

MONITOR: Acetaminophen may reduce the efficacy of immune checkpoint inhibitors (ICIs) such as anti-cytotoxic T-lymphocyte-associated protein (CTLA)-4 monoclonal antibodies and/or inhibitors of programmed cell death-1 (PD-1)/programmed death ligand-1 (PD-L1). The mechanism of this interaction has not been fully elucidated, but may involve the ability of acetaminophen to impair proliferation of immune cells and T-cell mediated antitumor immunity, which has been observed in some studies. In the CheckMate 025 trial, patients with advanced renal cell carcinoma (n=297) and detectable serum levels of acetaminophen or its metabolite acetaminophen glucuronide were observed to have significantly poorer overall survival (OS) than patients without detectable acetaminophen levels at treatment onset. Similarly, it was noted during an analysis of plasma samples from patients (n=34) in a separate study who were treated with anti-PD-L1 therapies, with or without anti-CTLA-4 antibodies, that those with a detectable serum acetaminophen level had a significantly lower objective response rate than those without a detectable acetaminophen level (0% vs. 29.4%, respectively). Although OS was numerically shorter for patients with detectable acetaminophen levels compared to those without, this difference was not statistically significant in this study. Likewise, an analysis of plasma samples from patients enrolled in the PREMIS study (n=297) treated with anti-PD-L1 therapies, with or without anti-CTLA-4 antibodies, found that the presence of detectable acetaminophen levels was associated with significantly worse progression-free survival (PFS, median 2.63 months vs. 50.3 months) and OS (median 8.43 months vs. 14.93 months) when compared to those without detectable acetaminophen levels. Similarly, a retrospective single-center study in patients (n=225) with stage IV non-small cell lung cancer (NSCLC) who underwent first-line therapy with pembrolizumab (alone or in combination with platinum-based chemotherapy) or second-line therapy with pembrolizumab, nivolumab, or atezolizumab noted that patients who were exposed to high intensity acetaminophen (defined as therapeutic intake lasting >24 hours or a total intake >60 doses of 1000 mg) between 30 days before to 90 days after the first ICI infusion had an increased risk of treatment failure and a shorter duration of median PFS and OS. Multivariate analyses confirmed that high exposure to acetaminophen was independently associated with a reduction in both PFS and OS. Data are not available for every ICI in combination with acetaminophen in every clinical situation.

MANAGEMENT: Until more information is available, caution and clinical monitoring for reduced efficacy of immune checkpoint inhibitors (ICIs) may be advisable if they are administered with acetaminophen. One study suggests that only a pronounced and/or prolonged intake of acetaminophen is able to reduce the immune response to anti-PD-1/PD-L1 agents in patients with advanced NSCLC and suggests a more restrained and discontinuous intake of acetaminophen (<4 doses of 1000 mg/week) may help avoid worsening patient outcomes in this patient population.