Drug interaction between idelalisib and diazepam resulting in altered mental status and respiratory failure

Abstract

In recent years, several new oral anticancer drugs have been approved, many via an accelerated approval process. These new agents have the potential for drug interactions, but lack of familiarity with these drugs by clinicians may increase the risk for drug interactions. We describe an interaction between the new anticancer agent idelalisib (CYP 3A4 inhibitor) and diazepam (CYP 3A4 substrate) that resulted in altered mental status and type II respiratory failure resulting in hospitalization. After discontinuation of both agents, the patient recovered quickly. Idelalisib was reinitiated after discharge. Lorazepam was substituted for diazepam since it is not metabolized via CYP 3A4. Both agents were tolerated well thereafter. This interaction was only flagged by two of four commonly used drug interaction databases. Clinicians should exercise caution with initiating new oral anticancer agents and consider the potential for drug interactions without solely relying on drug interaction databases.

Drug Interaction Database Sensitivity With Oral Antineoplastics: An Exploratory Analysis

“…The case of a patient experiencing altered mental status and type II respiratory failure due to an interaction between idelalisib and diazepam illustrates this concern, because the interaction was only flagged by two of four commonly used electronic DDI databases. 8 Previous researchers have used both MicroMedex and Drugs.com to evaluate the prevalence of DDIs with OAs. 3,9 However, whether any one database is superior for screening of OA interactions is unknown.…”

Clinically Significant Drug-Drug Interactions Involving Medications Used for Symptom Control in Patients With Advanced Malignant Disease: A Systematic Review

“…Twenty publications related to DDIs of symptomatic drugs and oncologic agents (Table 1). 15e32, 46,54 The details of all DDIs are given in Table 1.…”

“…We identified seven publications that reported DDIs of other drugs used for symptomatic treatment, including an opioid overdose caused by codeine used for cough concurrently with clarithromycin and voriconazole, 55 opioid overdose caused by concurrent use of methadone and cimetidine, 56 altered mental status and respiratory failure caused by coadministration of diazepam and idelalisib, 54 and two cases of bleeding reported to be secondary to the combined administration of drugs used for symptom control and anticoagulants (omeprazole and warfarin, and loperamide and dabigatran). 36,57 Two cases of DDIs with the possible contribution of cimetidine and midazolam are mentioned previously.…”

Pharmacokinetic drug-drug interactions of tyrosine kinase inhibitors: A focus on cytochrome P450, transporters, and acid suppression therapy

“…Among these drugs, ibrutinib should be prescribed with caution given its particular sensibility to CYP3A4 inhibitors with recent clinically documented interaction . Idelalisib as a perpetrator should be also prescribed with caution with drugs that are substrate of CYP3A4 with a case report of clinically significant interaction with diazepam …”

“…22 Idelalisib as a perpetrator should be also prescribed with caution with drugs that are substrate of CYP3A4 with a case report of clinically significant interaction with diazepam. 23 Besides DDIs, fruit juice interactions may be considered given the large consumption of fruit juices and the oral administration of TKIs. If grapefruit juice (GFJ) has a significant inhibitory effect on intestinal CYP3A4, other fruit juices such as orange juice (OJ), apple juice and other beverages such as green tea have a minimal effect on the pharmacokinetics of CYP3A4 substrates.…”