Drug Interaction Report

MONITOR: Coadministration of Janus kinase (JAK) inhibitors with corticosteroids, nonsteroidal anti-inflammatory drugs (NSAIDs), and/or opioids may increase the risk of gastrointestinal (GI) perforation. Patients with a prior history of peptic ulceration or diverticular disease may also have an increased risk. Adverse events of diverticulitis and GI perforation have been infrequently reported in clinical studies and postmarketing use of JAK inhibitors such as baricitinib, ruxolitinib, tofacitinib, and upadacitinib. However, the role of JAK inhibition in these events has not been determined. In studies with rheumatoid arthritis and ulcerative colitis patients, many were receiving background therapy with NSAIDs or corticosteroids.

MANAGEMENT: Caution is recommended when using JAK inhibitors in patients with a history of peptic ulceration or diverticular disease and in patients receiving concomitant treatment with drugs associated with an increased risk of GI perforation such as corticosteroids, NSAIDs, and opioids. Patients should be advised to contact their healthcare provider if they experience signs and symptoms of GI perforation such as severe abdominal pain, fever, chills, nausea, or vomiting.

GENERALLY AVOID: The concurrent use of levomethadyl acetate and alcohol may result in additive CNS and respiratory depression, hypotension, sedation, or coma. Grapefruit juice may increase the plasma concentrations of orally administered drugs which are substrates of the CYP450 3A4 isoenzyme, such as levomethadyl acetate. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits. The extent and clinical significance are unknown. Moreover, pharmacokinetic alterations associated with interactions involving grapefruit juice are often subject to a high degree of interpatient variability.

MANAGEMENT: Patients who are known to abuse alcohol should be warned of the risk of potentially fatal overdose if these substances are taken concurrently. Patients who regularly consume grapefruits and grapefruit juice should be monitored for adverse effects and altered plasma concentrations of levomethadyl acetate. A 12-lead ECG should be performed before initiating therapy, 12 to 14 days after initiating therapy, and periodically thereafter. Patients should be advised to immediately seek medical attention if they experience palpitations, dizziness, lightheadedness, fainting, or seizures. Grapefruits and grapefruit juice should be avoided if an interaction is suspected. Orange juice is not expected to interact.

MONITOR: Grapefruit juice may increase the plasma concentrations of tofacitinib. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits. The extent and clinical significance are unknown. Moreover, pharmacokinetic alterations associated with interactions involving grapefruit juice are often subject to a high degree of interpatient variability.

MANAGEMENT: Until more information is available, some authorities recommend avoiding consumption of grapefruit juice during tofacitinib therapy (Canada). Patients receiving tofacitinib therapy who ingest grapefruits or grapefruit juice should be monitored for adverse effects and undue fluctuations in plasma drug levels.