Drug Interactions between dexamethasone / lidocaine and tofacitinib

MONITOR CLOSELY: Coadministration of baricitinib or tofacitinib with other immuno- or myelosuppressive agents may potentiate the risk of infections as well as lymphoma and other malignancies. Serious and sometimes fatal infections due to bacterial, mycobacterial, invasive fungal, viral, or other opportunistic pathogens have been reported in patients receiving baricitinib and tofacitinib, most of whom were taking concomitant immunosuppressants such as methotrexate or high-dose corticosteroids. Lymphoma and other malignancies have also been observed with tofacitinib use, with or without concomitant immunosuppressants. Epstein Barr virus-associated posttransplant lymphoproliferative disorder has been observed at an increased rate in renal transplant patients treated with tofacitinib and concomitant immunosuppressive agents (basiliximab, high-dose corticosteroids, and mycophenolic acid) relative to cyclosporine plus the same induction regimen (2.3% vs. 0%). The most common serious infections reported with baricitinib treatment include pneumonia, herpes zoster, and urinary tract infection. Opportunistic infections include tuberculosis, multidermatomal herpes zoster, esophageal candidiasis, pneumocystosis, acute histoplasmosis, cryptococcosis, cytomegalovirus, and BK virus. Lymphoma and other malignancies have also been observed with baricitinib use, with or without concomitant immunosuppressants.

MANAGEMENT: Close monitoring for the development of infection is recommended if baricitinib or tofacitinib is used in combination with other immuno- or myelosuppressive agents (e.g., high-dose corticosteroids), including the possible development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy. Lymphocyte and neutrophil counts as well as hemoglobin should be evaluated at baseline and regularly during therapy, and the baricitinib or tofacitinib dosage adjusted as necessary in accordance with the product labeling. Patients should be advised to contact their physician if they develop signs and symptoms of infection such as fever, chills, diarrhea, sore throat, muscle aches, shortness of breath, blood in phlegm, weight loss, red or inflamed skin, body sores, and pain or burning during urination. If a serious infection, an opportunistic infection, or sepsis develops, baricitinib should be interrupted until the infection is controlled.

MONITOR CLOSELY: Baricitinib and tofacitinib, both Janus kinase (JAK) inhibitors, have been associated with an increased risk of diverticulitis (DV) and gastrointestinal (GI) perforation, particularly in patients with risk factors (e.g., history of diverticulosis or diverticulitis, concomitant use of other agents associated with DV). Cases of DV and GI perforation have been reported in patients receiving baricitinib concomitantly with other agents linked to an increased risk of DV, such as aspirin, non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, and opioids. The mechanism of this interaction and the role of JAK inhibition, if any, has not been determined.

MANAGEMENT: Caution is recommended when using baricitinib or tofacitinib in patients with a history of diverticular disease and in patients receiving long-term concomitant treatment with drugs associated with an increased risk of DV and/or GI perforation, such as aspirin, NSAIDs, corticosteroids, and opioids. Patients should be advised to contact their healthcare provider if they experience signs of DV or GI perforation, such as severe abdominal pain, fever, nausea, or vomiting.

GENERALLY AVOID: Tofacitinib has been shown to decrease heart rate and prolong the PR interval of the electrocardiogram in some patients. Theoretically, coadministration with other agents that prolong the PR interval (e.g., beta-blockers, digoxin, alpha-2 adrenoceptor agonists) may result in elevated risk of conduction disturbances and atrioventricular block. In clinical trials, use of tofacitinib (10 to 20 mg daily; at steady-state) was associated with significant decreases in heart rate (4 to 7 bpm) and increases in PR interval (4 to 10 ms) compared with placebo.

MANAGEMENT: According to the manufacturer, concomitant use of tofacitinib with other agents that lower heart rate and/or prolong the PR interval should be avoided when possible. Caution is advised if concomitant use is necessary, particularly in patients with known conduction problems or severe cardiac disease. An ECG should be considered in these patients before initiating concomitant therapy and after titration to steady-state. Patients should be advised to notify their physician if they experience dizziness, lightheadedness, fainting, or irregular heartbeats.

Coadministration with inducers of CYP450 1A2 and/or 3A4 may decrease the plasma concentrations of lidocaine, which is primarily metabolized by these isoenzymes. In four healthy volunteers (2 smokers and 2 nonsmokers), administration of a single 400 mg oral dose of lidocaine following pretreatment with the CYP450 inducer phenobarbital (15 mg/day for 4 weeks, followed by 30 mg/day for 4 weeks) decreased lidocaine systemic exposure (AUC) by 37% and increased its oral clearance by 56% compared to administration of lidocaine alone. In another study, the mean bioavailability of a single 750 mg oral dose of lidocaine in six patients receiving chronic antiepileptic drug therapy (consisting of one or more of the following enzyme-inducing anticonvulsants: phenobarbital, primidone, phenytoin, carbamazepine) was approximately 2.5-fold lower than that reported for six healthy control subjects, while intrinsic clearance was nearly threefold higher. By contrast, the interaction was modest for lidocaine administered intravenously, suggesting induction of primarily hepatic first-pass rather than systemic metabolism of lidocaine. When a single 100 mg dose of lidocaine was given intravenously, mean lidocaine AUC was reduced by less than 10% and serum clearance increased by just 17% in the epileptic patients compared to controls. These changes were not statistically significant. Likewise, mean lidocaine AUC decreased by approximately 11% and plasma clearance increased by 15% when a single 50 mg intravenous dose of lidocaine was administered following pretreatment with the potent CYP450 inducer rifampin (600 mg/day for six days) in ten healthy, nonsmoking male volunteers. Another pharmacokinetic study found that cigarette smoke, an inducer of CYP450 1A2, reduced the bioavailability of lidocaine when administered orally, but had only minor effects on lidocaine administered intravenously. When 4 smokers and 5 non-smokers received 2 doses of lidocaine (100 mg IV followed by 100 mg orally after a 2-day washout period), the smoker's systemic exposure (AUC) of oral lidocaine was 68% lower than non-smokers. The AUC of IV lidocaine was only 9% lower in smokers compared with non-smokers. The clinical impact of smoking on lidocaine has not been studied, however, a loss of efficacy may occur.