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Drug Interactions between etrasimod and MLK F2

This report displays the potential drug interactions for the following 2 drugs:

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Interactions between your drugs

Major

lidocaine BUPivacaine

Applies to: MLK F2 (bupivacaine / lidocaine / triamcinolone) and MLK F2 (bupivacaine / lidocaine / triamcinolone)

GENERALLY AVOID: Additive toxicities may occur when bupivacaine is coadministered with other local anesthetics. The potential for increased risk of systemic toxicities such as methemoglobinemia and central nervous system and cardiovascular adverse reactions should be recognized.

MANAGEMENT: Additional use of local anesthetics should generally be avoided within 96 hours following administration of bupivacaine. If coadministration cannot be avoided, overall local anesthetic exposure through 72 hours must be considered in addition to monitoring for the development of methemoglobinemia as well as central nervous system and cardiovascular adverse reactions. Signs and symptoms of methemoglobinemia may be delayed some hours after drug exposure. Patients or their caregivers should be advised to seek medical attention if they notice signs and symptoms of methemoglobinemia such as slate-grey cyanosis in buccal mucous membranes, lips, and nail beds; nausea; headache; dizziness; lightheadedness; lethargy; fatigue; dyspnea; tachypnea; tachycardia; palpitation; anxiety; and confusion. In severe cases, patients may progress to central nervous system depression, stupor, seizures, acidosis, cardiac arrhythmias, syncope, shock, coma, and death. Early warning signs of central nervous system toxicity may include restlessness, anxiety, incoherent speech, dizziness, lightheadedness, numbness and tingling of the mouth and lips, metallic taste, tinnitus, blurred vision, tremors, twitching, depression, and drowsiness. Cardiovascular toxicity may include atrioventricular block, ventricular arrhythmias, cardiac arrest, and decreased cardiac output and arterial blood pressure due to depressed cardiac conductivity, excitability, and myocardial contractility. Patients should have cardiovascular and respiratory vital signs and state of consciousness constantly monitored while under treatment.

References

  1. Cerner Multum, Inc. "UK Summary of Product Characteristics."
  2. Cerner Multum, Inc. "Australian Product Information."
  3. (2021) "Product Information. Zynrelef (bupivacaine-meloxicam)." Heron Therapeutics

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Major

triamcinolone etrasimod

Applies to: MLK F2 (bupivacaine / lidocaine / triamcinolone) and etrasimod

GENERALLY AVOID: Coadministration of etrasimod with antineoplastic, immunosuppressive, or other immune-modulating therapies may increase the risk of unintended additive immunosuppressive effects. Etrasimod causes reversible sequestration of lymphocytes in lymphoid tissues. When administered daily for 52 weeks, etrasimod produced a mean reduction in peripheral blood lymphocyte count to 45% of baseline values, which may increase the risk of infections. Life-threatening and rare fatal infections have occurred in association with other sphingosine 1-phosphate (S1P) receptor modulators. Decreased lymphocyte counts persist during chronic daily dosing and generally return to normal within 4 to 5 weeks after stopping the medication.

MANAGEMENT: The safety and efficacy of etrasimod in combination with antineoplastic, immunosuppressive, or immune-modulating agents have not been evaluated. Because its pharmacodynamic effects may persist for up to 5 weeks after treatment discontinuation, concomitant use during and within 5 weeks following the last dose of etrasimod with antineoplastic, immunosuppressive, or immune-modulating agents should generally be avoided. If concomitant use within this period is considered necessary, patients should be monitored for infectious complications during this extended period. When switching from drugs with prolonged immune effects to etrasimod, the half-life and mode of action of these drugs must also be considered to avoid unintended additive immunosuppressive effects.

References

  1. (2023) "Product Information. Velsipity (etrasimod)." Pfizer U.S. Pharmaceuticals Group

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Moderate

BUPivacaine etrasimod

Applies to: MLK F2 (bupivacaine / lidocaine / triamcinolone) and etrasimod

MONITOR: The risk of transient bradycardia and atrioventricular (AV) block may be increased during initiation of etrasimod treatment in patients receiving other drugs that slow the heart rate or AV conduction such as beta-blockers, certain calcium channel blockers (e.g., diltiazem, verapamil), and digitalis. Etrasimod may cause a decrease in heart rate during initiation of therapy. In the randomized placebo-controlled studies UC-1 and UC-2, following an initial dose of 2 mg, the greatest mean decrease in heart rate from baseline was 7.2 bpm and occurred at hour 2 (UC-2) and hour 3 on day 1. In studies UC-2 and UC-3, bradycardia was reported on day 1 in 2.9% of patients on etrasimod compared to none in the placebo group. On Day 2, bradycardia was reported in 1 patient (0.3%) treated with etrasimod compared to none in the placebo group. Overall, subjects who experienced bradycardia were generally asymptomatic. Few subjects experienced symptoms such as dizziness, and these symptoms resolved without intervention. Initiation of etrasimod treatment has also resulted in transient AV conduction delays. Initiation of etrasimod in patients stabilized on beta blockers did not cause additive heart rate reduction. However, the effects on heart rate reduction from initiating a beta blocker or other drugs that may decrease the heart rate in patients stabilized on etrasimod therapy are unknown.

MANAGEMENT: Advice from a cardiologist should be sought before initiation of beta blockers or drugs that may decrease heart rate (e.g., calcium channel blockers) in patients on a stable dose of etrasimod. Etrasimod can be initiated in patients stabilized on beta blockers. Cardiologist advice should also be sought if etrasimod is considered for use in patients with significant QT prolongation (QTcF greater than 450 msec in males or 470 msec in females), patients with arrhythmias requiring treatment with Class 1a or Class III antiarrhythmic agents, patients with unstable ischemic heart disease, heart failure, history of cardiac arrest, cerebrovascular disease, or uncontrolled hypertension. The use of etrasimod in patients with a history of Mobitz type I second-degree AV block is considered contraindicated unless the patient has a functioning pacemaker.

References

  1. (2023) "Product Information. Velsipity (etrasimod)." Pfizer U.S. Pharmaceuticals Group

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Drug and food interactions

Moderate

lidocaine food

Applies to: MLK F2 (bupivacaine / lidocaine / triamcinolone)

MONITOR: Grapefruit and grapefruit juice may increase the plasma concentrations of lidocaine, which is primarily metabolized by the CYP450 3A4 and 1A2 isoenzymes to active metabolites (monoethylglycinexylidide (MEGX) and glycinexylidide). The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. Inhibition of hepatic CYP450 3A4 may also contribute. The interaction has not been studied with grapefruit juice but has been reported with oral and/or intravenous lidocaine and potent CYP450 3A4 inhibitor, itraconazole, as well as moderate CYP450 3A4 inhibitor, erythromycin. A pharmacokinetic study of 9 healthy volunteers showed that the administration of lidocaine oral (1 mg/kg single dose) with itraconazole (200 mg daily) increased lidocaine systemic exposure (AUC) and peak plasma concentration (Cmax) by 75% and 55%, respectively. However, no changes were observed in the pharmacokinetics of the active metabolite MEGX. In the same study, when the moderate CYP450 3A4 inhibitor erythromycin (500 mg three times a day) was administered, lidocaine AUC and Cmax increased by 60% and 40%, respectively. By contrast, when intravenous lidocaine (1.5 mg/kg infusion over 60 minutes) was administered on the fourth day of treatment with itraconazole (200 mg once a day) no changes in lidocaine AUC or Cmax were observed. However, when lidocaine (1.5 mg/kg infusion over 60 minutes) was coadministered with erythromycin (500 mg three times a day) in the same study, the AUC and Cmax of the active metabolite MEGX significantly increased by 45-60% and 40%, respectively. The observed differences between oral and intravenous lidocaine when coadministered with CYP450 3A4 inhibitors may be attributed to inhibition of CYP450 3A4 in both the gastrointestinal tract and liver affecting oral lidocaine to a greater extent than intravenous lidocaine. In general, the effects of grapefruit products are concentration-, dose- and preparation-dependent, and can vary widely among brands. Certain preparations of grapefruit (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition. While the clinical significance of this interaction is unknown, increased exposure to lidocaine may lead to serious and/or life-threatening reactions including respiratory depression, convulsions, bradycardia, hypotension, arrhythmias, and cardiovascular collapse.

MONITOR: Certain foods and behaviors that induce CYP450 1A2 may reduce the plasma concentrations of lidocaine. The proposed mechanism is induction of hepatic CYP450 1A2, one of the isoenzymes responsible for the metabolic clearance of lidocaine. Cigarette smoking is known to be a CYP450 1A2 inducer. In one pharmacokinetic study of 4 smokers and 5 non-smokers who received 2 doses of lidocaine (100 mg IV followed by 100 mg orally after a 2-day washout period), the smokers' 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. Other CYP450 1A2 inducers include cruciferous vegetables (e.g., broccoli, brussels sprouts) and char-grilled meat. Therefore, eating large or variable amounts of these foods could also reduce lidocaine exposure. The clinical impact of smoking and/or the ingestion of foods that induce CYP450 1A2 on lidocaine have not been studied, however, a loss of efficacy may occur.

MANAGEMENT: Caution is recommended if lidocaine is to be used in combination with grapefruit and grapefruit juice. Monitoring for lidocaine toxicity and plasma lidocaine levels may also be advised, and the lidocaine dosage adjusted as necessary. Patients who smoke and/or consume cruciferous vegetables may be monitored for reduced lidocaine efficacy.

References

  1. Huet PM, LeLorier J (1980) "Effects of smoking and chronic hepatitis B on lidocaine and indocyanine green kinetics" Clin Pharmacol Ther, 28, p. 208-15
  2. (2024) "Product Information. Lidocaine Hydrochloride (lidocaine)." Hospira Inc.
  3. (2015) "Product Information. Lidocaine Hydrochloride (lidocaine)." Hospira Healthcare Corporation
  4. (2022) "Product Information. Lidocaine Hydrochloride (lidocaine)." Hameln Pharma Ltd
  5. (2022) "Product Information. Xylocaine HCl (lidocaine)." Aspen Pharmacare Australia Pty Ltd
  6. Isohanni MH, Neuvonen PJ, Olkkola KT (2024) Effect of erythromycin and itraconazole on the pharmacokinetics of oral lignocaine https://pubmed.ncbi.nlm.nih.gov/10193676/
  7. Isohanni MH, Neuvonen PJ, Olkkola KT (2024) Effect of erythromycin and itraconazole on the pharmacokinetics of intravenous lignocaine https://pubmed.ncbi.nlm.nih.gov/9832299/
View all 7 references

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Moderate

etrasimod food

Applies to: etrasimod

GENERALLY AVOID: Coadministration with moderate inhibitors of CYP450 3A4 such as grapefruit juice may increase the plasma concentrations of etrasimod in patients that are poor CYP450 2C9 metabolizers (e.g., *2/*3, *3/*3). Etrasimod is primarily metabolized by the CYP450 3A4, CYP450 2C8, and CYP450 2C9 isoenzymes. Pharmacokinetic studies reported that no single enzyme appears to dominate etrasimod elimination and that the involvement of multiple CYP450 isoforms reduces the likelihood of drug-drug interactions when only a single CYP450 isoform is strongly or moderately inhibited by a coadministered drug. In clinical drug interaction studies, when etrasimod was administered with the dual moderate CYP450 2C9 and 3A4 inhibitor fluconazole at steady-state levels, etrasimod systemic exposure (AUC) increased by 84%. However, concomitant use with the potent CYP450 3A4 inhibitor itraconazole increased the AUC of etrasimod by 32%, which was not considered by the manufacturer to be clinically significant. The effect on etrasimod systemic exposure in CYP450 2C9 intermediate metabolizers (e.g., *1/*2, *1/*3, *2/*2) treated with less potent CYP450 3A4 inhibitors is not known. Increased plasma concentrations of etrasimod may increase the risk of infection, bradyarrhythmia, AV conduction delays, elevated transaminase levels, and macular edema.

MANAGEMENT: Until further information is available, the consumption of grapefruit and grapefruit juice in combination with moderate to potent CYP450 2C8 inhibitors such as gemfibrozil should be avoided or limited during treatment with etrasimod in patients who are poor CYP450 2C9 metabolizers. Caution is recommended with grapefruit products consumption in patients who are intermediate CYP450 2C9 metabolizers. Patients should be advised to notify their physician if they experience potential adverse effects of etrasimod.

References

  1. (2023) "Product Information. Velsipity (etrasimod)." Pfizer U.S. Pharmaceuticals Group
  2. Lee C, Taylor C, Tang Y, Caballero LV, shan k, Randle A, Grundy JS (2022) Effects of fluconazole, gemfibrozil, and rifampin on the pharmacokinetics, safety, and tolerability of etrasimod https://gut.bmj.com/content/71/Suppl_1/A142.1

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Therapeutic duplication warnings

No warnings were found for your selected drugs.

Therapeutic duplication warnings are only returned when drugs within the same group exceed the recommended therapeutic duplication maximum.


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Drug Interaction Classification

These classifications are only a guideline. The relevance of a particular drug interaction to a specific individual is difficult to determine. Always consult your healthcare provider before starting or stopping any medication.
Major Highly clinically significant. Avoid combinations; the risk of the interaction outweighs the benefit.
Moderate Moderately clinically significant. Usually avoid combinations; use it only under special circumstances.
Minor Minimally clinically significant. Minimize risk; assess risk and consider an alternative drug, take steps to circumvent the interaction risk and/or institute a monitoring plan.
Unknown No interaction information available.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.