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Drug Interactions between fexinidazole 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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Moderate

lidocaine fexinidazole

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

GENERALLY AVOID: Coadministration with fexinidazole may increase the plasma concentrations and the risk of adverse effects of drugs that are substrates of CYP450 3A4. The proposed mechanism is decreased clearance due to fexinidazole-mediated inhibition of CYP450 3A4. Findings from a static mechanistic model-based analysis predicted that fexinidazole may significantly increase the systemic exposure (AUC) of sensitive CYP450 3A4 substrates. However, pharmacokinetic and clinical data regarding this interaction are currently lacking.

MANAGEMENT: Until more information is available, coadministration of fexinidazole with drugs that are substrates of CYP450 3A4 should generally be avoided. If concomitant use is unavoidable, clinical and laboratory monitoring may be appropriate whenever fexinidazole is added to or withdrawn from therapy with these drugs. Dosage adjustments may be considered if an interaction is suspected. Patients should be monitored for the development of adverse effects.

References

  1. (2021) "Product Information. Fexinidazole (fexinidazole)." sanofi-aventis

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Moderate

triamcinolone fexinidazole

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

GENERALLY AVOID: Coadministration with fexinidazole may increase the plasma concentrations and the risk of adverse effects of drugs that are substrates of CYP450 3A4. The proposed mechanism is decreased clearance due to fexinidazole-mediated inhibition of CYP450 3A4. Findings from a static mechanistic model-based analysis predicted that fexinidazole may significantly increase the systemic exposure (AUC) of sensitive CYP450 3A4 substrates. However, pharmacokinetic and clinical data regarding this interaction are currently lacking.

MANAGEMENT: Until more information is available, coadministration of fexinidazole with drugs that are substrates of CYP450 3A4 should generally be avoided. If concomitant use is unavoidable, clinical and laboratory monitoring may be appropriate whenever fexinidazole is added to or withdrawn from therapy with these drugs. Dosage adjustments may be considered if an interaction is suspected. Patients should be monitored for the development of adverse effects.

References

  1. (2021) "Product Information. Fexinidazole (fexinidazole)." sanofi-aventis

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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

fexinidazole food

Applies to: fexinidazole

GENERALLY AVOID: Use of alcohol or products containing alcohol during nitroimidazole therapy may result in a disulfiram-like reaction in some patients. There have been a few case reports involving metronidazole, although data overall are not convincing. The presumed mechanism is inhibition of aldehyde dehydrogenase (ALDH) by metronidazole in a manner similar to disulfiram. Following ingestion of alcohol, inhibition of ALDH results in increased concentrations of acetaldehyde, the accumulation of which can produce an unpleasant physiologic response referred to as the 'disulfiram reaction'. Symptoms include flushing, throbbing in head and neck, throbbing headache, respiratory difficulty, nausea, vomiting, sweating, thirst, chest pain, palpitation, dyspnea, hyperventilation, tachycardia, hypotension, syncope, weakness, vertigo, blurred vision, and confusion. Severe reactions may result in respiratory depression, cardiovascular collapse, arrhythmia, myocardial infarction, acute congestive heart failure, unconsciousness, convulsions, and death. However, some investigators have questioned the disulfiram-like properties of metronidazole. One study found neither elevations in blood acetaldehyde nor objective or subjective signs of a disulfiram-like reaction to ethanol in six subjects treated with metronidazole (200 mg three times a day for 5 days) compared to six subjects who received placebo.

GENERALLY AVOID: The potential exists for pharmacodynamic interactions and/or toxicities between fexinidazole and herbal medicines and supplements. In addition, grapefruit and grapefruit juice may, theoretically, increase the plasma concentrations of fexinidazole and the risk of adverse effects. The mechanism is decreased clearance of fexinidazole due to inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits. In general, the effect of grapefruit juice is concentration-, dose- and preparation-dependent, and can vary widely among brands. Certain preparations of grapefruit juice (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. Pharmacokinetic interactions involving grapefruit juice are also subject to a high degree of interpatient variability, thus the extent to which a given patient may be affected is difficult to predict.

ADJUST DOSING INTERVAL: Food significantly increases the oral absorption and bioavailability of fexinidazole. Compared with the fasted state, the systemic exposure (AUC) of fexinidazole and its metabolites (fexinidazole sulfoxide [M1], fexinidazole sulfone [M2]) were 4- to 5-fold higher following administration with food.

MANAGEMENT: To ensure maximal oral absorption, fexinidazole should be administered with food each day at about the same time of day (e.g., during or immediately after the main meal of the day). Coadministration of fexinidazole with grapefruit, grapefruit juice, or herbal medicines or supplements should be avoided. Because clear evidence is lacking concerning the safety of ethanol use during nitroimidazole therapy, patients should be apprised of the potential for interaction and instructed to avoid alcoholic beverages and products containing alcohol or propylene glycol while using oral, intravenous, or vaginal preparations of a nitroimidazole. Alcoholic beverages should not be consumed for at least 48 hours after completion of fexinidazole therapy.

References

  1. Giannini AJ, DeFrance DT (1983) "Metronidazole and alcohol: potential for combinative abuse." J Toxicol Clin Toxicol, 20, p. 509-15
  2. Alexander I (1985) "Alcohol-antabuse syndrome in patients receiving metronidazole during gynaecological treatment." Br J Clin Pract, 39, p. 292-3
  3. Harries DP, Teale KF, Sunderland G (1990) "Metronidazole and alcohol: potential problems." Scott Med J, 35, p. 179-80
  4. Edwards DL, Fink PC, Van Dyke PO (1986) "Disulfiram-like reaction associated with intravenous trimethoprim-sulfamethoxazole and metronidazole." Clin Pharm, 5, p. 999-1000
  5. (2002) "Product Information. Flagyl (metronidazole)." Searle
  6. Williams CS, Woodcock KR (2000) "Do ethanol and metronidazole interact to produce a disulfiram-like reaction?." Ann Pharmacother, 34, p. 255-7
  7. Visapaa JP, Tillonen JS, Kaihovaara PS, Salaspuro MP (2002) "Lack of disulfiram-like reaction with metronidazole and ethanol." Ann Pharmacother, 36, p. 971-4
  8. Krulewitch CJ (2003) "An unexpected adverse drug effect." J Midwifery Womens Health, 48, p. 67-8
  9. (2004) "Product Information. Tindamax (tinidazole)." Presutti Laboratories Inc
  10. (2021) "Product Information. Fexinidazole (fexinidazole)." sanofi-aventis
View all 10 references

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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.