Xylocaine (Cardiac) (Pf) (lidocaine HCl/PF)

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Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Class I And Iii Antiarrhythmics/Halofantrine

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Possibly additive effects on the QTc interval.

CLINICAL EFFECTS: Concurrent use of halofantrine and Class I or III antiarrhythmics may pre-dispose patients to development of prolonged QTc interval.(1)

PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: The manufacturer of halofantrine states under the contraindications section of the prescribing information that unless there are compelling clinical reasons, halofantrine should not be used with Class I and III antiarrhythmics.(1) If concurrent therapy is deemed medically necessary, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: Because concurrent use may pre-dispose patients to prolongation of the QTc interval, the manufacturer of halofantrine states in the contraindications section of the prescribing information that halofantrine should not be used with Class I or III antiarrhythmics unless compelling clinical reasons exist.(1) One or more of the drug pairs linked to this monograph have been included in a list of interactions that should be considered "high-priority" for inclusion and should not be inactivated in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.

Class Ib, Ii, And Iv Antiarrhythmics/Disopyramide

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Disopyramide has been shown to prolong the QTc interval. Concurrent use with other agents that affect the heart rate and rhythm may result in unpredictable effect on heart rhythm.(1-2)

CLINICAL EFFECTS: The concurrent use of disopyramide with other agents that affect the heart rate and rhythm may result in in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1-2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of disopyramide states that concurrent use of disopyramide with antiarrhythmic agents should be reserved for patients with life-threatening arrhythmias who are demonstrably unresponsive to single-agent antiarrhythmic therapy.(3) The Australian manufacturer of disopyramide states that the concurrent use of other antiarrhythmics, such as Class I, II, III, or IV is contraindicated.(1) The US manufacturer of verapamil states that disopyramide should not be administered within 48 hours before or 24 hours after verapamil.(2) The Australian manufacturer of celiprolol states that the concurrent use of antiarrhythmics such as disopyramide is contraindicated during treatment with celiprolol (exception: intensive care).(4) If concurrent therapy is deemed medically necessary, obtain serum calcium, magnesium, and potassium levels and monitor ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: Because combinations of antiarrhythmics are not well researched and concurrent use may result in unpredictable effects, the Australian manufacturer of disopyramide states that the concurrent use of other antiarrhythmics, such as Class I, II, III, or IV is contraindicated.(1)

Lidocaine/Saquinavir

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Saquinavir may inhibit the metabolism of lidocaine via CYP3A4. Concurrent use of saquinavir and lidocaine may increase the risk of lidocaine toxicity.(1,2)

CLINICAL EFFECTS: Concurrent use of saquinavir with antiarrhythmic doses of lidocaine may result in elevated levels and toxicity from lidocaine.(1,2)

PREDISPOSING FACTORS: Lidocaine clearance is significantly impaired in patients with moderate or severe hepatic impairment.

PATIENT MANAGEMENT: The US manufacturer of saquinavir mesylate states that concurrent use with lidocaine is contraindicated in patients receiving saquinavir.(1)

DISCUSSION: The US manufacturer of saquinavir mesylate states that concurrent use with lidocaine is contraindicated in patients receiving saquinavir.(1) Saquinavir has been shown to be a strong inhibitor of CYP3A4,(3) one of the metabolic pathways for lidocaine elimination.(4)

Selected Antiarrhythmics/Arbutamine

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Arbutamine may have additive or synergistic effects on the proarrhythmic effects of these agents.(1)

CLINICAL EFFECTS: Concurrent use may result in precipitation or exacerbation of supraventricular and ventricular arrhythmias.(1)

PREDISPOSING FACTORS: Possibly a history of sustained supraventricular or ventricular arrhythmias.(1)

PATIENT MANAGEMENT: The manufacturer of arbutamine states that arbutamine should not be administered with Class I antiarrhythmics such as flecainide, lidocaine, and quinidine or with digoxin.(1)

DISCUSSION: Because arbutamine may precipitate or exacerbate supraventricular or ventricular arrhythmias, the manufacturer of arbutamine states that it should not be administered with proarrhythmic agents such as Class I antiarrhythmics such as flecainide, lidocaine, or quinidine.(1) The manufacturer of arbutamine also states that it should not be administered with digoxin.(1) There is no published documentation for this interaction.

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Local Anesthetics/Long-Acting Bupivacaine

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Concurrent use of other local anesthetics or use of other local anesthetics within 96 hours following long-acting bupivacaine may result in additive neurologic and cardiovascular effects. Use of articaine, benzocaine, bupivacaine, lidocaine, mepivacaine, prilocaine, procaine, ropivacaine, and tetracaine may also increase the risk of methemoglobinemia.(1,2) Non-liposomal bupivacaine may impact the pharmacokinetic and/or physicochemical properties of the liposomal formulation when administered in the same syringe or used simultaneously unless the ratio of mg of non-liposomal bupivacaine to mg of bupivacaine liposomal does not exceed 1:2.(1) Local anesthetics other than bupivacaine may trigger the immediate release of bupivacaine from the liposomal formulation when administered together locally.(1)

CLINICAL EFFECTS: Concurrent or use of local anesthetics with 96 hours of use of long-acting bupivacaine may result in neurologic and cardiovascular toxicity. Use of articaine, benzocaine, bupivacaine, lidocaine, mepivacaine, prilocaine, procaine, ropivacaine, and tetracaine may also result in methemoglobinemia.(1,2) Non-liposomal bupivacaine may impact the pharmacokinetic and/or physicochemical properties of the liposomal formulation when administered in the same syringe or used simultaneously unless the ratio of mg of non-liposomal bupivacaine to mg of bupivacaine liposomal does not exceed 1:2.(1) Local anesthetics other than bupivacaine may trigger the immediate release of bupivacaine from the liposomal formulation when administered together locally.(1)

PREDISPOSING FACTORS: Use of additional agents that are associated with methemoglobinemia may further increase the risk of methemoglobinemia.(1) Patients who are at increased risk of developing methemoglobinemia include those with glucose-6-phosphate dehydrogenase deficiency, congenital or idiopathic methemoglobinemia, cardiac or pulmonary compromise, infants under 6 months of age, and concurrent exposure to oxidizing agents or their metabolites are more susceptible to developing clinical manifestations of the condition. If local anesthetics must be used in these patients, close monitoring for symptoms and signs of methemoglobinemia is recommended.(1)

PATIENT MANAGEMENT: Avoid the use of other local anesthetics within 96 hours following the administration of long-acting bupivacaine. In patients for whom use is required, monitor for neurologic and cardiovascular effects. Also monitor for methemoglobinemia with use of articaine, benzocaine, bupivacaine, lidocaine, mepivacaine, prilocaine, procaine, ropivacaine, and tetracaine.(1,2) Non-liposomal bupivacaine may be administered in the same syringe as bupivacaine liposomal or injected immediately before bupivacaine liposomal as long as the ratio of mg of non-liposomal bupivacaine to mg of bupivacaine liposomal does not exceed 1:2.(1) Lidocaine may be administered 20 minutes or more prior to bupivacaine. It is unknown if other local anesthetics may be used without compromising the release characteristic of bupivacaine liposomal.(1)

DISCUSSION: Concurrent use of other local anesthetics or use of other local anesthetics within 96 hours following long-acting bupivacaine may result in additive neurologic and cardiovascular effects. Use of articaine, benzocaine, bupivacaine, lidocaine, mepivacaine, prilocaine, procaine, ropivacaine, and tetracaine may also increase the risk of methemoglobinemia.(1,2) Non-liposome bupivacaine may impact the pharmacokinetic and/or physicochemical properties of the liposomal formulation when administered in the same syringe or used simultaneously unless the ratio of mg of non-liposomal bupivacaine to mg of bupivacaine liposomal does not exceed 1:2.(1) Local anesthetics other than bupivacaine may trigger the immediate release of bupivacaine from the liposomal formulation when administered together locally. Lidocaine may be administered 20 minutes or more prior to bupivacaine. It is unknown if other local anesthetics may be used without compromising the release characteristic of bupivacaine liposomal.(1)

Moderate Interaction: Assess the risk to the patient and take action as needed.

Lidocaine/Beta-Blockers

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Decreased cardiac output and hepatic blood flow due to beta-blockers may result in reduced elimination of lidocaine. Inhibition of hepatic microsomal enzymes may also contribute to decreased lidocaine clearance.

CLINICAL EFFECTS: Lidocaine toxicity is more likely to occur when these drugs are used in combination.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The lidocaine dose may need to be adjusted when a beta-blocker is added or discontinued. Clinical signs of lidocaine toxicity and lidocaine plasma levels should be monitored.

DISCUSSION: The effect seems to be more pronounced in the lipid soluble beta-blockers (eg. propranolol, metoprolol).

Lidocaine/Cimetidine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Cimetidine reduces the hepatic clearance of lidocaine. Changes in hepatic blood flow may contribute.

CLINICAL EFFECTS: Increased serum lidocaine levels with enhanced therapeutic and toxic response.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients receiving this combination should be monitored for signs of lidocaine toxicity. The dosage of lidocaine should be adjusted based on serum lidocaine levels and patient response. Since other H-2 antagonists (e.g., ranitidine, famotidine) do not appear to interact, substituting cimetidine with one of these agents may be desirable. However, if a patient is already receiving this combination and is not experiencing adverse effects, substitution is probably not necessary.

DISCUSSION: This interaction is likely to occur.

Lidocaine/Phenytoin

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Concurrent administration of lidocaine and phenytoin may result in additive effects. Lidocaine is a Class Ib antiarrhythmic. Phenytoin has Class Ib antiarrhythmic properties.

CLINICAL EFFECTS: Concurrent use of lidocaine and phenytoin may result in additive effects on the heart, including arrhythmias.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: When used for the treatment of neonatal seizures, lidocaine should not be given to patients who are currently or recently received phenytoin.(1) If concurrent use is needed, cardiac monitoring is required.(1) For pediatric and adult patients, concurrent use of lidocaine and phenytoin should be approached with caution and monitored closely.

DISCUSSION: Concurrent administration of lidocaine and phenytoin may result in additive effects. Lidocaine is a Class Ib antiarrhythmic. Phenytoin has Class Ib antiarrhythmic properties. Studies in neonates have evaluated the use of lidocaine and phenytoin for treatment of neonatal seizures. Studies recommended avoiding lidocaine use in neonates who are currently or recently received phenytoin.

Lidocaine/Selected Protease Inhibitors; Cobicistat

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Protease inhibitors(1-15) may inhibit the metabolism of lidocaine via CYP3A4.

CLINICAL EFFECTS: Concurrent use of protease inhibitors(1-15) with antiarrhythmic doses of lidocaine may result in elevated levels and toxicity from lidocaine.

PREDISPOSING FACTORS: Lidocaine clearance is significantly impaired in patients with moderate or severe hepatic impairment.

PATIENT MANAGEMENT: The US manufacturers of atazanavir,(1) atazanavir-cobicistat,(2) darunavir,(4) darunavir-cobicistat,(5) fosamprenavir,(8) indinavir,(10) lopinavir-ritonavir,(11) nelfinavir,(12) nirmatrelvir/ritonavir,(13) ombitasvir-paritaprevir-ritonavir,(14) and tipranavir(15) recommend caution and therapeutic concentration monitoring when lidocaine is administered concurrently as an antiarrhythmic. Recommendations differ in other regions. The UK manufacturer of atazanavir-cobicistat(3) and the Canadian manufacturer of darunavir,(6) darunavir-cobicistat,(7) and fosamprenavir(9) state that concurrent use of lidocaine is contraindicated.

DISCUSSION: The protease inhibitors are moderate to strong inhibitors of CYP3A4, one of the metabolic pathways for lidocaine elimination.(16-17)

Lidocaine/Strong Cyp1a2 Inhibitors

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Strong CYP1A2 inhibitors may inhibit the metabolism of lidocaine by CYP1A2.(1-4)

CLINICAL EFFECTS: Concurrent or recent use of strong CYP1A2 inhibitors may result in increased effects of lidocaine.(1-4)

PREDISPOSING FACTORS: This interaction may be more severe in patients taking strong CYP3A4 inhibitors.(2,3) The interaction may be less clinically significant in patients with severe liver impairment.(4)

PATIENT MANAGEMENT: Patients receiving this combination should be closely monitored for signs of lidocaine toxicity. The dosage of lidocaine should be adjusted based on serum lidocaine levels and patient response.

DISCUSSION: In a study in 8 subjects, pretreatment with fluvoxamine (100 mg daily) for 6 days increased the peak concentration (Cmax) and area-under-curve (AUC) of oral lidocaine (1 mg/kg) by 220% and 305%, respectively. Pretreatment with fluvoxamine (100 mg daily) and erythromycin (1500 mg daily) for 6 days increased lidocaine Cmax and AUC by 250% and 360%, respectively.(2) In a study in 9 subjects, pretreatment with fluvoxamine (100 mg daily) for 6 days decreased the clearance of intravenous lidocaine by 41%. Pretreatment with fluvoxamine (100 mg daily) and erythromycin (1500 mg daily) for 6 days decreased the clearance of intravenous lidocaine by 53%.(3) In a study in 10 healths subjects, 10 patients with mild (Child grade A) liver impairment, and 10 patients with severe (Child grade C) liver impairment, fluvoxamine decreased lidocaine clearance by 60% in healthy subjects and by 44% in patients with mild liver impairment. However, there was no significant effect in patients with severe liver impairment.(4) Strong CYP1A2 inhibitors linked include: angelica root, enasidenib, enoxacin, fluvoxamine, and rofecoxib.(5,6)

Lidocaine; Procaine/Succinylcholine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Since both succinylcholine and procaine are metabolized by plasma pseudocholinesterase, competitive inhibition of succinylcholine metabolism by procaine is believed to be responsible. The mechanism between succinylcholine and lidocaine is not well understood.

CLINICAL EFFECTS: The neuromuscular blocking activity of succinylcholine may be increased, producing profound sedation, respiratory depression, coma, and/or death.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: If it is necessary to administer these drugs concurrently, do so with extreme caution. Monitor neuromuscular function and adjust the dose of the neuromuscular blocking agent accordingly. If concurrent use is necessary, monitor patients for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.

DISCUSSION: Available data indicate that intravenous administration of high doses of procaine prolonged the neuromuscular activity of succinylcholine.

Sodium Channel Blocker; Potassium Channel Blocker/Lacosamide

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Lacosamide may enhance the slow inactivation of voltage-gated sodium channels and may cause dose-dependent bradycardia, prolongation of the PR interval, atrioventricular (AV) block, or ventricular tachyarrhythmia.(1)

CLINICAL EFFECTS: Concurrent use of lacosamide and agents that affect cardiac conduction (sodium channel blockers and potassium channel blockers) may increase the risk of bradycardia, prolongation of the PR interval, atrioventricular (AV) block, or ventricular tachyarrhythmia.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Lacosamide should be used with caution in patients on concomitant medications that affect cardiac conduction, including sodium channel blockers and potassium channel blockers.(1) If concurrent use is needed, obtain an ECG before lacosamide therapy and after lacosamide dose is titrated to steady-state.(1) Patients should be monitored closely when lacosamide is given intravenously.(1)

DISCUSSION: In a clinical trial in patients with partial-onset seizures, asymptomatic first-degree atrioventricular (AV) block occurred in 4/944 (0.4%) of patient who received lacosamide compared to 0/364 (0%) with placebo.(1) In a clinical trial in patients with diabetic neuropathy, asymptomatic first-degree AV block occurred in 5/1023 (0.5%) of patients who received lacosamide compared to 0/291 (0%) with placebo.(1) Second-degree and complete AV block have been reported in patients with seizures.(1) One case of profound bradycardia was observed in a patient during a 15-minute infusion of 150 mg of lacosamide.(1) A case report of a 49 year old male with refractory complex partial and generalized seizures described the development of ventricular tachycardia four months after addition of lacosamide 400 mg/day to the existing regimen of carbamazepine, lamotrigine, clonazepam, and valproate. The patient's ECG showed first-degree AV block, posterior left fascicular block, and severe widening of the QRS complex, all of which resolved upon discontinuation of lacosamide.(2)

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• Adams-stokes syndrome
• Methemoglobinemia
• Severe heart block
• Systemic lidocaine toxicity
• Wolff-parkinson-white pattern

• Chronic heart failure
• Chronic kidney disease stage 4 (severe) GFR 15-29 ml/min
• Glucose-6-phosphate dehydrogenase (g6Pd) deficiency
• Hemolytic anemia from pyruvate kinase and g6PD deficiencies
• Hypokalemia
• Hypomagnesemia
• Hypovolemia
• Hypoxia
• Incomplete AV heart block
• Myasthenia gravis
• Respiratory depression
• Shock
• Sinus bradycardia

• Atrial fibrillation
• Disease of liver

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Less Frequent

• Bradycardia
• Hypotension

Rare or Very Rare

• Anaphylaxis
• Cardiac arrest
• Diplopia
• Dyspnea
• Edema
• Methemoglobinemia
• Nausea
• Paralysis
• Respiratory depression
• Seizure disorder
• Unconsciousness

Less Frequent

• Dizziness
• Drowsy
• Injection site sequelae
• Muscle fasciculation
• Nervousness
• Paresthesia
• Sensation of cold
• Symptoms of anxiety

Rare or Very Rare

• Accidental fall
• Apprehension
• Back pain
• Blurred vision
• Euphoria
• General weakness
• Oral hypoesthesia
• Skin lesion
• Tinnitus
• Tremor
• Urticaria
• Vomiting

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