Disulfiram (disulfiram)

The initial dosage of disulfiram is a maximum of 500 mg every morning for 1-2 weeks, then 250 mg daily. The daily dose can be taken in the evening if drowsiness occurs. Maintenance dosage may range from 125-500 mg daily, but the dosage should not exceed 500 mg daily. Daily uninterrupted administration of disulfiram should be continued until a basis for permanent self-control is established. Treatment may be required for months or years.

The practice of inducing an alcohol-disulfiram reaction to demonstrate the reaction to the patient has been largely abandoned; it is considered by most clinicians to be unnecessary, and may, in fact, be associated with increased drug toxicity. An explicit description of the alcohol-disulfiram reaction is usually sufficient to deter the patient from ingesting alcohol during treatment with disulfiram. If an alcohol trial is deemed necessary, it should be performed only under careful medical supervision and with adequate facilities (including oxygen) available for treatment of a severe reaction. Patients older than 50 years of age should not undergo an alcohol test reaction. The procedure for alcohol trial consists of administering 15 mL of 100 proof whiskey (or its equivalent) to the patient after 1-2 weeks of disulfiram therapy. The dose of alcohol may be repeated once, but should not exceed 30 mL of whiskey. Alcohol should be discontinued as soon as symptoms develop.

Disulfiram is administered orally. If compliance becomes a problem during disulfiram therapy, the patient should take the drug under close supervision, preferably as crushed tablets well mixed with liquid. Disulfiram has also been administered as an implant (not commercially available in the US) subcutaneously into the abdominal wall; however, blood concentrations of disulfiram are lower than those obtained following oral administration and safety and efficacy of this route of administration have not been established.

Disulfiram should not be administered until the patient has abstained from alcohol for at least 12 hours and should never be administered without the patient's knowledge.

Disulfiram interferes with the hepatic metabolism of alcohol, barbiturates, coumarin anticoagulants, paraldehyde (no longer commercially available in the US), terfenadine (no longer commercially available in the US), and phenytoin and its congeners, and therefore may increase blood concentrations and toxicity of these drugs.

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

Cyp1a2 Inhibitors/Fezolinetant

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: Inhibitors of CYP1A2 may inhibit the metabolism of fezolinetant.(1-4)

CLINICAL EFFECTS: Concurrent use of a CYP1A2 inhibitor may increase levels of and adverse effects from fezolinetant.(1-4)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Recommendations for concurrent use of fezolinetant with CYP1A2 inhibitors differ in different regions. The US manufacturer of fezolinetant states that concurrent use with strong, moderate, and weak CYP1A2 inhibitors is contraindicated.(1) The Australian, Canadian, and UK manufacturers of fezolinetant state that concurrent use with strong and moderate CYP1A2 inhibitors is contraindicated, while weak CYP1A2 inhibitors are not predicted to cause clinically relevant changes in fezolinetant exposure.(2-4)

DISCUSSION: In a study, fluvoxamine, a strong CYP1A2 inhibitor, increased fezolinetant maximum concentration (Cmax) and area-under-curve (AUC) by 80% and 840%, respectively. Mexiletine (400 mg every 8 hours), a moderate CYP1A2 inhibitor, increased fezolinetant Cmax and AUC by 40% and 360%, respectively. Cimetidine (300 mg every 6 hours), a weak CYP1A2 inhibitor, increased fezolinetant Cmax and AUC by 30% and 100%, respectively.(1) Strong CYP1A2 inhibitors linked to this monograph include angelica root, ciprofloxacin, enasidenib, enoxacin, fluvoxamine, and rofecoxib. Moderate CYP1A2 inhibitors linked to this monograph include capmatinib, centanafadine, dipyrone, fexinidazole, genistein, hormonal contraceptives, methoxsalen, mexiletine, osilodrostat, phenylpropanolamine, pipemidic acid, rucaparib, troleandomycin, vemurafenib, and viloxazine. Weak CYP1A2 inhibitors linked to this monograph include acyclovir, allopurinol, artemisinin, belumosudil, caffeine, cannabidiol, cimetidine, curcumin, dan-shen, deferasirox, disulfiram, Echinacea, famotidine, ginseng, norfloxacin, obeticholic acid, parsley, piperine, propafenone, propranolol, ribociclib, simeprevir, thiabendazole, ticlopidine, triclabendazole, valacyclovir, verapamil, and zileuton.(5-7)

Disulfiram Derivatives/Ethyl Alcohol

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: Disulfiram alters the intermediary metabolism of alcohol. Acetaldehyde is produced as a result of an initial metabolism of alcohol in the liver. Acetaldehyde is normally further oxidized by aldehyde dehydrogenase. However, this step is slowed by disulfiram and results in elevated acetaldehyde levels in the blood, which produces the undesirable effects.(1-2)

CLINICAL EFFECTS: Patients taking preparations that contain alcohol or using topical preparations that contain alcohol while taking disulfiram or agents related to it may experience throbbing in the head and neck, palpitations, tachycardia, hypotension, sweating, nausea, and vomiting.(3)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer recommends that disulfiram never be administered to a patient who is in a state of alcohol intoxication. Patients should be advised that even small amounts of alcohol may trigger the reaction. U.S. manufacturer states that taking any alcohol containing products during the course of therapy with disulfiram or its derivatives is contraindicated.(2) Patients should be informed about unsuspected sources of alcohol such as elixirs and topical preparations.(2) Alcohol is used to improve docetaxel and paclitaxel solubility. - The quantity of alcohol in paclitaxel injection formulations (0.385-0.396 grams/mL) is similar across manufacturers. A paclitaxel 200 mg dose contains approximately 13 grams of alcohol. - The quantity of alcohol in docetaxel formulations varies approximately 3-fold depending upon the manufacturer. FDA data on alcohol content (13): Product Manufacturer Alcohol/200 mg dose Docetaxel Inj. Pfizer 6.4 grams Docetaxel Inj. Sandoz 5.5 grams Docetaxel Inj. Accord 4.0 grams Taxotere-one vial Sanofi 4.0 grams formulation Docetaxel Inj. Hospira 3.7 grams Docefrez Sun Pharma 2.9 grams Taxotere-two vial Sanofi 2.0 grams formulation

DISCUSSION: Disulfiram is used therapeutically in the treatment of alcoholism. The quantity of alcohol required to elicit the interaction varies with individuals.(2,4-5) Consumption of even small doses (e.g., 15 ml may lead to this interaction; therefore, concomitant administration should be avoided. Patients have suffered from this interaction from ingest-ing cough mixtures(6) and using topical preparations such as aftershave lotions(7) and antipsoriatic preparations(8) that contained alcohol. The duration of this interaction varies from 30 to 60 minutes to several hours, depending on the amount of alcohol consumed.(2,9) An overdose of disulfiram and alcohol may have caused a case of severe polyneuritis in one report,(10) and another report attributes the death of a patient to this interaction.(11) This interaction has also been reported in patients who came in contact with other organic solvents (e.g., paint, "mineral spirits") through inhalation; therefore, patients should be advised of this potential hazard as well.(12)

Disulfiram/Amprenavir-Propylene Glycol

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: Disulfiram inhibits the alcohol and aldehyde dehydrogenase pathway, which is responsible for the metabolism of propylene glycol.(1)

CLINICAL EFFECTS: The concurrent administration of propylene glycol and disulfiram may result in the accumulation of propylene glycol, resulting in adverse effects such as seizures, stupor, tachycardia, hyperosmolality, lactic acidosis, renal toxicity, and hemolysis.(1,2)

PREDISPOSING FACTORS: Certain ethnic populations (Asians, Eskimos, and Native Americans) and women may have a decreased ability to metabolize propylene glycol.(1,2)

PATIENT MANAGEMENT: Because of the high concentration of propylene glycol in the oral solution formulation of amprenavir, the manufacturer states that the concurrent administration of amprenavir oral solution and disulfiram is contraindicated. Patients receiving treatment with disulfiram should receive the capsule formulation of amprenavir. If the capsule formulation of amprenavir or another protease inhibitor formulation is not an option, then disulfiram should be discontinued.(1,2)

DISCUSSION: The Agenerase oral solution formulation of amprenavir contains 550 mg of propylene glycol per mL. The recommended daily dosage of amprenavir results in an intake of propylene glycol of 1650 mg/kg per day. Propylene glycol is metabolized by the alcohol and aldehyde dehydrogenase enzyme pathway. Disulfiram inhibits this pathway. The concurrent administration of disulfiram and amprenavir oral solution may result in the accumulation of propylene glycol and toxicity. Therefore, the manufacturer of amprenavir oral solution states that the concurrent use of amprenavir oral solution with disulfiram is contraindicated. Patients receiving treatment with disulfiram should receive the oral capsule formulation of amprenavir. If the oral capsule formulation of amprenavir or another protease inhibitor formulation is not an option, then disulfiram should be discontinued.(1,2)

Disulfiram/Selected Nitroimidazole Antimicrobials

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: Since disulfiram has been associated with psychotic behavior in some patients, this interaction has been attributed to a combined toxicity with metronidazole or benznidazole.(1)

CLINICAL EFFECTS: May observe psychotic reactions of confusional states.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturers of benznidazole,(2) fexinidazole,(3) metronidazole,(4) and tinidazole(5) state that these agents should not be administered to patients who have received disulfiram in the previous two weeks.

DISCUSSION: In a study in hospitalized alcoholics, six of 29 patients receiving concurrent disulfiram and metronidazole developed acute psychosis or confusion. Of these six, five had paranoid delusions and three experienced visual and auditory hallucinations. These reactions were not reported in any of the 29 patients who received placebo with disulfiram.(6,7) An increased central effect of ethyl alcohol was observed in a single patient during concurrent disulfiram and metronidazole.(8) Psychotic symptoms were reported during concurrent use in another case report.(9)

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

Disulfiram/Hydantoins

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

MECHANISM OF ACTION: Disulfiram may inhibit the CYP2C9 mediated metabolism of phenytoin and other hydantoins.

CLINICAL EFFECTS: Hydantoin concentrations may increase producing toxicity. Phenytoin has a narrow therapeutic range. Early symptoms of phenytoin toxicity may include nystagmus, ataxia, dysarthria, tremor, hyperreflexia, lethargy, slurred speech, blurred vision, nausea, and vomiting. Severe toxicity may produce organ dysfunction (e.g. coma, irreversible cerebellar dysfunction and atrophy, hypotension, bradycardia, seizures, and cardiac arrest) and may be fatal.

PREDISPOSING FACTORS: Risk factors for phenytoin toxicity include renal impairment, hepatic impairment, or hypoalbuminemia.

PATIENT MANAGEMENT: Monitor closely to decrease the risk of hydantoin toxicity. Adjust the hydantoin dose as needed based on hydantoin plasma levels and clinical symptoms. Counsel patient to assure they know signs and symptoms of hydantoin toxicity and understand the importance of follow-up laboratory testing. Monitor the patient for signs of hydantoin toxicity (e.g. nystagmus, ataxia, dysarthria, tremor, hyperreflexia, lethargy, slurred speech, blurred vision, nausea, and vomiting).

DISCUSSION: There are multiple case reports of increased half-life, decreased phenytoin clearance, and significantly increased phenytoin concentrations with concurrent administration of phenytoin and disulfiram.(3,7) Patients showed symptoms of acute phenytoin toxicity; such as, nystagmus, delirium, ataxia, and dizziness. A study in six patients showed a 40% and 55% increase in phenytoin concentrations with concomitant administration of phenytoin and disulfiram (400 mg daily).(4) One patient showed signs of phenytoin toxicity including ataxia. One study in 10 healthy patients showed a 73% increase in phenytoin half-life and a 34% decrease in phenytoin clearance with concomitant administration of phenytoin (100 mg intravenously) with disulfiram (1st day 400 mg three times a day, 2nd day 400 mg, 3rd and 4th day 200 mg).(2) A study in 4 patients showed a 100-500% increase in phenytoin concentrations with concomitant disulfiram (400 mg daily) and phenytoin administration.(5)

Disulfiram/Intranasal Cocaine

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

MECHANISM OF ACTION: Disulfiram may inhibit the metabolism of intranasally administered cocaine by plasma and microsomal carboxylesterases and plasma cholinesterase.

CLINICAL EFFECTS: Increased concentrations of cocaine may result in increased heart rate, increased blood pressure, paranoia, and anxiety.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of intranasal cocaine recommends avoiding using intranasal cocaine in patients taking disulfiram. Consider using other local anesthetic agents.(1) Monitor for signs of cocaine toxicity such as increased blood pressure or heart rate.

DISCUSSION: In a randomized, double-blind, placebo controlled study in 6 adults with cocaine and alcohol dependence, concomitant administration of disulfiram (250 mg/day) with intranasal cocaine (1mg/kg) increased cocaine's area-under-the-curve (AUC) by 68%. Administration of intranasal cocaine (2mg/kg) with disulfiram increased cocaine's AUC by 77%. Significant increases were also seen in heart rate and blood pressure.(2) In a study in 8 cocaine dependent subjects, concomitant administration of disulfiram (250 mg) with cocaine (2mg/kg intranasally) increased cocaine's maximum concentration (Cmax) by 32%. An increase in nervousness and paranoia was seen in 3 patients.(3) In a case report, concomitant administration of cocaine (1 g intranasally) with disulfiram (250 mg) caused severe paranoia, severe anxiety, sweating, tremor, and increased pulse rate.(4)

Selected Moderate And Weak Cyp1a2 Inhibitors/Tizanidine

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

MECHANISM OF ACTION: Moderate and weak CYP1A2 inhibitors may inhibit the metabolism of tizanidine by CYP1A2.(1)

CLINICAL EFFECTS: Concurrent use of moderate and weak CYP1A2 inhibitors may result in elevated levels of and effects from tizanidine, including hypotension, bradycardia, drowsiness, sedation, and decreased psychomotor function.

PREDISPOSING FACTORS: The risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(2)

PATIENT MANAGEMENT: The US manufacturer of tizanidine states that concurrent use of tizanidine with inhibitors of CYP1A2 should be avoided.(3) If adverse reactions such as hypotension, bradycardia or excessive drowsiness occur, reduce tizanidine dosage or discontinue tizanidine therapy.(3)

DISCUSSION: In a study, cannabidiol 750 mg twice daily (a weak CYP1A2 inhibitor) increased the maximum concentration (Cmax) and area-under-curve (AUC) of a 200 mg single dose of caffeine (a sensitive CYP1A2 substrate) by 15% and 95%, respectively.(1) In a study in 10 healthy subjects, concurrent fluvoxamine, a strong inhibitor of CYP1A2, increased tizanidine Cmax, AUC, and half-life (T1/2) by 12-fold, 33-fold, and 3-fold, respectively. Significant decreases in blood pressure and increases in drowsiness and psychomotor impairment occurred.(3) In a study in 10 healthy subjects, concurrent ciprofloxacin, a strong inhibitor of CYP1A2, increased tizanidine Cmax and AUC by 7-fold and 10-fold, respectively. Significant decreases in blood pressure and increases in drowsiness and psychomotor impairment occurred.(3) Moderate CYP1A2 inhibitors linked to this monograph include: centanafadine, dipyrone, fexinidazole, genistein, methoxsalen, phenylpropanolamine, pipemidic acid, propranolol, rucaparib, and troleandomycin. Weak CYP1A2 inhibitors linked to this monograph include: allopurinol, artemisinin, belumosudil, caffeine, cannabidiol, curcumin, dan-shen, disulfiram, Echinacea, ginseng, parsley, piperine, ribociclib, simeprevir, thiabendazole, and triclabendazole.(4)

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

Cyp2b6 Inhibitors/Levomethadone; Methadone

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

MECHANISM OF ACTION: Methadone is metabolized primarily by CYP2B6. Inhibitors of CYP2B6 may decrease the metabolism of methadone.(1-3) Levomethadone is the active (R)-enantiomer of methadone.(4)

CLINICAL EFFECTS: Concurrent administration of CYP2B6 inhibitors may result in increased levels and clinical effects of levomethadone or methadone, which may result in QTc prolongation and life-threatening arrhythmias. Elevated levels can also cause profound sedation, respiratory depression, coma, and/or death. The discontinuation of CYP2B6 inhibitors in patients maintained on levomethadone or methadone may result in symptoms of opiate withdrawal. Levomethadone and methadone have been associated with serotonin syndrome. Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(3)

PREDISPOSING FACTORS: The risk of QT prolongation or torsade 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.(5) 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).(5)

PATIENT MANAGEMENT: If concomitant use of levomethadone or methadone and CYP2B6 inhibitors is necessary, closely monitor the patient when a CYP2B6 inhibitor is initiated or withdrawn. The dosage of levomethadone or methadone may need to be adjusted.(3) 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. Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with agents that may increase opioid drug levels.(6) If concurrent use is necessary, monitor patients for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness. If concurrent therapy is warranted, patients should be monitored for signs and symptoms of serotonin syndrome. Instruct patients to report muscle twitching, tremors, shivering and stiffness, fever, heavy sweating, heart palpitations, restlessness, confusion, agitation, trouble with coordination, or severe diarrhea. Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(7)

DISCUSSION: In a clinical study, oral voriconazole (400 mg every 12 hours for 1 day, then 200 mg every 12 hours for 4 days, a CYP2B6 inhibitor) increased the maximum concentration (Cmax) and area-under-curve (AUC) of (R)-methadone by 31% and 47%, respectively, in subjects receiving a methadone maintenance dose of 30 mg to 100 mg daily. The Cmax and AUC of (S)-methadone increased by 65% and 103%, respectively.(3) In healthy subjects, ticlopidine (250 mg twice daily for 4 days, a CYP2B6 inhibitor) increased the dose-adjusted AUC of (R)-methadone and (S)-methadone by about 20% and 60%, respectively.(8) Inhibitors of CYP2B6 linked to this monograph include: clopidogrel, disulfiram, prasugrel, rolapitant, and ticlopidine.(9)

Cyp2b6 Inhibitors/Naltrexone-Bupropion

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

MECHANISM OF ACTION: CYP2B6 inhibitors may inhibit the metabolism of naltrexone-bupropion. Bupropion is primarily metabolized to active metabolites by CYP2B6.(1-2)

CLINICAL EFFECTS: Coadministration of CYP2B6 inhibitors may cause an increase in naltrexone-bupropion levels and effects, including increased risk of seizures.(1)

PREDISPOSING FACTORS: The risk of seizures may be increased in patients with a history of head trauma or prior seizure; CNS tumor; severe hepatic cirrhosis; excessive use of alcohol or sedatives; addiction to opiates, cocaine, or stimulants; use of over-the-counter stimulants an anorectics; a total daily dose of bupropion greater than 450 mg or single doses greater than 150 mg; rapid escalation of bupropion dosage; diabetics treated with oral hypoglycemics or insulin; or with concomitant medications known to lower seizure threshold (antidepressants, theophylline, systemic steroids).(1)

PATIENT MANAGEMENT: The US manufacturer of naltrexone-bupropion states that the dose of naltrexone-bupropion should not exceed two tablets (one tablet each morning and evening) during concurrent use with CYP2B6 inhibitors .(1)

DISCUSSION: Repeated administration of ticlopidine (250 mg twice daily for 4 days, a inhibitor of CYP2B6) increased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of bupropion by 38% and 85%, respectively. Cmax and AUC of the metabolite hydroxybupropion decreased 78% and 84%.(1) Repeated administration of clopidogrel(75 mg twice daily for 4 days, a inhibitor of CYP2B6) increased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of bupropion by 40% and 60%, respectively. Cmax and AUC of the metabolite hydroxybupropion decreased 50% and 52%.(1) Inhibitors of CYP2B6 include: clopidogrel, disulfiram, prasugrel, rolapitant, ticlopidine.(2-3)

Disulfiram/Selected Anticoagulants (VIT K ANTAGONISTS)

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

MECHANISM OF ACTION: Disulfiram may inhibit the CYP2C9 mediated metabolism of warfarin or other selected vitamin K antagonists.

CLINICAL EFFECTS: The anticoagulant effect of warfarin may be increased resulting in bleeding.

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs). Pharmacogenomic information: patients with a CYP2C9 intermediate metabolizer genotype, and/or 1-2 copies of a reduced function VKORC1 gene are expected to be more susceptible to this interaction. Although patients with a pre-existing CYP2C9 poor metabolizer genotype are expected to be less susceptible to effects from this drug combination, their reduced function genotypes (e.g. CYP2C9 *1/*3, *2/*2, *2/*3, and *3/*3) result in an inherently higher warfarin half-life and risk for warfarin-associated bleeding. CYP2C9 poor metabolizers generally require lower anticoagulant doses and more time (>2 to 4 weeks) to achieve effective and safe anticoagulation than patients without these CYP2C9 variants.

PATIENT MANAGEMENT: Closely monitor patient INR until stabilized and adjust the anticoagulant dose accordingly. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. When concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin and/or hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling.

DISCUSSION: Disulfiram is classified as a weak inhibitor of CYP2C9 by the FDA. However, given the low therapeutic index of warfarin, even weak CYP2C9 inhibitors may have clinically significant effects. Clinical investigation has substantiated that combined administration of warfarin and disulfiram increases serum warfarin concentrations and produces an increase in the anticoagulant effect of warfarin. Case reports have documented the occurrence of bleeding.

Selected Cyp1a2 Inhibitors/Theophylline Derivatives

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

MECHANISM OF ACTION: CYP1A2 inhibitors may reduce the elimination rate of theophylline derivatives.

CLINICAL EFFECTS: The concurrent administration of selected CYP1A2 inhibitors and theophylline or their derivatives may result in increased levels and toxicity of theophylline.(1-19)

PREDISPOSING FACTORS: Concomitant therapy with inhibitors of CYP3A4 (e.g. clarithromycin, itraconazole, ritonavir) which block a secondary metabolic pathway for theophylline, may increase the magnitude of this interaction.

PATIENT MANAGEMENT: Theophylline levels should be closely monitored in patients receiving concurrent therapy. The dosage of theophylline may need to be decreased after a CYP1A2 inhibitor is initiated. If the CYP1A2 inhibitor is discontinued in a patient stabilized on the combination, the theophylline level may fall. Monitor theophylline levels and adjust dose accordingly.

DISCUSSION: A study in 5 patients with active hepatitis B and 4 healthy subjects examined the effects of a single dose of interferon alpha (9 million units in 8 subjects, 18 million units in 1 subject). There was no effect on theophylline in 1 subject. In the other 8 subjects, interferon increased theophylline half-life by 70% and decreased theophylline clearance by 49% (range 33% to 81%).(1) A study in 11 healthy subjects examined the effects of interferon alpha (3 million International Units daily for 3 days) on a single aminophylline (4 mg/kg) infusion. Interferon increased the half-life, area-under-curve (AUC), and mean residence time by 13.7%, 17.9%, and 16.3%, respectively. Theophylline clearance decreased by 9.1%.(2) In a study in healthy males, peginterferon alfa-2a (180 mcg once weekly for 4 weeks) increased theophylline AUC by 25%.(3,4) Concurrent interferon alfa has been shown to increase theophylline levels by 100%.(5) A study in 7 patients with chronic hepatitis C examined the effects of interferon beta (3 million to 9 million International Units daily for 8 weeks) on theophylline ethylenediamine (single 250 mg infusion). Interferon decreased theophylline clearance by 26.3% and increased theophylline half-life by 39.3%. There was no correlation between interferon dose and effect. The greatest effect was seen in a patient who received 3 million International Units daily, while no effect was seen in a patient who received 9 million International Units daily.(6) Increased serum theophylline levels with signs and symptoms of theophylline toxicity have been reported in patients following the addition of mexiletine to their treatment.(7-15) In a study evaluated the combination of disulfiram and theophylline in 20 recovering alcoholics. Patients received a single IV dose of theophylline while being given either 250 mg or 500 mg of disulfiram daily. Both dosages of disulfiram decreased the clearance of theophylline. However, the effect was greatest in patients receiving disulfiram 500 mg daily.(16) Increases in serum theophylline concentration and half-life have been reported during concurrent administration of theophylline and ticlopidine.(17) In healthy subjects, rofecoxib (12.5 mg/day, 25 mg/day, or 50 mg/day for seven days) increased the area-under-curve (AUC) of a single dose of theophylline (300 mg) by 38% to 60%. Therefore, the manufacturer of rofecoxib recommends that theophylline levels be monitored if rofecoxib is initiated or changed in patients receiving theophylline.(18) Selected CYP1A2 inhibitors linked to this monograph include: acyclovir, Angelica dahurica, artemisinin, belumosudil, centanafadine, cannabidiol, curcumin, danshen, dipyrone, disulfiram, echinacea, enasidenib, fexinidazole, genistein, ginseng, interferons, methoxsalen, mexiletine, parsley, phenylpropanolamine, pipemidic acid, piperine, propafenone, ribociclib, rofecoxib, rucaparib, simeprevir, ticlopidine, triclabendazole, valacyclovir, and verapamil.(19)

There is no enhanced messaging for this drug.

• Alcohol intoxication
• Severe psychosis

• Cardiac arrhythmia
• Chronic heart failure
• Severe coronary artery disease

• Diabetes mellitus
• Disease of liver
• Hepatic cirrhosis
• Hypothyroidism
• Nephritis
• Organic mental disorder
• Seizure disorder

There is no enhanced messaging for this drug.

Less Frequent

• CNS toxicity
• Drug-induced psychosis
• Mood changes
• Optic neuritis
• Peripheral neuropathy
• Polyneuropathy

Rare or Very Rare

• Encephalopathy
• Hepatic necrosis
• Jaundice

More Frequent

• Alcohol intolerance
• Drowsy

Less Frequent

• Erectile dysfunction
• Headache disorder

Rare or Very Rare

• Dysgeusia
• Fatigue
• Skin rash

No enhanced messaging available.

No enhanced messaging available.

Safe use of disulfiram during pregnancy has not been established. The drug should be administered during pregnancy only when the potential benefits justify the possible risks to the fetus.

No enhanced messaging available.

No enhanced messaging available.