Diazepam Interactions
- Aluminum Hydroxide
- Amiodarone
Anti-retroviral protease inhibitors
Anxiolytics, Sedatives, and Hypnotics
- Aprepitant
- Aripiprazole
Barbiturates
- Bosentan
- Buprenorphine
- Butorphanol
- Carbamazepine
- Chloroquine
- Cimetidine
- Ciprofloxacin
- Citalopram
- Clarithromycin
- Clozapine
- Conivaptan
- Dalfopristin; Quinupristin
- Delavirdine
- Digoxin
- Diltiazem
- Disulfiram
- Dronabinol, THC
- Echinacea
- Efavirenz
- Entacapone
- Erythromycin
- Escitalopram
- Ethanol
- Ethotoin
- Fluconazole
- Flumazenil
- Fluoxetine
- Fluvoxamine
- food
- Fosphenytoin
General Anesthetics
- grapefruit juice
- Imatinib, STI-571
- Isoniazid, INH
- Itraconazole
- Kava Kava, Piper methysticum
- Ketoconazole
- Levodopa
- Magaldrate
- Melatonin
- Miconazole
- Nabilone
- Nalbuphine
- Nefazodone
- Nicardipine
- Olanzapine
- Omeprazole
Opiate agonists
Oral contraceptives
- Pentazocine
Phenothiazines
- Phenytoin
- Pregabalin
- Probenecid
Radiopaque Contrast Agents
- Ranolazine
- Rifabutin
- Rifampin
- Rifapentine
Sedating H1-blockers
- Sodium Phosphate Monobasic Monohydrate; Sodium Phosphate Dibasic Anhydrous
- St. John’s Wort, Hypericum perforatum
- Telithromycin
- Theophylline, Aminophylline
- tobacco
- Tolcapone
- Tramadol
Tricyclic antidepressants
- Troleandomycin
- Valdecoxib
- Valerian, Valeriana officinalis
- Valproic Acid, Divalproex Sodium
- Verapamil
- Voriconazole
- Zafirlukast
- Zileuton
Diazepam Interactions
Diazepam is metabolized by oxidative metabolism, specifically, the hepatic isozymes CYP2C19 and CYP3A4. As a result, diazepam is susceptible to interactions with drugs that inhibit these hepatic enzymes. Clinicians should note that while diazepam clearance may be inhibited, diazepam pharmacodynamics are not always affected. Fluoxetine inhibits both metabolic pathways for diazepam, however the effect on diazepam pharmacodynamics is unclear. Studies of the impact of fluoxetine on diazepam may have been compromised by not continuing fluoxetine long enough to achieve steady-state with norfluoxetine. Other drugs that may inhibit diazepam metabolism include : amiodarone, anti-retroviral protease inhibitors , cimetidine, clarithromycin, dalfopristin; quinupristin, delavirdine, diltiazem, disulfiram, efavirenz (inducer or inhibitor), erythromycin, fluconazole, fluvoxamine, imatinib, STI-571, itraconazole, ketoconazole, IV miconazole, nefazodone, nicardipine, ranolazine, troleandomycin, verapamil, voriconazole, zafirlukast, and zileuton. This list is not inclusive of all agents that may inhibit diazepam metabolism. Itraconazole has been shown to alter diazepam pharmacokinetics, but not diazepam pharmacodynamics. Ciprofloxacin also inhibits diazepam clearance, although diazepam pharmacodynamics do not appear to be affected. Probenecid may also inhibit the hepatic metabolism of benzodiazepines. Patients receiving diazepam should be monitored for signs of an exaggerated response if any of the above drugs are used concomitantly.
Omeprazole can exhibit a dose-dependent inhibition of the hepatic cytochrome P-450 enzyme system. Omeprazole inhibits the CYP2C19 metabolic pathway for diazepam; however, the effect on diazepam pharmacodynamics is not known. Omeprazole can increase the plasma concentrations and the elimination half-life of diazepam. It is recommended that patients receiving omeprazole and diazepam concomitantly should be monitored for enhanced diazepam response. Rabeprazole has no effect on diazepam pharmacokinetics in poor and extensive CYP2C19 metabolizers. However, the AUC of desmethyldiazepam is increased during concurrent rabeprazole and diazepam administration in poor metabolizers, but this change is not clinically significant. Therefore, rabeprazole as a substrate is metabolized less by CYP2C19 isoenzymes and has less potential to interact with diazepam compared with omeprazole. The plasma elimination half-life, clearance, and volume of distribution of diazepam are not affected by concurrent use of lansoprazole.
Benzodiazepines should be combined cautiously with clozapine because they could cause additive CNS depressant effects. Severe confusion, hypotension and respiratory depression have occurred rarely in those patients receiving clozapine concurrently or following benzodiazepine therapy. In patients receiving concomitant clozapine, the starting doses of the benzodiazepine should be approximately one-half of the usual dose until experience with the patient has been gained.
The manufacturer of olanzapine (Zyprexa® ) recommends that concurrent use of intramuscular olanzapine and parenteral benzodiazepines be avoided if possible since safety of the combination has not been studied. Potential adverse effects of the combination include excess sedation and/or cardiorespiratory depression.
The manufacturer of aripiprazole (Abilify® ) injection recommends that patients be monitored for sedation and orthostatic hypotension during concurrent use of a parenteral benzodiazepine and intramuscular aripiprazole. Potential adverse effects of the combination include excess sedation and/or cardiorespiratory depression.
Rifampin is a potent inducer of the hepatic isoenzyme CYP3A4, one of the pathways responsible for the hepatic metabolism of diazepam. Patients receiving rifamycins (e.g., rifampin, rifapentine, rifabutin) may require higher doses of diazepam to achieve the desired clinical effect. In addition, patients should be monitored closely for signs of reduced diazepam effects if a rifamycin is added. Rifabutin may exert similar effects on diazepam clearance, although not to the degree that rifampin does. Other significant CYP3A4 inducers include: barbiturates, bosentan, carbamazepine, ethotoin, phenytoin or fosphenytoin, and St. John’s Wort. In addition, clonazepam, chlordiazepoxide, and diazepam have been reported to have an unpredictable effect on phenytoin serum concentrations (e.g., to increase, decrease, or cause no change in phenytoin serum concentrations). Conflicting results may have been observed due to saturable phenytoin metabolism and/or other conditions associated with the reported data. Since definitive controlled trial data are lacking, phenytoin concentrations should be monitored more closely when diazepam is added or discontinued.
Concomitant administration of diazepam with CNS-depressant drugs , including opiate agonists, buprenorphine, butorphanol, nalbuphine, pentazocine, phenothiazines, pregabalin , barbiturates , dronabinol, THC, nabilone, ethanol , sedating H1-blockers, entacapone, general anesthetics, tolcapone, tramadol, tricyclic antidepressants, or other anxiolytics, sedatives, and hypnotics can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. The dose of any opiate agonist administered with parenteral diazepam should be reduced by at least one-third.
Concurrent use of isoniazid, INH and diazepam can increase serum concentrations of diazepam due to alterations in the half-life and clearance of diazepam. Diazepam is a substrate at both the CYP2C19 and 3A4 isoenzyme, while isoniazid inhibits both of these metabolic sites. Slow acetylators of isoniazid may be at greater risk for adverse events due to elevated plasma concentrations. Although patient response to diazepam has not been reported, patients should be observed for signs of altered diazepam effects if isoniazid therapy is initiated or discontinued.
An interaction between digoxin, when administered concomitantly with either alprazolam or diazepam, has been reported. Digoxin toxicity has occurred in a patient receiving alprazolam and digoxin. This interaction may be the result of increased plasma protein binding of digoxin and/or an effect of the benzodiazepine at the renal tubules that results in decreased digoxin elimination. Pending further clarification of this interaction, patients receiving alprazolam or diazepam and digoxin concurrently should be monitored for increased serum digoxin levels.
Oral contraceptives can increase the effects of diazepam because they inhibit oxidative metabolism, thereby increasing serum concentrations of concomitantly administered benzodiazepines that undergo oxidation. Patients receiving oral contraceptive therapy should be observed for evidence of increased response to diazepam.
The administration of valproic acid to patients receiving diazepam can cause an increase in diazepam serum concentrations. This interaction appears to be the result of inhibition of hepatic metabolism of diazepam during concurrent use. Valproate displaces diazepam from its plasma albumin binding sites and inhibits its metabolism. Coadministration of valproate (1500 mg daily) with diazepam (10 mg) increased the free fraction of diazepam by 90% in healthy volunteers (n=6). Plasma clearance and volume of distribution for free diazepam were reduced by 25% and 20%, respectively, in the presence of valproate. The elimination half-life of diazepam remained unchanged upon addition of valproate If therapeutic effect is altered in patients receiving these medications, an alternative anticonvulsant should be instituted; however, the clinical significance of this potential drug interaction is not known.
Diazepam 2 mg/kg IV, in combination with epinephrine and mechanical ventilation, was used successfully in treating severe chloroquine poisoning. Ten patients receiving diazepam and epinephrine survived compared to one patient in a retrospective control group. Diazepam is reported to antagonize the toxic effects of chloroquine, although the mechanism is unclear. Further study is needed to confirm the usefulness of diazepam in chloroquine poisoning.
Flumazenil and benzodiazepines are pharmacological opposites. Flumazenil is specifically used to reverse the actions of benzodiazepines. Clinicians should note that the duration of action for some benzodiazepines may be much longer than that of flumazenil and repeat doses of flumazenil may be necessary.
It appears prudent to recommend caution when diazepam is prescribed in conjunction with melatonin. In animal studies, melatonin has been shown to increase benzodiazepine binding to receptor sites, and this may result in clinically significant drug interactions. Case reports exist of concomitant benzodiazepine and melatonin use in humans; the cases resulted in lethargy, short-term amnestic responses, or prolonged benzodiazepine activity. These apparent interactions could have been the result of a pharmacokinetic or pharmacodynamic enhancement of benzodiazepine activity by melatonin.
The German Commission E warns that any substances that act on the CNS, including psychotropic agents, may interact with kava kava. While the interactions can be pharmacodynamic in nature, kava kava has been reported to inhibit many CYP isozymes (i.e., CYP1A2, 2C9, 2C19, 2D6, 3A4, and 4A9/11) and important pharmacokinetic interactions with agents that undergo oxidative metabolism (e.g., selected benzodiazepines) are also possible. Patients on benzodiazepine therapy should avoid concomitant administration of kava kava. Patients should discuss the use of herbal supplements with their health care professional prior to consuming kava kava and should not abruptly stop taking their prescribed medications.
Any substances that act on the CNS, including benzodiazepines, may interact with valerian, Valeriana officinalis. These interactions are probably pharmacodynamic in nature. Patients taking diazepam should avoid concomitant administration of valerian.
Prior to general anesthesia, levodopa or carbidopa; levodopa therapy may be continued as long as the patient is permitted to take oral medication. If levodopa-based therapy is interrupted temporarily, the patient should be observed for signs of neuroleptic malignant syndrome, and the usual dosage should be administered as soon as the patient is able to take oral medication.
Telithromycin, a ketolide antibiotic, can compete with diazepam for metabolism by CYP3A4. This can result in increased concentrations of diazepam if the two drugs are coadministered.
The effect of citalopram or escitalopram on benzodiazepine metabolism is not known. The combined administration of citalopram with triazolam has not been reported to significantly affect the pharmacokinetics of either drug. However, clinicians should use citalopram or escitalopram cautiously with alprazolam or diazepam since coadministration could potentially result in additive pharmacodynamic effects within the CNS.
Theophylline has been reported to counteract the pharmacodynamic effects (e.g., sedative and anxiolytic effects) of diazepam. A proposed mechanism is competitive binding of theophylline to adenosine receptors in the brain. Whether a similar interaction occurs with other benzodiazepines is not known. If theophylline therapy is initiated or discontinued, monitor the clinical response to benzodiazepines.
Consider the potential for increased CNS side effects when aprepitant (a moderate CYP3A4 inhibitor) is administered with benzodiazepines that are CYP3A4 substrates (e.g., alprazolam, diazepam, midazolam, triazolam); reduced benzodiazepine dosages may be needed. If a benzodiazepine must be used with aprepitant, it would be prudent to select an agent that is not metabolized via CYP3A4 isoenzymes (e.g., lorazepam, oxazepam, temazepam).
Clinicians should be aware of the possibility of that orally-administered diazepam may interact with certain food products (i.e., grapefruit juice). Grapefruit juice has been shown to increase diazepam peak serum concentrations and AUC by 1.5-fold and 3.2-fold, respectively, when diazepam was administered orally. Grapefruit juice contains furano-coumarins and certain flavonoids which may inhibit the CYP3A4 isozyme. Increased sedation may be possible. To prevent this interaction, it would be prudent to avoid taking oral diazepam with grapefruit juice.
Tobacco smoke contains polycyclic aromatic hydrocarbons that induce hepatic CYP450 microsomal enzymes; tobacco smoking may thus increase the clearance of selected drugs. Tobacco smoke does not affect the metabolism of the parent drug diazepam, but does accelerate the metabolism of its major active metabolite, N-desmethyldiazepam, by up to 3-fold. Conversely, because the effect on hepatic microsomal enzymes is not related to the nicotine component of tobacco, sudden smoking cessation may result in a reduced clearance of this diazepam metabolite, despite the initiation of nicotine replacement. No specific dosage adjustment recommendations are available, but monitor patients for the desired clinical effects when changes in tobacco smoking status occur.
One study found that aluminium hydroxide gel and sodium citrate marginally increased and a magnesium trisilicate mixture slightly delayed the soporific effect of diazepam, when used as a premedication before minor surgery. Generally, however, the coadministration of diazepam with antacids results in delayed diazepam absorption due to the fact that antacids delay gastric emptying. While an interaction between diazepam and magaldrate or aluminum hydroxide-containing antacids will not likely result in a clinically significant drug interaction, it may be prudent to separate dosing by 2 hours to limit any potential interaction.
Exposure to diazepam (10 mg twice daily) was increased 28% following administration with valdecoxib (40 mg twice daily) for 12 days, while the exposure to valdecoxib was not substantially changed. Although the magnitude of the change in diazepam exposure does not necessitate a dosage change, patients may experience increased sedative effects due to the increase in diazepam exposure. Patients should be cautioned against participating in activities that require mental alertness, such as operating machinery or driving a vehicle, until they know how this combination may affect them.
The use of intrathecal radiopaque contrast agents is associated with a risk of seizures. Patients should be instructed to continue using benzodiazepines during procedures or exams that require the use of intrathecal radiopaque contrast agents as abrupt discontinuation of benzodiazepines may also increase seizure risk.
Conivaptan should be used with caution with CYP3A4 substrates. Conivaptan is a potent inhibitor of CYP3A4 and may increase plasma concentrations of drugs that are primarily metabolized by CYP3A4. Intravenous conivaptan 40 mg/day increases the mean AUC values by approximately 2-fold and 3-fold when coadministered with midazolam 1 mg IV or 2 mg PO, respectively. Use conivaptan with caution with midazolam or other oxidized benzodiazepines such as alprazolam , chlordiazepoxide , clonazepam , clorazepate , diazepam , estazolam , flurazepam , midazolam , prazepam , quazepam , and triazolam . The concomitant use of conivaptan with drugs that are primarily metabolized by CYP3A4 should be closely monitored, or the combination should be avoided. If a clinical decision is made to discontinue concomitant drugs at recommended doses, allow an appropriate time interval following the conivaptan administration before resuming these drugs.
Diazepam is a substrate of CYP3A4. In vivo data indicate that echinacea inhibits intestinal CYP3A4, but induces hepatic CYP3A4. The serum concentration of parenterally administered diazepam may be lowered if administered to patients receiving echinacea. However, the overall effect when diazepam is administered orally/rectally is unknown and may be negligible. It may be prudent to closely monitor for changes in efficacy or toxicity when echinacea is coadministered with diltiazem until more data are available.
Sodium phosphate monobasic monohydrate; sodium phosphate dibasic anhydrous should be used with caution in patients at a higher risk of seizures. The abrupt withdrawal of benzodiazepines may increase the risk of seizures. There have been reports of tonic-clonic seizures and/or loss of consciousness in patients who are undergoing withdrawal from benzodiazepines.
[ Last revised: 10/19/2006 3:14:00 PM ]
References
. Riou B, Barriot P, Rimailho A et al. Treatment of severe chloroquine poisoning. N Engl J Med 1988;318:1 - 6.
. Guerrero RM, Shifrar KA. Diagnosis and treatment of neuroleptic malignant syndrome. Clin Pharm 1988;7:697 - 701.
. Lefebvre RA, Flouvat B, Karolac-Tamisier S, et al. Influence of lansoprazole treatment on diazepam plasma concentrations. Clin Pharmacol Ther 1992;52:458 - 63.
. Ishizaki T, Chiba K, Manabe K, et al. Comparison of the interaction potential of a new proton pump inhibitor, E3810, versus omeprazole with diazepam in extensive and poor metabolizers of S-mephenytoin 4’-hydroxylation. Clin Pharmacol Ther 1995;58:155 - 64.
. Desta Z, Soukhova NV, Flockhart DA. Inhibition of cytochrome P450 (CYP450) isoforms by isoniazid: potent inhibition of CYP2C19 and CYP3A. Antimicrob Agents Chemother 2001;45:382 - 92.
. Hansten PD, Horn JR. Cytochrome P450 Enzymes and Drug Interactions, Table of Cytochrome P450 Substrates, Inhibitors, Inducers and P-glycoprotein, with Footnotes. In: The Top 100 Drug Interactions - A guide to Patient Management. 2007 Edition. Freeland, WA: H&H Publications; 2007:159 - 175.
. Raghavendra V, Naidu PS, Kulkarni SK. Reversal of reserpine-induced vacuous chewing movements in rats by melatonin: involvement of peripheral benzodiazepine receptors. Brain Res. 2001;904:149 - 52.
. McIntyre IM, Norman TR, Burrows GD, et al. Alterations to plasma melatonin and cortisol after evening alprazolam administration in humans. Chronobiol Int. 1993;10:205 - 13.
. Mattila MJ, Nuotto E. Caffeine and theophylline counteract diazepam effects in man. Med Biol. 1983;61:337 - 43.
. Wellbutrin XL® (bupropion) package insert. Research Triangle Park, NC: GlaxoSmithKline; 2006 June.
. Ketek™ (telithromycin) package insert. Kansas City, MO: Aventis Pharmaceuticals; 2005 Feb.
. Celexa® (citalopram) package insert. St. Louis, MO; Forest Pharmaceuticals, Inc.; 2004 Jan.
. Norvir® (Ritonavir) package insert. Chicago, IL: Abbott Laboratories; 2007 July.
. Hadley S, Petry JJ. Valerian. Am Fam Physician. 2003;67:1755 - 8.
. Tanaka E. Clinically significant pharmacokinetic drug interactions with benzodiazepines. J Clin Pharm Ther 1999;24:347 - 55.
. Wittbrodt ET, Spinler SA. Prevention of anaphylactoid reactions in high-risk patients receiving radiographic contrast media. Ann Pharmacother 1994;28:236 - 41.
. Valium® (diazepam) package insert. Nutley, NJ: Roche Laboratories, Inc.; 2000 Mar.
. Zyprexa® (olanzapine, all formulations) package insert. Indianapolis IN: Eli Lilly and Company; 2006.
. German Commission E. Kava Kava, Piperis methystici rhizoma, monograph Published June 1, 1990. In: Blumenthal, M et al ., eds. The complete German Commission E Monographs -Therapeutic Guide to Alternative Medicines. Boston MA: Integrative Medicine Communications for the American Botanical Council; 1998:156 - 7.
. Leuschner J, Muller J, Rudmann M. Characterisation of the central nervous depressant activity of a commercially available valerian root extract. Arzneimittelforschung 1993;43:638 - 41.
. Mathews JM, Etheridge AS, Black SR. Inhibition of human cytochrome P450 activities by kava extract and kavalactones. Drug Metab Dispos 2002;30:1153 - 7.
. Omnipaque™ (iohexol) package insert. Princeton, NJ: Amersham Health; 2003 Apr.
. Hooymans PM, Merkus FW. Current status of cardiac glycoside drug interactions. Clin Pharm 1985;4:404 - 13.
. Tollefson G, Lesar T, Grothe D, et al. Alprazolam-related digoxin toxicity. Am J Psychiatry 1984;131:1612 - 3.
. Romazicon® (flumazenil) package insert. Nutley, NJ: Roche Laboratories Inc.; 2003 Dec.
. Prilosec® (omeprazole) package insert. Wilmington, DE: AstraZeneca; 2003 Dec.
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