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Interactions with Clonazepam

Contents
Clozapine, Fentanyl topical, Fluoxetine, Fluphenazine, Flurazepam, Hydromorphone (oral), Metoclopramide, Morphine, Oxycodone, Prochlorperazine, Temazepam, Thioridazine (oral), Thiothixene, Trazodone, Triazolam, Clemastine, Tripelennamine, Brompheniramine, Promethazine (oral), Cyproheptadine, Azatadine, Phenindamine, Levorphanol, Oxymorphone, Perphenazine, Thiethylperazine, Meclizine, Trimethobenzamide, Dronabinol, Sertraline, Mesoridazine, Trifluoperazine, Molindone, Loxapine, Pimozide (oral), Halazepam, Zolpidem, Estazolam, Quazepam, Carisoprodol, Chlorphenesin, Chlorzoxazone, Cyclobenzaprine, Metaxalone, Methocarbamol, Orphenadrine, Baclofen, Dantrolene, Procyclidine, Trihexyphenidyl, Biperiden, Apraclonidine ophthalmic, Paroxetine, Risperidone (oral), Venlafaxine (oral), Lamotrigine, Tramadol, Fentanyl (buccal), Fentanyl citrate (oral transmucosal), Hydromorphone (injection), Hydromorphone (rectal), Triprolidine, Promethazine (rectal), Promethazine (injection), Buprenorphine (oral), Buprenorphine (injection), Maprotiline, Flavoxate, Mirtazapine, Pramipexole (oral), Ropinirole (oral), Quetiapine, Butorphanol, Sibutramine (oral), Tolcapone, Thalidomide, Citalopram (oral), Zaleplon, Entacapone, Nabilone, Ziprasidone, Escitalopram, Aripiprazole, Duloxetine, Eszopiclone, Ziconotide, Pregabalin, Rotigotine (transdermal), Paliperidone

If you are currently being treated with any of the following medications, you should not use Clonazepam without reading these interactions.

Disulfiram

ADJUST DOSE: The combination of disulfiram and benzodiazepines may increase CNS depression. The mechanism may relate to the inhibition of hepatic oxidation of benzodiazepines by disulfiram. Diazepam and chlordiazepoxide may interact with disulfiram to a greater extent than other benzodiazepines. However, the interaction has also been reported with temazepam, even though it is metabolized by glucuronidation.

MANAGEMENT: The benzodiazepine dosage may require reduction. Patients should be monitored for excessive and prolonged sedation.

Calcium carbonate, Sodium bicarbonate, Aluminum hydroxide, Aluminum carbonate, Magnesium hydroxide, Magnesium oxide

A number of studies have reported that antacids can delay the gastrointestinal absorption and reduce the peak plasma concentration (Cmax) of some benzodiazepines, including clorazepate, chlordiazepoxide and diazepam, although the overall extent of absorption is generally not affected. The exact mechanism of interaction is unknown but may involve delayed gastric emptying or cation binding of the benzodiazepine. As a result, benzodiazepine onset of action may be delayed and clinical effects diminished. However, one study reported a significant increase in diazepam absorption during coadministration with aluminum hydroxide, and there was a marginal increase in the onset of sedative effect. Aluminum hydroxide also increased the Cmax and systemic exposure (AUC) of triazolam in 11 dialysis patients such that their drug levels reached into the range observed for the matched controls. In contrast, another study by the same group of investigators found no significant effect of aluminum hydroxide on temazepam absorption or Cmax in 11 patients with end-stage renal disease. A multi-dose study also failed to find an effect of antacids on the steady-state levels of N-desmethyldiazepam, the active metabolite of clorazepate, although an acidic environment is thought to be necessary for the rapid conversion. Based on available data, the clinical significance of this interaction appears to be minor. As a precaution, patients may want to consider separating the administration times of benzodiazepines and antacids or oral medications that contain antacids (e.g., didanosine buffered tablets or pediatric oral solution) by 2 to 3 hours.

Bexarotene

Coadministration with bexarotene may theoretically decrease the plasma concentrations of drugs that are primarily metabolized by CYP450 3A4. The proposed mechanism is increased clearance due to induction of CYP450 3A4 activity by bexarotene. The clinical significance is unknown; however, the therapeutic efficacy of CYP450 3A4 substrates may be affected.

Modafinil

Coadministration with modafinil may decrease the plasma concentrations of drugs that are substrates of the CYP450 3A4 isoenzyme. Modafinil is a modest inducer of CYP450 3A4 in vitro, and pharmacokinetic studies suggest that its effects may be primarily intestinal rather than hepatic. Thus, clinically significant interactions would most likely be expected with drugs that have low oral bioavailability due to significant intestinal CYP450 3A4-mediated first-pass metabolism (e.g., buspirone, cyclosporine, felodipine, lovastatin, midazolam, nifedipine, nisoldipine, saquinavir, simvastatin, sirolimus, tacrolimus, triazolam, verapamil). However, the potential for interaction should be considered with any drug metabolized by CYP450 3A4, especially given the high degree of interpatient variability with respect to CYP450-mediated metabolism. Pharmacologic response to these drugs may be altered and should be monitored more closely whenever modafinil is added to or withdrawn from therapy. Dosage adjustments may be required if an interaction is suspected.

Evening primrose

Evening primrose oil contains gamolenic acid which lowers the seizure threshold, which may theoretically offset the beneficial effects of anticonvulsants. However, data have been conflicting and an interaction has not been clearly established. The possibility of an interaction should be considered if loss of seizure control occurs in patients taking anticonvulsants and evening primrose oil.

Kava

GENERALLY AVOID: A case report suggests that kava may increase the central nervous system adverse effects of benzodiazepines. In the report, a 54-year-old man treated with alprazolam became semicomatose with lethargy and disorientation following self-medication with kava for 3 days. The exact mechanism of interaction is unknown, but an additive or synergistic CNS effect is suspected.

MANAGEMENT: Until further information is available, concomitant use of kava and benzodiazepines is not recommended. Patients on benzodiazepines should be advised to consult their caregiver before using any alternative medicines.

Apomorphine

GENERALLY AVOID: Central nervous system (CNS) depressant effects may be additively or synergistically increased in patients using apomorphine in combination with other drugs that can also cause these effects. Apomorphine alone has been frequently associated with somnolence and dizziness. Patients may suddenly fall asleep during activities of daily living.

MANAGEMENT: The use of other sedating drugs should generally be avoided during apomorphine treatment. Patients prescribed these agents concurrently should be monitored for potentially excessive or prolonged CNS depression, especially if they are elderly or debilitated. Ambulatory patients should be made aware of the possibility of additive CNS effects (e.g., drowsiness, dizziness, lightheadedness, confusion) and counseled to avoid activities requiring mental alertness until they know how these agents affect them. If patients experience increased episodes of falling asleep during normal daily activities, they should avoid driving and other potentially hazardous activities until they have contacted their physician.

Mefloquine

GENERALLY AVOID: Mefloquine may increase the risk of seizures and decrease the effectiveness of anticonvulsant drugs in patients with epilepsy. The mechanism is unknown, and it is unclear whether the seizures occur due to drug-drug or drug-disease interactions, as mefloquine alone and in combination with other related drugs (e.g., quinine, quinidine, chloroquine) have also been associated with seizures in some patients. It has been proposed that mefloquine may reduce the plasma levels of certain anticonvulsants such as sodium valproate, phenobarbital, carbamazepine, and phenytoin.

MANAGEMENT: Because it can increase the risk of seizures in patients with epilepsy, mefloquine should only be used for curative treatment of malaria in such patients and only if there are compelling medical reasons for its use. Patient clinical status and anticonvulsant blood levels should be closely monitored if mefloquine is prescribed. Dosage adjustments may be required. Patients should be advised to notify their physician if they experience a loss of seizure control. Mefloquine should not be prescribed for malaria prophylaxis in patients with a history of convulsions.

Flumazenil

GENERALLY AVOID: The administration of flumazenil can result in convulsions in patients who have been receiving long-term treatment with benzodiazepines for epilepsy or sedation or who have recently received repeated doses of parenteral benzodiazepines. The mechanism is abrupt reversal of the benzodiazepine's anticonvulsive effects. In addition, withdrawal seizures may occur in patients who are physically dependent on benzodiazepines.

MANAGEMENT: The use of flumazenil is not recommended in patients with epilepsy who have been receiving long-term treatment with benzodiazepines. In addition, flumazenil is contraindicated in patients who have received a benzodiazepine to control potentially life-threatening conditions such as status epilepticus or increased intracranial pressure. Extreme caution, dose individualization, and close monitoring is recommended for other patients. Clinicians should be prepared to manage convulsions. Most seizures have been successfully managed with benzodiazepines, phenytoin, or barbiturates.

Sodium oxybate

GENERALLY AVOID: The central nervous system (CNS)- and respiratory-depressant effects of sodium oxybate may be potentiated by other agents with CNS-depressant effects.

MANAGEMENT: Agents with CNS depressant effects should be avoided during sodium oxybate therapy.

Olanzapine

GENERALLY AVOID: The safety and efficacy of intramuscular olanzapine administered in combination with benzodiazepines have not been established. Deaths have been reported in patients who received IM olanzapine during postmarketing use. The cause has not been determined but in many of the deaths, patients were treated with multiple concomitant drugs including IM benzodiazepines and other IM antipsychotics that are known to have the potential to induce hypotension, bradycardia, or respiratory or CNS depression. In addition, IM olanzapine may have been administered to some patients in a manner that was inconsistent with product labeling and/or to patients with significant medical comorbidities.

MONITOR: CNS- and/or cardiorespiratory-depressant effects may be increased during concomitant use of olanzapine and benzodiazepines, especially in elderly or debilitated patients. In clinical trials of elderly patients with dementia-related psychosis, the incidence of death in olanzapine-treated patients was significantly greater than in placebo-treated patients (3.5% vs. 1.5%). Risk factors for the increased mortality with olanzapine include age greater than 80 years, dysphagia, sedation, malnutrition and dehydration, concomitant use of benzodiazepines, and presence of pulmonary conditions such as pneumonia. Limited data in 15 healthy subjects receiving IM olanzapine followed by an IM benzodiazepine (lorazepam) found that the combination prolonged somnolence by 3.3 hours compared to IM olanzapine alone and 5.8 hours compared to IM lorazepam alone.

MANAGEMENT: Caution is necessary during coadministration of olanzapine with other drugs having effects that can induce hypotension, bradycardia, respiratory or CNS depression such as benzodiazepines. Ambulatory patients should be made aware of the possibility of additive CNS effects and counseled to avoid activities requiring mental alertness until they know how these agents affect them. They should also be advised to avoid rising abruptly from a sitting or recumbent position and to contact their physician if they experience symptoms of hypotension such as dizziness, lightheadedness, or fainting. Concomitant administration of IM olanzapine and parenteral benzodiazepine has not been studied and is therefore not recommended. If this combination is necessary, careful evaluation of clinical status for excessive sedation and cardiorespiratory depression is recommended.

Ginkgo

Ginkgo toxin (found in both the Ginkgo leaf and seed) is a known neurotoxin. Some investigators have concluded that the amount of toxin is too low to exert a detrimental effect. However, avoiding use of Ginkgo in known epileptics has been recommended because the Ginkgo toxin that is present may diminish the effectiveness of anticonvulsant medications.

Oxtriphylline, Aminophylline, Dyphylline

Methylxanthines may antagonize the sedative effects of benzodiazepines. Aminophylline in particular has been demonstrated to attenuate the sedative effects of diazepam. The mechanism of this interaction may be related to competitive binding to intracerebral adenosine receptors. One study demonstrated that alprazolam serum concentrations were significantly lower in patients receiving chronic theophylline therapy than in patients not receiving theophylline. Clinical and laboratory monitoring is warranted if these agents are given concurrently. Patients receiving this combination should be monitored for adequate response to the benzodiazepine.

Fluvoxamine

MONITOR: Administration of fluvoxamine with certain benzodiazepines may increase CNS depression (e.g., sedation, ataxia). The mechanism appears to be inhibition of the CYP450 3A4 hepatic oxidative metabolism of the benzodiazepine. This interaction has been reported for alprazolam and diazepam, but may also occur with other benzodiazepines.

MANAGEMENT: The patient should be observed for increased CNS depression. Dosage adjustments may be required. Lorazepam, temazepam, and oxazepam, which are not metabolized by oxidative metabolism, may be better alternatives if a benzodiazepine is required.

Divalproex sodium

MONITOR: A single study has suggested that combination therapy with clonazepam and valproic acid may cause severe drowsiness and decreased seizure control. Other studies have not supported this finding. Several case reports have suggested that the combination of clonazepam and valproic acid may precipitate absence status; however, this combination has had beneficial effects in the treatment refractory absence seizures. The mechanism and causality have not been determined.

MANAGEMENT: Monitoring for altered efficacy and safety is recommended if valproic acid (or its derivatives) and clonazepam are used together. Alternative therapy may be appropriate if significant side effects or loss of seizure control occur.

Pentobarbital, Phenobarbital, Primidone, Secobarbital, Mephobarbital

MONITOR: Barbiturates may increase the plasma clearance of clonazepam and thereby reduce its clinical effectiveness. Phenobarbital is the only barbiturate specifically implicated in this interaction. However, other barbiturates may behave in a similar fashion. Also, clonazepam may increase the effectiveness of barbiturates. A case of respiratory depression and coma has been reported in a patient receiving high doses of both clonazepam and amobarbital.

MANAGEMENT: If these drugs are used together, close observation for altered clonazepam and barbiturate effects is indicated.

Oxcarbazepine

MONITOR: Based on in vitro data, coadministration with oxcarbazepine may decrease the plasma concentrations of drugs that are substrates of the CYP450 3A4 and 3A5 isoenzymes. The mechanism is accelerated clearance due to induction of CYP450 3A activities by oxcarbazepine. In one study, a single dose of oxcarbazepine (600 mg) had no effect on the pharmacokinetics of felodipine, a CYP450 3A4 substrate, while repeated doses (450 mg twice a day) decreased the peak plasma concentration and area under the concentration-time curve of felodipine (10 mg once daily) by 34% and 28%, respectively. Likewise, in a single case study, cyclosporine trough concentrations decreased to subtherapeutic levels a little over 2 weeks after addition of oxcarbazepine in a renal transplant patient. These results indicate that enzymatic induction occurs after multiple doses.

MANAGEMENT: Caution is advised if oxcarbazepine must be used concurrently with medications that undergo metabolism by CYP450 3A4 and/or 3A5, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever oxcarbazepine is added to or withdrawn from therapy.

Grepafloxacin

MONITOR: Based on in vitro inhibition data, coadministration with grepafloxacin may increase the plasma concentrations of drugs that are substrates of the CYP450 3A4 isoenzyme. The mechanism is decreased clearance due to inhibition of CYP450 3A4 activity by grepafloxacin.

MANAGEMENT: Caution is advised if grepafloxacin must be used concurrently with medications that undergo metabolism by CYP450 3A4, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever grepafloxacin is added to or withdrawn from therapy.

Mifepristone

MONITOR: Based on in vitro inhibition data, coadministration with mifepristone may increase the plasma concentrations of drugs that are substrates of the CYP450 3A4 isoenzyme. The mechanism is decreased clearance due to inhibition of CYP450 3A4 activity by mifepristone.

MANAGEMENT: Caution is advised if mifepristone must be used concomitantly with medications that undergo metabolism by CYP450 3A4, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever mifepristone is added to or withdrawn from therapy. Because mifepristone is eliminated slowly from the body, drug interactions may be observed for a prolonged period.

Dichlorphenamide, Methazolamide

MONITOR: Benzodiazepines may counteract the beneficial effects of acetazolamide in preventing altitude sickness by inhibiting respiratory responses to hypoxia. The medical team that accompanied the China-Japan-Nepal Friendship Expedition to Mount Everest in 1988 reports severe hypoventilation in some climbers when acetazolamide and triazolam were given together. One affected climber could be ordered to breath regularly, but repeatedly 'forgot' to continue breathing. This syndrome has been referred to as 'Ondine's curse'.

MANAGEMENT: Caution is recommended if a CAI and a benzodiazepine must be used together. Until more information is available, it may be prudent to avoid the concurrent use of triazolam and acetazolamide at extreme altitudes.

Levodopa

MONITOR: Benzodiazepines may decrease the therapeutic effects of levodopa in patients with Parkinson's disease. The mechanism is unknown.

MANAGEMENT: Patients receiving this combination should be monitored for altered clinical response. The benzodiazepine should be discontinued if an interaction is suspected.

Digoxin (oral)

MONITOR: Benzodiazepines may increase serum levels of digoxin. The mechanism is unknown, but may be related to alterations of digoxin protein binding. Data have been conflicting; however, some cases of digoxin toxicity have been reported. Elderly patients may have a greater risk of developing toxicity.

MANAGEMENT: Close observation for clinical and laboratory evidence of digoxin toxicity is recommended if these drugs must be used together. Patients should be advised to notify their physician if they experience nausea, anorexia, visual disturbances, slow pulse, or irregular heartbeats.

Doxepin, Imipramine, Trimipramine, Amoxapine, Protriptyline, Clomipramine

MONITOR: Central nervous system- and/or respiratory-depressant effects may be additively or synergistically increased in patients taking clonazepam and tricyclic antidepressants. However, one case report has described decreased desipramine levels during concurrent administration with clonazepam. The mechanism is unknown.

MANAGEMENT: Patients should be monitored for excessive or prolonged CNS and respiratory depression. Ambulatory patients should made aware of the possibility of additive CNS effects (e.g., drowsiness, dizziness, lightheadedness, or confusion) and counseled to avoid activities requiring alertness until they know how these agents affect them. Patients should also be advised to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.

Clozapine, Fentanyl topical, Fluoxetine, Fluphenazine, Flurazepam, Hydromorphone (oral), Metoclopramide, Morphine, Oxycodone, Prochlorperazine, Temazepam, Thioridazine (oral), Thiothixene, Trazodone, Triazolam, Clemastine, Tripelennamine, Brompheniramine, Promethazine (oral), Cyproheptadine, Azatadine, Phenindamine, Levorphanol, Oxymorphone, Perphenazine, Thiethylperazine, Meclizine, Trimethobenzamide, Dronabinol, Sertraline, Mesoridazine, Trifluoperazine, Molindone, Loxapine, Pimozide (oral), Halazepam, Zolpidem, Estazolam, Quazepam, Carisoprodol, Chlorphenesin, Chlorzoxazone, Cyclobenzaprine, Metaxalone, Methocarbamol, Orphenadrine, Baclofen, Dantrolene, Procyclidine, Trihexyphenidyl, Biperiden, Apraclonidine ophthalmic, Paroxetine, Risperidone (oral), Venlafaxine (oral), Lamotrigine, Tramadol, Fentanyl (buccal), Fentanyl citrate (oral transmucosal), Hydromorphone (injection), Hydromorphone (rectal), Triprolidine, Promethazine (rectal), Promethazine (injection), Buprenorphine (oral), Buprenorphine (injection), Maprotiline, Flavoxate, Mirtazapine, Pramipexole (oral), Ropinirole (oral), Quetiapine, Butorphanol, Sibutramine (oral), Tolcapone, Thalidomide, Citalopram (oral), Zaleplon, Entacapone, Nabilone, Ziprasidone, Escitalopram, Aripiprazole, Duloxetine, Eszopiclone, Ziconotide, Pregabalin, Rotigotine (transdermal), Paliperidone

MONITOR: Central nervous system- and/or respiratory-depressant effects may be additively or synergistically increased in patients taking multiple drugs that cause these effects, especially in elderly or debilitated patients.

MANAGEMENT: During concomitant use of these drugs, patients should be monitored for potentially excessive or prolonged CNS and respiratory depression. Ambulatory patients should be counseled to avoid hazardous activities requiring complete mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.

Brimonidine ophthalmic

MONITOR: Central nervous system (CNS) depressant effects may be additively or synergistically increased in patients using brimonidine ophthalmic solution in combination with other drugs that can also cause these effects, especially in elderly or debilitated patients.

MANAGEMENT: Patients prescribed brimonidine ophthalmic drops with other agents that can cause CNS depression should be made aware of the possibility of additive CNS effects (e.g., drowsiness, dizziness, lightheadedness, confusion) and counseled to avoid activities requiring mental alertness until they know how these agents affect them. Patients should be advised to contact their physician if they experience excessive or prolonged CNS depression.

Propoxyphene

MONITOR CLOSELY: Sedatives, tranquilizers, muscle relaxants, antidepressants, and other central nervous system (CNS) depressants may have additive CNS- and/or respiratory-depressant effects with propoxyphene. Misuse of propoxyphene, either alone or in combination with other CNS depressants, has been a major cause of drug-related deaths, particularly in patients with a history of emotional disturbances, suicidal ideation, or alcohol and drug abuse. In a large Canadian study, propoxyphene use was also associated with a 60% increased risk of hip fracture in the elderly, and the risk was further increased by concomitant use of psychotropic agents (sedatives, antidepressants, neuroleptics), presumably due to additive psychomotor impairment. Therefore, these drugs may constitute a dangerous combination in certain susceptible populations. Pharmacokinetically, propoxyphene is an inhibitor of CYP450 2D6 and may increase the plasma concentrations of many psychotropic agents that are metabolized by the isoenzyme such as phenothiazines, haloperidol, risperidone, phenobarbital, and some tricyclic antidepressants and serotonin reuptake inhibitors.

MANAGEMENT: Caution is advised if propoxyphene is used with sedatives, tranquilizers, muscle relaxants, antidepressants, and other CNS depressants, particularly in the elderly and in patients with a history of emotional disturbances, suicidal ideation, or alcohol and drug abuse. Dosage reductions may be appropriate. Patients should be monitored for potentially excessive or prolonged CNS and respiratory depression and other CNS adverse effects. Patients should be warned not to exceed recommended dosages, to avoid alcohol, and to avoid activities requiring mental alertness until they know how these agents affect them.

Tacrolimus (oral), Sirolimus

MONITOR: Coadministration of sirolimus or tacrolimus with other drugs that are also metabolized by CYP450 3A4 may result in elevated plasma concentrations of the macrolide immunosuppressant and/or the coadministered drug(s). The mechanism is decreased drug clearance due to competitive inhibition of CYP450 3A4 activity. Although clinical data are lacking, the possibility of prolonged and/or increased pharmacologic effects of the drugs should be considered.

MANAGEMENT: Pharmacologic responses and/or plasma drug levels should be monitored more closely whenever a macrolide immunosuppressant or another substrate of CYP450 3A4 is added to or withdrawn from therapy, and the dosage(s) adjusted as necessary.

Amprenavir, Fosamprenavir

MONITOR: Coadministration with amprenavir or its prodrug, fosamprenavir, may increase the plasma concentrations of drugs that are substrates of the CYP450 3A4 isoenzyme. The mechanism is decreased clearance due to inhibition of CYP450 3A4 activity by amprenavir.

MANAGEMENT: Caution is advised if amprenavir must be used concurrently with medications that undergo metabolism by CYP450 3A4, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever amprenavir is added to or withdrawn from therapy.

Aprepitant

MONITOR: Coadministration with aprepitant may increase the plasma concentrations of benzodiazepines that are metabolized by CYP450 3A4. The mechanism is decreased clearance due to inhibition of CYP450 3A4 activity by aprepitant. According to the manufacturer, coadministration of aprepitant (125 mg single dose on day 1 and 80 mg/day on days 2 through 5) and midazolam (2 mg orally on days 1 and 5) resulted in an increase in the area under the plasma concentration-time curve (AUC) of midazolam by 2.3-fold on day 1 and 3.3-fold on day 5. The same regimen of aprepitant given for 3 days with intravenous midazolam (2 mg prior to initiation of aprepitant and on days 4, 8 and 15) increased midazolam AUC by 25% on day 4 but decreased it by 19% on day 8. Midazolam AUC on day 15 was similar to that observed at baseline. Thus, the effect of aprepitant on the pharmacokinetics of CYP450 3A4 substrates is expected to be greater when the substrates are administered orally as opposed to intravenously and may be altered following prolonged administration. Benzodiazepines known to be metabolized by CYP450 3A4 include alprazolam, diazepam, midazolam, and triazolam.

MANAGEMENT: Caution is advised if aprepitant is administered with benzodiazepines that are metabolized by CYP450 3A4. The potential for increased pharmacologic effects of the benzodiazepine, including central nervous system and respiratory depression, should be considered. The interaction is not expected to occur with lorazepam, oxazepam or temazepam, which are primarily metabolized via glucuronidation. Chronic, continuous use of aprepitant for prevention of nausea and vomiting is not recommended because it has not been studied and because the drug interaction profile may change during long-term use.

Bosentan

MONITOR: Coadministration with bosentan may decrease the plasma concentrations of drugs that are substrates of the CYP450 2C9 and/or 3A4 isoenzymes. The mechanism is accelerated clearance due to induction of those isoenzymes by bosentan.

MANAGEMENT: When drugs that are known substrates of CYP450 2C9 and/or 3A4 are coadministered with bosentan, the possibility of a diminished therapeutic response to those drugs should be considered. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs, particularly those with a narrow therapeutic range, whenever bosentan is added to or withdrawn from therapy.

Conivaptan

MONITOR: Coadministration with conivaptan may increase the plasma concentrations of drugs that are substrates of the CYP450 3A4 isoenzyme. The mechanism is decreased clearance due to inhibition of CYP450 3A4 activity by conivaptan. In pharmacokinetic studies with drugs that are primarily metabolized by CYP450 3A4 such as midazolam, simvastatin, and amlodipine, conivaptan has increased systemic exposure (AUC) by 2- to 3-fold.

MANAGEMENT: Caution is advised if conivaptan must be used concurrently with medications that undergo metabolism by CYP450 3A4, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever conivaptan is added to or withdrawn from therapy, or the combination avoided altogether. If a clinical decision is made to discontinue concomitant medications at recommended doses, clinicians should allow an appropriate amount of time following the end of conivaptan administration before resuming these medications.

Dasatinib

MONITOR: Coadministration with dasatinib may increase the plasma concentrations of drugs that are substrates of the CYP450 3A4 isoenzyme. The mechanism is decreased clearance due to inhibition of CYP450 3A4 activity by dasatinib, which is a time-dependent inhibitor of the isoenzyme. In a pharmacokinetic study of 54 healthy subjects, administration of simvastatin with a single 100 mg dose of dasatinib increased the peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of simvastatin by 37% and 20%, respectively, compared to administration without dasatinib.

MANAGEMENT: Caution is advised if dasatinib must be used concurrently with medications that undergo metabolism by CYP450 3A4, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever dasatinib is added to or withdrawn from therapy.

Efavirenz

MONITOR: Coadministration with efavirenz may decrease the plasma concentrations of drugs that are substrates of the CYP450 3A4 isoenzyme. The mechanism is accelerated clearance due to induction of CYP450 3A4 activity by efavirenz.

MANAGEMENT: Caution is advised if efavirenz must be used concomitantly with medications that undergo metabolism by CYP450 3A4, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever efavirenz is added to or withdrawn from therapy.

Imatinib (oral)

MONITOR: Coadministration with imatinib may increase the plasma concentrations of drugs that are substrates of CYP450 2C9, 2D6 and/or 3A4. The mechanism is decreased clearance due to inhibition of these isoenzymes by imatinib. According to the manufacturer, imatinib increased the mean peak plasma concentration and area under the concentration-time curve of simvastatin (a CYP450 3A4 substrate) by 2- and 3.5-fold, respectively. Data for other substrates are not currently available, although human liver microsome studies indicate that imatinib is a potent competitive inhibitor of all three isoenzymes.

MANAGEMENT: Caution is advised if imatinib must be used concomitantly with medications that undergo metabolism by CYP450 2C9, 2D6 and/or 3A4, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever imatinib is added to or withdrawn from therapy.

Lapatinib

MONITOR: Coadministration with lapatinib may increase the plasma concentrations of drugs that are substrates of the CYP450 2C8 isoenzyme, CYP450 3A4 isoenzyme, and/or P-glycoprotein efflux transporter. The mechanism is decreased clearance via these routes due to inhibition by lapatinib.

MANAGEMENT: Caution is advised if lapatinib must be used concurrently with medications that are substrates of the CYP450 2C8 isoenzyme, CYP450 3A4 isoenzyme, and/or P-glycoprotein efflux transporter, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever lapatinib is added to or withdrawn from therapy.

Rifapentine

MONITOR: Coadministration with rifapentine may decrease the plasma concentrations of drugs that are substrates of the CYP450 2C8, 2C9, and/or 3A4 isoenzymes. The mechanism is accelerated clearance due to induction of those isoenzymes by rifapentine. Enzyme activities may be induced within 4 days of the first dose and return to normal 14 days after discontinuation of rifapentine. In vitro and in vivo enzyme studies have suggested rifapentine induction potential to be less than that of rifampin but greater than that of rifabutin. In addition, the magnitude of induction is dependent on dose and dosing frequency.

MANAGEMENT: When drugs that are known substrates of CYP450 2C8, 2C9, and/or 3A4 are coadministered with rifapentine, the possibility of a diminished therapeutic response to those drugs should be considered. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs, particularly those with a narrow therapeutic range, whenever rifapentine is added to or withdrawn from therapy.

Saquinavir

MONITOR: Coadministration with saquinavir may increase the plasma concentrations of drugs that are substrates of the CYP450 3A4 isoenzyme. The mechanism is decreased clearance due to inhibition of CYP450 3A4 activity by saquinavir.

MANAGEMENT: Caution is advised if saquinavir must be used concomitantly with medications that undergo metabolism by CYP450 3A4, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever saquinavir is added to or withdrawn from therapy.

Mephenytoin, Ethotoin

MONITOR: Coadministration with some benzodiazepines may alter the serum concentrations of phenytoin. Both increases and decreases have been cited by case reports and pharmacokinetic studies, while a few reported no changes. The exact mechanism of interaction is unknown, and it is uncertain whether other hydantoins are also affected. Phenytoin toxicity has been reported in patients treated with various benzodiazepines, including clobazam, chlordiazepoxide, clonazepam, and diazepam. Conversely, phenytoin may reduce the plasma concentrations of some benzodiazepines by inducing their metabolism via hepatic microsomal enzymes. In one study, pretreatment with phenytoin (4.3 mg/kg/day for 19 days) increased the clearance of clonazepam (0.03 mg/kg single oral dose) by 46% to 58% and decreased its half-life by 31% in eight healthy volunteers. In another study, mean peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of midazolam (15 mg oral dose) in six epileptic patients treated concomitantly with phenytoin or carbamazepine were 7.4% and 5.7%, respectively, of those observed in seven control subjects who were not receiving enzyme inducers. The low plasma midazolam concentrations in the patient group were associated with reduced pharmacodynamic effects as compared with control subjects.

MANAGEMENT: Pharmacologic response and serum hydantoin levels should be monitored more closely whenever a benzodiazepine is added to or withdrawn from therapy, and the hydantoin dosage adjusted as necessary. Patients should be advised to contact their physician if they experience symptoms of hydantoin toxicity such as nausea, vomiting, tremors, ataxia, lethargy, slurred speech, visual disturbances, or changes in mental status. The potential for diminished or inadequate benzodiazepine effects should be considered during concomitant use with phenytoin.

Telithromycin

MONITOR: Coadministration with telithromycin may increase the plasma concentrations of drugs that are substrates of the CYP450 3A4 isoenzyme. The mechanism is decreased clearance due to inhibition of CYP450 3A4 activity by telithromycin.

MANAGEMENT: Caution is advised if telithromycin must be used concurrently with medications that undergo metabolism by CYP450 3A4, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever telithromycin is added to or withdrawn from therapy.

Voriconazole

MONITOR: Coadministration with voriconazole may increase the plasma concentrations of drugs that are substrates of CYP450 2C19, 2C9, and/or 3A4. The mechanism is decreased clearance due to inhibition of those isoenzymes by voriconazole. Increased plasma levels and/or pharmacologic effects of drugs such as cyclosporine, sirolimus, tacrolimus (3A4 substrates), and warfarin (2C9 substrate) have been reported during coadministration with voriconazole.

MANAGEMENT: Caution is advised if voriconazole must be used concomitantly with medications that undergo metabolism by CYP450 2C19, 2C9 and/or 3A4, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever voriconazole is added to or withdrawn from therapy. The manufacturer specifically recommends that a dosage reduction be considered for benzodiazepines, HMG-CoA reductase inhibitors (i.e. statins), and vinca alkaloids that are metabolized by the affected isoenzymes when used with voriconazole.

Cetirizine

MONITOR: Concurrent use of cetirizine or levocetirizine with alcohol or other central nervous system (CNS) depressants may result in additive impairment of mental alertness and performance. Several studies have shown no effect of racemic cetirizine on cognitive function, motor performance, or sleep latency as indicated by objective measurements. However, there have been reports of somnolence, fatigue, and asthenia in some patients treated with cetirizine or levocetirizine in clinical trials.

MANAGEMENT: Concomitant use of cetirizine or levocetirizine with alcohol or other CNS depressants should generally be avoided if possible. In the event that they are used together, patients should be counseled to avoid hazardous activities requiring complete mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.

Pemoline

MONITOR: Decreased seizure threshold has been reported in patients receiving pemoline concomitantly with antiepileptic medications. The mechanism of this interaction has not been reported.

MANAGEMENT: These drugs should be coadministered cautiously with careful clinical monitoring. Patients should be advised to notify their physician if they experience loss of seizure control.

Indinavir

MONITOR: Indinavir may interfere with the metabolism of benzodiazepines. The mechanism is competitive inhibition of the CYP450 3A4 enzyme. The accumulation of benzodiazepines is associated with potentially serious and/or life-threatening events (e.g., prolonged sedation, respiratory depression).

MANAGEMENT: Patients receiving benzodiazepines should be monitored for excessive pharmacological effects such as sedation. Lorazepam, temazepam and oxazepam are metabolized by glucuronidation and are not expected to be affected by indinavir.

Phenelzine, Tranylcypromine, Selegiline (oral), Procarbazine, Isocarboxazid, Selegiline (transdermal), Rasagiline

MONITOR: Limited clinical data suggest that the concomitant use of clonazepam and monoamine oxidase inhibitors (MAOIs) may precipitate a hypertensive and/or flushing reaction. The mechanism is unknown. Phenelzine has been specifically implicated in this interaction. Data for other combinations of MAOIs and benzodiazepines are not available.

MANAGEMENT: Until more is known about this potential interaction, patients should be monitored for development of hypertension during coadministration of clonazepam with an MAOI or other agents that possess MAOI activity (e.g., furazolidone, procarbazine). Patients should be advised to notify their physician if they develop severe headaches or flushing.

Troleandomycin

MONITOR: Macrolide antibiotics may increase and prolong the CNS effects of certain benzodiazepines. The mechanism is inhibition of CYP450 3A4 hepatic oxidation of the benzodiazepines. Midazolam, triazolam, and alprazolam have been specifically studied in this regard. Lorazepam, oxazepam, and temazepam are hepatically conjugated and are not expected to interact. Azithromycin and dirithromycin do not inhibit CYP450 isoenzymes.

MANAGEMENT: Patients receiving this combination should be monitored for excessive or prolonged sedation. Non-interacting benzodiazepines or antimicrobials may be considered as alternatives.

Nefazodone

MONITOR: Nefazodone, when administered with alprazolam or triazolam, has been reported to increase their half-life, area under the plasma concentration-time curve, and peak plasma concentrations. Increased sedation and altered psychomotor performance have resulted. The mechanism appears to be inhibition of the CYP450 3A4 enzyme by nefazodone. This interaction may occur with all benzodiazepines that undergo oxidative metabolism, although it has been reported only with alprazolam and triazolam.

MANAGEMENT: Patients receiving this combination should be monitored for excessive and prolonged sedation. It may be necessary to adjust benzodiazepine dosage when nefazodone is started or stopped. Lorazepam, oxazepam, and temazepam undergo conjugative metabolism and may be suitable alternatives.

Nelfinavir

MONITOR: Nelfinavir competitively inhibits the CYP450 3A4 isoenzyme and may interfere with the metabolism of some benzodiazepines.

MANAGEMENT: Caution is advised if benzodiazepines are administered with nelfinavir. Patients should be monitored for the possibility of potentially serious and/or life threatening events (e.g. prolonged sedation, respiratory depression) associated with the accumulation of these agents.

Omeprazole

MONITOR: Omeprazole may increase the pharmacologic effects and serum levels of certain benzodiazepines via hepatic enzyme inhibition. Diazepam and triazolam are the only benzodiazepines that have been specifically studied in this regard.

MANAGEMENT: Patient should be observed for increased sedation. Reduced benzodiazepine dosage may be indicated, especially in the elderly. Benzodiazepines not metabolized via oxidation (i.e., lorazepam, oxazepam, temazepam) are not expected to interact and may be considered as alternatives.

Tizanidine

MONITOR: Sedation is a major side effect of tizanidine and may be potentiated by coadministration with other substances that have central nervous system-depressant effects or that may commonly cause drowsiness.

MANAGEMENT: Use of tizanidine with other substances that commonly cause sedation should be approached with caution, particularly in elderly or debilitated patients. Ambulatory patients should be counseled to avoid hazardous activities requiring complete mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.

Ritonavir

MONITOR: The coadministration of ritonavir and benzodiazepines that are substrates of the CYP450 3A4 enzymatic pathway may result in elevated plasma concentrations of the latter. The mechanism is decreased clearance of benzodiazepines due to inhibition of CYP450 3A4 activity by ritonavir.

MANAGEMENT: While clinical data are not available for all agents in the class, the possibility of prolonged and/or increased pharmacologic effects of benzodiazepines, including sedation and respiratory depression, should be considered in patients receiving ritonavir therapy. It may be appropriate to use lower benzodiazepine dosages in these patients, or use agents that are not metabolized by the CYP450 3A4 pathway (e.g., lorazepam, oxazepam, temazepam).

Fosinopril, Hydrochlorothiazide, Indapamide, Isosorbide dinitrate, Isosorbide mononitrate, Metolazone, Nitroglycerin (oral/buccal/sublingual/spray), Nitroglycerin topical (patches and ointment), Quinapril, Reserpine, Spironolactone, Triamterene, Ethacrynic acid, Carteolol, Bisoprolol, Guanfacine, Guanadrel, Ramipril, Benazepril, Lisinopril, Phenoxybenzamine, Torsemide, Losartan, Moexipril, Carvedilol, Trandolapril, Esmolol, Penbutolol, Sotalol, Sotalol AF, Irbesartan, Eprosartan, Candesartan, Telmisartan, Perindopril, Alfuzosin, Olmesartan, Eplerenone

MONITOR: The concomitant administration of agents with hypotensive effects and psychotherapeutic agents (e.g., anxiolytics, sedatives, hypnotics, antidepressants, antipsychotics), narcotic analgesics, alcohol, or muscle relaxants may additively increase hypotensive and/or central nervous system depressant effects.

MANAGEMENT: During concomitant use of these drugs, patients should be monitored for hypotension and excessive or prolonged CNS depression. Ambulatory patients should be made aware of the possibility of additive effects (e.g., drowsiness, dizziness, lightheadedness, confusion, orthostasis, fainting) and be cautioned about driving, operating machinery, or performing other hazardous tasks, and to arise slowly from a sitting or lying position. Patients should also be advised to notify their doctor if they experience excessive side effects that interfere with their normal activities, or dizziness and fainting.

Rifabutin

Rifampin may decrease benzodiazepine serum levels. The mechanism is probably related to stimulation of the hepatic metabolism of benzodiazepines. Diazepam and triazolam have been specifically studied in this regard, although other benzodiazepines also may interact with rifampin. Additionally, rifabutin may have an interaction with benzodiazepines similar to that of rifampin.

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