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    Anxiolytics, Benzodiazepines

    BOXED WARNING

    Chronic obstructive pulmonary disease (COPD), coadministration with other CNS depressants, pulmonary disease, respiratory depression, sleep apnea

    As with other benzodiazepines, alprazolam should be avoided in patients with pulmonary disease if possible. Additionally, avoid coadministration with other CNS depressants, especially opioids, unless no other alternatives are available as coadministration significantly increases the risk for respiratory depression, low  blood pressure, and death. Alprazolam should be avoided if possible in patients with respiratory depression severe chronic obstructive pulmonary disease (COPD), or sleep apnea because the drug can exacerbate ventilatory failure. In rare instances, death has occurred in patients with severe pulmonary disease shortly after the initiation of alprazolam.

    DEA CLASS

    Rx, schedule IV

    DESCRIPTION

    Oral benzodiazepine used for the management of anxiety including panic disorder; relatively shorter half-life and absence of active metabolites; potential for significant CYP3A4 interactions.

    COMMON BRAND NAMES

    Niravam, Xanax, Xanax XR

    HOW SUPPLIED

    Alprazolam Oral Sol: 1mg, 1mL
    Alprazolam/Niravam Oral Tab Orally Dis: 0.25mg, 0.5mg, 1mg, 2mg
    Alprazolam/Xanax Oral Tab: 0.25mg, 0.5mg, 1mg, 2mg
    Alprazolam/Xanax XR Oral Tab ER: 0.5mg, 1mg, 2mg, 3mg

    DOSAGE & INDICATIONS

    For the treatment of transient symptoms of anxiety, anxiety associated with depression, or generalized anxiety disorder (GAD).
    Oral dosage (immediate-release tablets, orally disintegrating tablets or oral solution)
    Adults

    Initially, 0.25 mg to 0.5 mg PO 3 times per day. Use the lower dose for debilitated adults initially. If clinically indicated, increase the dose as tolerated at intervals of 3 to 4 days, up to a maximum of 4 mg/day in divided doses. If discontinuation becomes necessary, the manufacturer suggests that the daily dose be decreased by no more than 0.5 mg every 3 days. Some patients may require a more gradual and individualized taper.

    Geriatric Adults

    Initially, 0.25 mg PO 2 or 3 times daily. Lower initial doses may be appropriate in some patients. If indicated, the dose may be increased gradually as tolerated. The maximum adult dosage is 4 mg/day PO. The elderly may be more sensitive to the effects of benzodiazepines. If discontinuation becomes necessary, the manufacturer suggests that the daily dose be decreased by no more than 0.5 mg every 3 days. Some patients may require a more gradual and individualized taper. The federal Omnibus Budget Reconciliation Act (OBRA) regulates the use of anxiolytics in long-term care facility (LTCF) residents. Max: 0.75 mg/day PO in residents meeting the criteria for treatment, except when documentation is provided showing that higher doses are necessary to maintain or improve the resident's functional status. In addition, the facility should attempt periodic tapering of the medication or provide documentation of medical necessity in accordance with OBRA guidelines.

    Children† and Adolescents† 7 years and older

    Definitive dosage not established. In a study of children 7 to 16 years old (n = 13), initial doses of 0.005 mg/kg/dose PO or 0.125 mg/dose PO were given 3 times per day for situational anxiety. Doses were increased in 0.125 mg to 0.25 mg increments. Max: 0.02 mg/kg/dose PO or 0.06 mg/kg/day PO. In another study of children with overanxious or avoidant disorder (n = 30), initial doses were 0.25 mg PO per day for children 40 kg or less and 0.5 mg PO per day for those more than 40 kg. Doses were titrated at 2-day intervals to a maximum of 0.04 mg/kg/day. Required doses ranged from 0.5 mg to 3.5 mg/day with a mean dose of 1.6 mg/day.

    For the treatment of panic disorder with or without agoraphobia.
    Oral dosage (immediate-release tablets, orally disintegrating tablets or oral solution)
    Adults

    Initially, 0.5 mg PO 3 times per day. In debilitated adults, a lower initial dose of 0.25 mg PO 2 or 3 times daily is recommended. The dose may be increased gradually as tolerated, by no more than 1 mg/day at intervals of 3 to 4 days. Many patients require more than 4 mg/day. It is advisable to slowly titrate to higher doses and divide the doses throughout the waking hours on a 3 to 4 times per day schedule. Periodically reassess for possible dose reduction. During clinical trials, the mean effective dosage was 5 to 6 mg/day, although doses up to 10 mg/day were required in some patients. If discontinuation becomes necessary, decrease the daily dose by no more than 0.5 mg every 3 days. Some patients may require a more gradual and individualized taper.

    Geriatric Adults

    Initially, 0.25 mg PO 2 or 3 times daily. Lower initial doses may be appropriate in some patients. The dose may be increased gradually as tolerated, at intervals of 3 to 4 days. During clinical trials in younger adults, the mean effective dosage was 5 to 6 mg/day. The geriatric patient is more sensitive to the effects of benzodiazepines; use lowest effective dose. If discontinuation becomes necessary, decrease the daily dose by no more than 0.5 mg every 3 days. Some patients may require a more gradual and individualized taper. The federal Omnibus Budget Reconciliation Act (OBRA) regulates the use of anxiolytics in long-term care facility (LTCF) residents. Max: 0.75 mg/day PO in residents meeting the criteria for treatment, except when documentation is provided showing that higher doses are necessary to maintain or improve the resident's functional status. In addition, the facility should attempt periodic tapering of the medication or provide documentation of medical necessity in accordance with OBRA guidelines.

    Oral dosage (extended-release tablets, Xanax XR)
    Adults

    Initially, 0.5 mg to 1 mg PO once a day, preferably in the morning. Use the lower initial dose in debilitated adult patients. Increase by no more than 1 mg/day, at intervals of every 3 to 4 days, as needed and tolerated. 3 to 6 mg PO once daily was the effective dose in most patients during clinical trials. Up to 10 mg/day has been required in occasional patients. To switch from immediate-release alprazolam, calculate the total daily dose and administer once daily using the XR formulation. If discontinuation becomes necessary, decrease the daily dose by no more than 0.5 mg every 3 days. Some patients may require a more gradual and individualized taper.

    Geriatric Adults

    Initially, 0.5 mg PO once daily, preferably in the morning. Gradually increase as needed and tolerated. In younger patients, doses were increased in increments of 1 mg/day or less, at intervals of every 3 to 4 days. Doses as high as 10 mg/day have been used in adults. However, the elderly are more sensitive to the effects of benzodiazepines; use the lowest effective dose. To switch from immediate-release alprazolam, calculate the total daily dose and administer once daily using the XR formulation. The federal Omnibus Budget Reconciliation Act (OBRA) regulates the use of anxiolytics in long-term care facility (LTCF) residents. Max: 0.75 mg/day PO in residents meeting criteria for treatment, except when documentation is provided showing that higher doses are necessary to maintain or improve the resident's functional status. In addition, the facility should attempt periodic tapering of the medication or provide documentation of medical necessity in accordance with OBRA guidelines.

    For the treatment of anxiety and mood-symptoms associated with premenstrual syndrome (PMS)† or premenstrual dysphoric disorder (PMDD)† that are unresponsive to non-pharmacologic therapy.
    Oral dosage (immediate-release tablets or oral solution)
    Adult females

    0.25 mg PO three times daily administered during the luteal phase through the second day of menses has been studied and was found to be superior to placebo in treating the emotional symptoms associated with PMS. A maximum dose up to 4 mg/day is recommended. Dose should be tapered by 25% per day through menses. In a placebo-controlled, comparative study with oral progesterone of 138 subjects, after 3 months, alprazolam was superior to progesterone or placebo overall but progesterone was better than alprazolam for physical symptoms while alprazolam was better than progesterone for controlling mood and mental function. Alprazolam was initially dosed at 0.25 mg PO four times per day administered from day 18 of the menstrual cycle to the first day of menses with a taper on the first 2 menstrual days, however, dosing was flexible; patients could receive up to twelve 0.25 mg capsules/day if necessary. The actual alprazolam dose taken during the third treatment cycle was 1.5 mg/day PO.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    10 mg/day PO.

    Geriatric

    10 mg/day PO.

    Adolescents

    Safety and efficacy have not been established; 0.06 mg/kg/day PO (immediate-release tablets or oral solution) has been suggested for the treatment of anxiety.

    Children

    7 years and older: Safety and efficacy have not been established; 0.06 mg/kg/day PO (immediate-release tablets or oral solution) has been suggested for the treatment of anxiety.
    Less than 7 years: Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Quantitative guidelines are not available for the immediate-release product; consider initial dose reduction in those with hepatic impairment. A lower initial adult dose of extended-release alprazolam (e.g., 0.5 mg PO once daily) is suggested. Titrate as needed and tolerated to attain clinical goals.

    Renal Impairment

    Guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

    ADMINISTRATION

    Oral Administration
    Oral Solid Formulations

    Immediate-release tablets
    May be administered without regard to meals.
     
    Orally disintegrating tablets (ODT)
    Do not remove ODT from the package until just prior to administration.
    With dry hands, place the tablet on top of the tongue where it will disintegrate and be swallowed with saliva.
    Administration with liquid is not necessary.
     
    Extended-release tablets
    Do not chew, break or crush. Patient should swallow whole with a drink of water.
    Extended-release tablets should be taken preferably in the morning.

    Oral Liquid Formulations

    Oral solution
    May be administered without regard to meals.
    Measure with a calibrated oral liquid medicine measuring device to give an accurate dose.

    STORAGE

    Generic:
    - Discard opened bottle after 90 days
    - Protect from light
    - Store at room temperature (between 59 to 86 degrees F)
    Niravam:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Xanax:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Xanax XR:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    Benzodiazepine hypersensitivity

    Alprazolam is contraindicated in any patient with a known alprazolam or other benzodiazepine hypersensitivity or known allergies to any component of the formulation.

    Abrupt discontinuation, benzodiazepine dependence, seizure disorder, seizures, status epilepticus, substance abuse

    Alprazolam can cause physical and psychological dependence, and should be used with caution in patients with known, suspected, or a history of substance abuse. The risk of dependence with alprazolam appears to be most probable with daily dosages greater than 4 mg and with a treatment period of more than 12 weeks. Abrupt discontinuation of alprazolam after prolonged use should be avoided. Abrupt discontinuation of benzodiazepine therapy has been reported to cause a withdrawal syndrome (see Adverse Effects), especially following high dose or prolonged benzodiazepine therapy. However, benzodiazepine dependence can occur with therapeutic doses administered for as few as 1—2 weeks and withdrawal symptoms may be seen following the discontinuance of therapy. Benzodiazepine withdrawal also can be more intense if the benzodiazepine involved possesses a relatively short duration of action such as alprazolam. Panic rebound may be particularly problematic for patients receiving higher doses for panic disorder. Patients with a history of a seizure disorder or who are taking other drugs that lower the seizure threshold (i.e., TCAs, phenothiazines) should not be withdrawn abruptly from alprazolam due to the risk of precipitating seizures; status epilepticus has also been reported during therapy with immediate-release alprazolam. During withdrawal, the greatest risk of seizure appears to be during the first 24 to 72 hours. Seizures have also been reported with the use of the extended-release formulation of alprazolam, due to abrupt withdrawal and/or concomitant alcohol intake. Alprazolam (immediate-release or extended-release formulations) should be withdrawn slowly, using a gradual tapering schedule. Flumazenil, a benzodiazepine receptor antagonist, is indicated for partial or complete reversal of the depressive effects of benzodiazepines, and may be useful in overdose situations (see Flumazenil monograph). The prescriber should be aware of the risk for seizure activity with flumazenil use, particularly in long-term users of benzodiazepines or patients presenting with a cyclic antidepressant overdose.

    Anxiety

    Worsening of daytime anxiety has been reported with the use of some hypnotic benzodiazepines, such as alprazolam, as few as 10 days after continuous use. In some patients this may be due to interdose withdrawal. If increased daytime anxiety is observed, it may be advisable to discontinue treatment gradually.

    Bipolar disorder, depression, mania, psychosis, suicidal ideation

    Although alprazolam is occasionally beneficial for patients with major depression, the drug should be administered to these patients with careful monitoring. According to the manufacturer, alprazolam typically has no use in the treatment of psychosis; use with extreme caution if at all in patients with suicidal ideation. Alprazolam should be used cautiously in patients with bipolar disorder because mania and hypomania have been reported in conjunction with the use of alprazolam in depressive disorders.

    Chronic obstructive pulmonary disease (COPD), coadministration with other CNS depressants, pulmonary disease, respiratory depression, sleep apnea

    As with other benzodiazepines, alprazolam should be avoided in patients with pulmonary disease if possible. Additionally, avoid coadministration with other CNS depressants, especially opioids, unless no other alternatives are available as coadministration significantly increases the risk for respiratory depression, low  blood pressure, and death. Alprazolam should be avoided if possible in patients with respiratory depression severe chronic obstructive pulmonary disease (COPD), or sleep apnea because the drug can exacerbate ventilatory failure. In rare instances, death has occurred in patients with severe pulmonary disease shortly after the initiation of alprazolam.

    CNS depression, coma, driving or operating machinery, ethanol intoxication, shock

    Due to CNS depression, patients should be cautioned against driving or operating machinery until they know how alprazolam may affect them. Some patients may experience excessive sedation and an impaired ability to perform tasks; although this is usually less than that seen with intermediate- or long-acting benzodiazepines. Increased CNS effects may be seen with concurrent use of alprazolam and other CNS depressant agents, and in patients with acute ethanol intoxication, or psychosis. Patients with ethanol intoxication who have also consumed alprazolam have an increased risk of respiratory depression and coma. Ethanol should be avoided during treatment with alprazolam. Benzodiazepines should be used cautiously in patients in shock or coma due to the increased risk of respiratory depression. Anterograde amnesia may occur with any short-acting benzodiazepine if given in sufficient doses.

    Closed-angle glaucoma

    Alprazolam is contraindicated in patients with acute closed-angle glaucoma. However, the benzodiazepine may be used in patients with open-angle glaucoma who are receiving appropriate therapy. The mechanistic rational for this contraindication has been questioned, as benzodiazepines do not have antimuscarinic activity and do not raise intraocular pressure; few cases have been reported.

    Myasthenia gravis

    Alprazolam should be used with extreme caution in patients with myasthenia gravis because the drug can exacerbate this condition.

    Parkinson's disease

    Patients with late stage Parkinson's disease may experience worsening of their psychosis or impaired cognition with administration of benzodiazepines, such as alprazolam. Benzodiazepines may also cause incoordination or paradoxical reactions that may worsen symptoms of Parkinson's disease.

    Porphyria

    The administration of alprazolam can exacerbate acute intermittent porphyria, so the drug should be used with caution in patients with this condition.

    Labor, neonates, obstetric delivery, pregnancy

    Alprazolam is classified as FDA pregnancy risk category D because it could harm the fetus when administered to pregnant women. Positive evidence of human fetal risk exists based on investigational, marketing, or human studies, but the potential benefit to the mother may outweigh the potential risks to the fetus. In general, the use of benzodiazepines is not life-saving and thus should be avoided in pregnancy whenever possible. An increased risk of congenital malformations and other developmental abnormalities is associated with benzodiazepine use during the first trimester. If alprazolam is to be used during pregnancy or the patient becomes pregnant while taking alprazolam, the patient should be apprised of the potential hazard to the fetus. The possibility that a woman of childbearing age may be pregnant when initiating therapy with alprazolam should be considered. Patients who become pregnant or intend to become pregnant while taking alprazolam should be advised to discuss the possibility of discontinuing the drug with their physician. It should be anticipated that neonates may experience withdrawal symptoms if the mother has been using benzodiazepines during pregnancy. Neonatal flaccidity has been reported in an infant whose mother was using benzodiazepines during pregnancy. Alprazolam has no established use in labor or obstetric delivery.

    Breast-feeding

    Many benzodiazepines distribute into breast milk. Because of the potential for adverse effects in the nursing infant, such as sedation, feeding difficulties, and weight loss, alprazolam generally is not recommended during breast-feeding. The estimated dose that a breast-feeding infant would receive based on breat milk concentrations after single oral doses of 0.5 mg has been reported to be 0.5—5 mcg/kg/day or approximately 3% of the maternal weight-adjusted dose. Irritability and withdrawal symptoms have been reported in babies exposed to alprazolam through breast milk upon discontinuation of either breast-feeing or alprazolam. Alprazolam is listed by the American Academy of Pediatrics as a drug whose effect on the nursing infant is not known but may be of concern, particularly with prolonged exposure. If occasional maternal therapy with a benzodiazepine is required, a shorter-acting agent such as lorazepam may be considered. Some experts have concluded that occasional maternal treatment with usual doses of lorazepam would pose little risk to a nursing infant. If any benzodiazepine is used by a breast-feeding mother, monitor the infant for adverse effects, such as sedation. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding baby experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Hepatic disease, obesity

    Alprazolam should be administered cautiously to patients with severe hepatic disease because the elimination half-life of the drug can be prolonged, possibly resulting in toxicity. Patients with hepatic disease are more likely to experience adverse CNS reactions and should receive reduced initial dosages. Additionally, alprazolam is significantly metabolized via the hepatic microsomal P450 isoenzyme CYP3A4. Concomitant administration of alprazolam and potent inhibitors of CYP3A4 is contraindicated. Medications considered to be potent CYP3A4 inhibitors which should not be used concurrently with alprazolam include systemically-administered azole antifungals, some macrolide antibiotics, and anti-retroviral protease inhibitors (see Drug Interactions). Other CYP3A4 inhibitors could potentially cause alprazolam toxicity (see Drug Interactions). This list is not inclusive of all agents that may potently inhibit CYP3A4. Reduced elimination of alprazolam has also been reported in obesity.

    Renal failure, renal impairment

    Patients with renal impairment, including renal failure, should be carefully monitored during prolonged treatment with benzodiazepines, such as alprazolam, in order to avoid the adverse reactions that may occur from drug accumulation.

    Dementia, geriatric

    Use alprazolam with caution in geriatric adults as the clearance and/or elimination of alprazolam are reduced. The mean half-life of alprazolam is prolonged to 16.3 hours in the geriatric population compared to 11.2 hours in healthy adult subjects. Delayed elimination can either intensify or prolong the actions of adverse reactions of the drug. It is recommended that the dosage be limited to the smallest effective dose to preclude the development of ataxia or oversedation which may be a particular problem in debilitated or geriatric patients. The impairment of cognitive and motor function may be more marked in this patient group and a lower dosage is recommended together with close monitoring. Benzodiazepines have been associated with falls in the elderly. According to the Beers Criteria, benzodiazepines are considered potentially inappropriate medications (PIMs) for use in geriatric patients and avoidance is generally recommended, although some agents from this class may be appropriate for conditions such as rapid eye movement sleep disorders, severe generalized anxiety disorder, and end of life care. Older adults have an increased sensitivity to benzodiazepines. In general, all benzodiazepines increase the risk of cognitive impairment, delirium, falls, fractures, and motor vehicle accidents in older adults. The Panel recommends avoiding benzodiazepines in geriatric patients with the following disease states or symptoms due to the potential for exacerbation of the condition or increased risk of adverse effects: delirium (possible new-onset or worsening delirium), dementia (adverse CNS effects), and history of falls/fractures (ataxia, impaired psychomotor function, syncope, and additional falls). If a benzodiazepine must be used in a patient with a history of falls or fractures, consider reducing use of other CNS-active medications that increase the risk of falls and fractures and implement other strategies to reduce fall risk. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities (LTCFs). Specific criteria for anxiolytics must be met, including 1) limiting use to indications specified in the OBRA guidelines (e.g., generalized anxiety disorder, panic disorder, significant anxiety to a situational trigger, alcohol withdrawal) which meet the Diagnostic and Statistical Manual of Mental Disorders (DSM) criteria for the indication, and 2) evidence exists that other possible reasons for the individual's distress have been considered, and 3) use results in maintenance or improvement in mental, physical, and psychosocial well-being as reflected on the Minimum Data Set (MDS) or other assessment tool. Anxiolytics should be used for delirium, dementia, or other cognitive disorders only when there are associated behaviors that are 1) quantitatively and objectively documented, and 2) are persistent, and 3) are not due to preventable or correctable reasons, and 4) constitute clinically significant distress or dysfunction to the LTCF resident or represent a danger to the resident or others. There are exceptions that may warrant the use of an anxiolytic such as a long-acting benzodiazepine for withdrawal from a short-acting benzodiazepine, use for neuromuscular syndromes (e.g., tardive dyskinesia, restless legs syndrome, seizure disorder, cerebral palsy), or end of life care. Benzodiazepines may increase the risk of confusion, sedation, and falls. OBRA provides dosing guidance for alprazolam as an anxiolytic. When a medication is being used to manage behavior, stabilize mood, or treat a psychiatric disorder, the facility should attempt periodic tapering of the medication or provide documentation of medical necessity in accordance with OBRA guidelines.

    Children, infants

    The safe and effective use of alprazolam in neonates, infants, children and adolescents less than 18 years old has not been established. Children are generally more sensitive to the CNS effects of benzodiazepines.

    ADVERSE REACTIONS

    Severe

    seizures / Delayed / 0.1-0.9
    angioedema / Rapid / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    hepatic failure / Delayed / Incidence not known
    teratogenesis / Delayed / Incidence not known

    Moderate

    withdrawal / Early / 10.0-35.0
    memory impairment / Delayed / 5.5-33.1
    impaired cognition / Early / 7.2-28.8
    constipation / Delayed / 8.1-26.2
    dysarthria / Delayed / 10.9-23.3
    sinus tachycardia / Rapid / 0.1-15.4
    depression / Delayed / 12.1-13.9
    confusion / Early / 1.5-10.4
    ataxia / Delayed / 7.2-7.2
    edema / Delayed / 0.1-4.9
    hypotension / Rapid / 0.1-4.7
    akathisia / Delayed / 1.6-3.0
    dyskinesia / Delayed / 1.7-1.7
    hot flashes / Early / 1.5-1.5
    amnesia / Delayed / 0.1-0.9
    euphoria / Early / 0.1-0.9
    mania / Early / 0.1-0.9
    dysphonia / Delayed / 0.1-0.9
    hypotonia / Delayed / 0.1-0.9
    urinary incontinence / Early / 0.1-0.9
    dysuria / Early / 0.1-0.9
    photophobia / Early / 0.1-0.9
    dyspnea / Early / 0.1-0.9
    hallucinations / Early / 0.1-0.9
    blurred vision / Early / 1.0
    palpitations / Early / 1.0
    chest pain (unspecified) / Early / 1.0
    tolerance / Delayed / Incidence not known
    psychological dependence / Delayed / Incidence not known
    physiological dependence / Delayed / Incidence not known
    hostility / Early / Incidence not known
    peripheral edema / Delayed / Incidence not known
    jaundice / Delayed / Incidence not known
    hyperbilirubinemia / Delayed / Incidence not known
    elevated hepatic enzymes / Delayed / Incidence not known
    hyperprolactinemia / Delayed / Incidence not known
    hepatitis / Delayed / Incidence not known
    galactorrhea / Delayed / Incidence not known

    Mild

    drowsiness / Early / 23.0-76.8
    fatigue / Early / 13.9-48.6
    appetite stimulation / Delayed / 7.0-32.7
    dizziness / Early / 1.8-29.8
    weight gain / Delayed / 2.7-27.2
    weight loss / Delayed / 2.3-22.6
    nausea / Early / 6.0-22.0
    anxiety / Delayed / 1.1-16.6
    xerostomia / Early / 10.2-14.7
    libido decrease / Delayed / 6.0-14.4
    menstrual irregularity / Delayed / 10.4-10.4
    libido increase / Delayed / 1.0-7.7
    hypersalivation / Early / 0.1-5.6
    infection / Delayed / 1.9-4.3
    syncope / Early / 0.1-3.8
    dysmenorrhea / Delayed / 3.6-3.6
    paresthesias / Delayed / 2.4-2.4
    arthralgia / Delayed / 2.4-2.4
    influenza / Delayed / 2.4-2.4
    lethargy / Early / 1.7-1.7
    myalgia / Early / 1.5-1.5
    anorexia / Delayed / 1.5-1.5
    pruritus / Rapid / 1.1-1.1
    psychomotor impairment / Early / 0.1-0.9
    asthenia / Delayed / 0.1-0.9
    tinnitus / Delayed / 0.1-0.9
    epistaxis / Delayed / 0.1-0.9
    rhinorrhea / Early / 0.1-0.9
    rash (unspecified) / Early / 0.1-0.9
    mydriasis / Early / 0.1-0.9
    urticaria / Rapid / 0.1-0.9
    fever / Early / 0.1-0.9
    agitation / Early / 1.0
    irritability / Delayed / 1.0
    nightmares / Early / 1.0
    tremor / Early / 1.0
    malaise / Early / 1.0
    back pain / Delayed / 1.0
    vertigo / Early / 1.0
    muscle cramps / Delayed / 1.0
    insomnia / Early / 1.0
    weakness / Early / 1.0
    headache / Early / 1.0
    hyperventilation / Early / 1.0
    diaphoresis / Early / 1.0
    nasal congestion / Early / 1.0
    rhinitis / Early / 1.0
    diarrhea / Early / 1.0
    dyspepsia / Early / 1.0
    abdominal pain / Early / 1.0
    vomiting / Early / 1.0
    diplopia / Early / Incidence not known
    gynecomastia / Delayed / Incidence not known

    DRUG INTERACTIONS

    Acetaminophen; Aspirin, ASA; Caffeine: (Minor) Patients taking benzodiazepines for insomnia should not use caffeine-containing products prior to going to bed as these products may antagonize the sedative effects of the benzodiazepine.
    Acetaminophen; Butalbital: (Major) Additive CNS depression may occur with concomitant use of benzodiazepines and barbiturates. Barbiturates may also induce the metabolism of some benzodiazepines. Monitor for alterations in response to therapy.
    Acetaminophen; Butalbital; Caffeine: (Major) Additive CNS depression may occur with concomitant use of benzodiazepines and barbiturates. Barbiturates may also induce the metabolism of some benzodiazepines. Monitor for alterations in response to therapy. (Minor) Patients taking benzodiazepines for insomnia should not use caffeine-containing products prior to going to bed as these products may antagonize the sedative effects of the benzodiazepine.
    Acetaminophen; Butalbital; Caffeine; Codeine: (Major) Additive CNS depression may occur with concomitant use of benzodiazepines and barbiturates. Barbiturates may also induce the metabolism of some benzodiazepines. Monitor for alterations in response to therapy. (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opiate cough medications in patients taking benzodiazepines. (Minor) Patients taking benzodiazepines for insomnia should not use caffeine-containing products prior to going to bed as these products may antagonize the sedative effects of the benzodiazepine.
    Acetaminophen; Caffeine; Dihydrocodeine: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opiate cough medications in patients taking benzodiazepines. (Minor) Patients taking benzodiazepines for insomnia should not use caffeine-containing products prior to going to bed as these products may antagonize the sedative effects of the benzodiazepine.
    Acetaminophen; Caffeine; Magnesium Salicylate; Phenyltoloxamine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination. (Minor) Patients taking benzodiazepines for insomnia should not use caffeine-containing products prior to going to bed as these products may antagonize the sedative effects of the benzodiazepine.
    Acetaminophen; Caffeine; Phenyltoloxamine; Salicylamide: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination. (Minor) Patients taking benzodiazepines for insomnia should not use caffeine-containing products prior to going to bed as these products may antagonize the sedative effects of the benzodiazepine.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination. (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Acetaminophen; Chlorpheniramine; Phenylephrine; Phenyltoloxamine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination. (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Acetaminophen; Codeine: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opiate cough medications in patients taking benzodiazepines.
    Acetaminophen; Dextromethorphan; Doxylamine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Acetaminophen; Dextromethorphan; Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Acetaminophen; Dichloralphenazone; Isometheptene: (Moderate) The CNS depressant effects of dichloralphenazone can be potentiated by benzodiazepines.
    Acetaminophen; Diphenhydramine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Acetaminophen; Guaifenesin; Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Acetaminophen; Hydrocodone: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If hydrocodone is initiated in a patient taking a benzodiazepine, reduce initial dosage and titrate to clinical response; for hydrocodone extended-release products, initiate hydrocodone at 20% to 30% of the usual dosage. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid opiate cough medications in patients taking benzodiazepines.
    Acetaminophen; Oxycodone: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If oxycodone is initiated in a patient taking a benzodiazepine, reduce dosages and titrate to clinical response. For acetaminophen; oxycodone extended-release tablets, start with 1 tablet PO every 12 hours, and for other oxycodone products, use an initial dose of oxycodone at one-third to one-half the usual dosage. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Acetaminophen; Pentazocine: (Major) Concomitant use of mixed opiate agonists/antagonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of mixed opiate agonists/antagonists with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If a mixed opiate agonist/antagonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the mixed opiate agonist/antagonist and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking a mixed opiate agonist/antagonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Acetaminophen; Propoxyphene: (Moderate) Coadministration 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.
    Acetaminophen; Tramadol: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Acetazolamide: (Moderate) Concomitant administration of alprazolam with CNS-depressant drugs, including anticonvulsants, can potentiate the CNS effects of either agent.
    Acrivastine; Pseudoephedrine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Aldesleukin, IL-2: (Moderate) Aldesleukin, IL-2 may affect CNS function significantly. Therefore, psychotropic pharmacodynamic interactions could occur following concomitant administration of drugs with significant CNS activity. Use with caution.
    Alfentanil: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Amiodarone: (Moderate) Amiodarone is a CYP3A4 inhibitors and may theoretically inhibit CYP3A4 metabolism of alprazolam.
    Amitriptyline; Chlordiazepoxide: (Moderate) Concomitant administration of alprazolam with CNS-depressant drugs can potentiate the CNS effects of either agent.
    Amobarbital: (Major) Additive CNS depression may occur with concomitant use of benzodiazepines and barbiturates. Barbiturates may also induce the metabolism of some benzodiazepines. Monitor for alterations in response to therapy.
    Amoxapine: (Moderate) Amoxapine may enhance the response to the effects of benzodiazepines and other CNS depressants. Patients should be warned of the possibility of drowsiness that may impair performance of potentially hazardous tasks such as driving an automobile or operating machinery.
    Amoxicillin; Clarithromycin; Lansoprazole: (Moderate) Clarithromycin inhibits CYP3A4 and may profoundly decrease alprazolam clearance. Use this combination with caution and consider a dose reduction of alprazolam of up to 50%.
    Amoxicillin; Clarithromycin; Omeprazole: (Moderate) Clarithromycin inhibits CYP3A4 and may profoundly decrease alprazolam clearance. Use this combination with caution and consider a dose reduction of alprazolam of up to 50%. (Moderate) Omeprazole inhibits CYP2C19. There have been some case reports describing an interaction between omeprazole and benzodiazepines metabolized via the cytochrome P450 system, such as alprazolam. Patients should be monitored to determine if it is necessary to adjust the dosage of the benzodiazepine when taken concomitantly with omeprazole.
    Amprenavir: (Major) Due to potent inhibition of alprazolam metabolism, it is recommended that alprazolam be avoided or reduced doses given when co-administered with anti-retroviral protease inhibitors.
    Amyl Nitrite: (Moderate) Administration of nitrates such as amyl nitrite to patients receiving other hypotension-producing agents, such as benzodiazepines, can cause additive hypotensive or orthostatic effects.
    Apomorphine: (Moderate) Apomorphine causes significant somnolence. Concomitant administration of apomorphine and CNS depressants could result in additive depressant effects.
    Apraclonidine: (Minor) No specific drug interactions were identified with systemic agents and apraclonidine during clinical trials. Theoretically, apraclonidine might potentiate the effects of CNS depressant drugs such as the anxiolytics, sedatives, and hypnotics, including barbiturates or benzodiazepines.
    Aprepitant, Fosaprepitant: (Major) Use caution if alprazolam and aprepitant, fosaprepitant are used concurrently and monitor for an increase in alprazolam-related adverse effects for several days after administration of a multi-day aprepitant regimen. If a benzodiazepine is necessary, a dosage adjustment of the multi-day regimen may be necessary depending on the clinical situation (e.g., elderly patients) and degree of monitoring available; no dosage adjustment is needed for a single dose of aprepitant (40 mg) or fosaprepitant (150 mg). Consider selection of an agent that is not metabolized via CYP3A4 isoenzymes (e.g., lorazepam, oxazepam, temazepam). Alprazolam is a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may increase plasma concentrations of alprazolam. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important.
    Aripiprazole: (Moderate) Due to the primary CNS effects of aripiprazole, caution should be used when aripiprazole is given in combination with other centrally-acting medications including benzodiazepines and other anxiolytics, sedatives, and hypnotics. The intensity of sedation and orthostatic hypotension is greater during concurrent use of lorazepam and oral aripiprazole and during use of a parenteral benzodiazepine and intramuscular (IM) aripiprazole compared to aripiprazole alone; therefore, patients receiving a benzodiazepine with oral or parenteral aripiprazole should be monitored for sedation and blood pressure and the dose should be adjusted accordingly. Data from the manufacturer indicate there are no clinically significant pharmacokinetic changes when aripiprazole is given with lorazepam.
    Asenapine: (Moderate) Drugs that can cause CNS depression, if used concomitantly with asenapine, may increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness. Caution should be used when asenapine is given in combination with other centrally-acting medications including anxiolytics, sedatives, and hypnotics (including barbiturates), buprenorphine, buprenorphine; naloxone, butorphanol, dronabinol, THC, nabilone, nalbuphine, opiate agonists, pentazocine, acetaminophen; pentazocine, aspirin, ASA; pentazocine, and pentazocine; naloxone.
    Aspirin, ASA; Butalbital; Caffeine: (Major) Additive CNS depression may occur with concomitant use of benzodiazepines and barbiturates. Barbiturates may also induce the metabolism of some benzodiazepines. Monitor for alterations in response to therapy. (Minor) Patients taking benzodiazepines for insomnia should not use caffeine-containing products prior to going to bed as these products may antagonize the sedative effects of the benzodiazepine.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Major) Additive CNS depression may occur with concomitant use of benzodiazepines and barbiturates. Barbiturates may also induce the metabolism of some benzodiazepines. Monitor for alterations in response to therapy. (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opiate cough medications in patients taking benzodiazepines. (Minor) Patients taking benzodiazepines for insomnia should not use caffeine-containing products prior to going to bed as these products may antagonize the sedative effects of the benzodiazepine.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opiate cough medications in patients taking benzodiazepines. (Minor) Patients taking benzodiazepines for insomnia should not use caffeine-containing products prior to going to bed as these products may antagonize the sedative effects of the benzodiazepine.
    Aspirin, ASA; Carisoprodol; Codeine: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opiate cough medications in patients taking benzodiazepines.
    Aspirin, ASA; Omeprazole: (Moderate) Omeprazole inhibits CYP2C19. There have been some case reports describing an interaction between omeprazole and benzodiazepines metabolized via the cytochrome P450 system, such as alprazolam. Patients should be monitored to determine if it is necessary to adjust the dosage of the benzodiazepine when taken concomitantly with omeprazole.
    Aspirin, ASA; Oxycodone: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If oxycodone is initiated in a patient taking a benzodiazepine, reduce dosages and titrate to clinical response. For acetaminophen; oxycodone extended-release tablets, start with 1 tablet PO every 12 hours, and for other oxycodone products, use an initial dose of oxycodone at one-third to one-half the usual dosage. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Atazanavir: (Major) Coadministration of alprazolam and atazanavir is not recommended. If coadministration cannot be avoided, a dosage reduction of alprazolam should be considered. Atazanavir is a potent CYP3A4 inhibitor. The initial step in alprazolam metabolism is hydroxylation catalyzed by cytochrome CYP3A. Drugs that inhibit this metabolic pathway may profoundly decrease alprazolam clearance, resulting in increased potential for serious alprazolam-related adverse events, such as respiratory depression and prolonged sedation. Consequently, alprazolam should be avoided in patients receiving very potent inhibitors of CYP3A isoenzymes.
    Atazanavir; Cobicistat: (Major) Coadministration of alprazolam and atazanavir is not recommended. If coadministration cannot be avoided, a dosage reduction of alprazolam should be considered. Atazanavir is a potent CYP3A4 inhibitor. The initial step in alprazolam metabolism is hydroxylation catalyzed by cytochrome CYP3A. Drugs that inhibit this metabolic pathway may profoundly decrease alprazolam clearance, resulting in increased potential for serious alprazolam-related adverse events, such as respiratory depression and prolonged sedation. Consequently, alprazolam should be avoided in patients receiving very potent inhibitors of CYP3A isoenzymes. (Moderate) The plasma concentrations of alprazolam may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as drowsiness or dizziness, is recommended during coadministration. Cobicistat is a CYP3A4 inhibitor and alprazolam is a CYP3A4 substrate.
    Atracurium: (Moderate) Concurrent use of benzodiazepines and other CNS active medications including neuromuscular blockers, can potentiate the CNS effects of either agent. Lower doses of one or both agents may be required. The severity of this interaction may be increased when additional CNS depressants are given.
    Atropine; Difenoxin: (Moderate) Concomitant administration of benzodiazepines with CNS-depressant drugs, such as diphenoxylate/difenoxin, can potentiate the CNS effects of either agent.
    Atropine; Diphenoxylate: (Moderate) Concomitant administration of benzodiazepines with CNS-depressant drugs, such as diphenoxylate/difenoxin, can potentiate the CNS effects of either agent.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Major) Additive CNS depression may occur with concomitant use of benzodiazepines and barbiturates. Barbiturates may also induce the metabolism of some benzodiazepines. Monitor for alterations in response to therapy. (Moderate) Scopolamine may cause dizziness and drowsiness. Concurrent use of scopolamine and CNS depressants can adversely increase the risk of CNS depression.
    Azelastine: (Moderate) An enhanced CNS depressant effect may occur when azelastine is combined with CNS depressants including benzodiazepines.
    Azelastine; Fluticasone: (Moderate) An enhanced CNS depressant effect may occur when azelastine is combined with CNS depressants including benzodiazepines.
    Barbiturates: (Major) Additive CNS depression may occur with concomitant use of benzodiazepines and barbiturates. Barbiturates may also induce the metabolism of some benzodiazepines. Monitor for alterations in response to therapy.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) Additive CNS depression may occur with concomitant use of benzodiazepines and barbiturates. Barbiturates may also induce the metabolism of some benzodiazepines. Monitor for alterations in response to therapy. (Moderate) Drugs that may inhibit CYP3A4, such as ergotamine, may reduce the metabolism of alprazolam. Use alprazolam and ergotamine with caution and consider alprazolam dose reduction of up to 50%.
    Belladonna; Opium: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Benztropine: (Moderate) CNS depressants, such as anxiolytics, sedatives, and hypnotics, can increase the sedative effects of benztropine.
    Boceprevir: (Major) Coadministration of alprazolam and boceprevir is not recommended. If coadministration cannot be avoided, a dosage reduction of alprazolam should be considered. Boceprevir is a potent CYP3A4 inhibitor. The initial step in alprazolam metabolism is hydroxylation catalyzed by cytochrome CYP3A. Drugs that inhibit this metabolic pathway may profoundly decrease alprazolam clearance, resulting in increased potential for serious alprazolam-related adverse events, such as respiratory depression and prolonged sedation. Consequently, alprazolam should be avoided in patients receiving very potent inhibitors of CYP3A isoenzymes.
    Bosentan: (Moderate) Bosentan is an inducer of cytochrome P450 enzymes, specifically the CYP2C9 and CYP3A4 isoenzymes, and may decrease concentrations of drugs metabolized by these enzymes, including alprazolam.
    Brexpiprazole: (Moderate) Due to the CNS effects of brexpiprazole, caution should be used when brexpiprazole is given in combination with other centrally-acting medications including benzodiazepines and other anxiolytics, sedatives, and hypnotics.
    Brigatinib: (Moderate) Monitor for decreased efficacy of alprazolam if coadministration with brigatinib is necessary. Alprazolam is a CYP3A substrate and brigatinib induces CYP3A in vitro; plasma concentrations of alprazolam may decrease.
    Brimonidine: (Moderate) Based on the sedative effects of brimonidine in individual patients, brimonidine administration has potential to enhance the CNS depressants effects of the anxiolytics, sedatives, and hypnotics including benzodiazepines.
    Brimonidine; Brinzolamide: (Moderate) Based on the sedative effects of brimonidine in individual patients, brimonidine administration has potential to enhance the CNS depressants effects of the anxiolytics, sedatives, and hypnotics including benzodiazepines.
    Brimonidine; Timolol: (Moderate) Based on the sedative effects of brimonidine in individual patients, brimonidine administration has potential to enhance the CNS depressants effects of the anxiolytics, sedatives, and hypnotics including benzodiazepines.
    Brompheniramine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Brompheniramine; Carbetapentane; Phenylephrine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination. (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including benzodiazepines. (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Brompheniramine; Dextromethorphan; Guaifenesin: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Brompheniramine; Guaifenesin; Hydrocodone: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If hydrocodone is initiated in a patient taking a benzodiazepine, reduce initial dosage and titrate to clinical response; for hydrocodone extended-release products, initiate hydrocodone at 20% to 30% of the usual dosage. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid opiate cough medications in patients taking benzodiazepines. (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If hydrocodone is initiated in a patient taking a benzodiazepine, reduce initial dosage and titrate to clinical response; for hydrocodone extended-release products, initiate hydrocodone at 20% to 30% of the usual dosage. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid opiate cough medications in patients taking benzodiazepines. (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Brompheniramine; Pseudoephedrine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Buprenorphine: (Major) Concomitant use of mixed opiate agonists/antagonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of mixed opiate agonists/antagonists with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If a mixed opiate agonist/antagonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the mixed opiate agonist/antagonist and titrate to clinical response. Reduce injectable buprenorphine dose by 1/2, and for the buprenorphine transdermal patch, start therapy with the 5 mcg/hour patch. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking a mixed opiate agonist/antagonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Buprenorphine; Naloxone: (Major) Concomitant use of mixed opiate agonists/antagonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of mixed opiate agonists/antagonists with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If a mixed opiate agonist/antagonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the mixed opiate agonist/antagonist and titrate to clinical response. Reduce injectable buprenorphine dose by 1/2, and for the buprenorphine transdermal patch, start therapy with the 5 mcg/hour patch. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking a mixed opiate agonist/antagonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Buspirone: (Moderate) It is common for patients to overlap anxiety treatment when switching from benzodiazepines to buspirone. Buspirone has a slow onset of action and the drug will not block the withdrawal syndrome often seen with cessation of benzodiazepine therapy in those with benzodiazepine dependence. Therefore, before starting therapy with buspirone, withdraw patients gradually from the benzodiazepine. Alternatively, conversion to buspirone therapy may require treatment overlap to allow for the downward titration of the benzodiazepine while buspirone takes effect. It should be noted that the combination of buspirone and benzodiazepines can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent.
    Butabarbital: (Major) Additive CNS depression may occur with concomitant use of benzodiazepines and barbiturates. Barbiturates may also induce the metabolism of some benzodiazepines. Monitor for alterations in response to therapy.
    Butorphanol: (Major) Concomitant use of mixed opiate agonists/antagonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of mixed opiate agonists/antagonists with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If a mixed opiate agonist/antagonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the mixed opiate agonist/antagonist and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking a mixed opiate agonist/antagonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Caffeine: (Minor) Patients taking benzodiazepines for insomnia should not use caffeine-containing products prior to going to bed as these products may antagonize the sedative effects of the benzodiazepine.
    Caffeine; Ergotamine: (Moderate) Drugs that may inhibit CYP3A4, such as ergotamine, may reduce the metabolism of alprazolam. Use alprazolam and ergotamine with caution and consider alprazolam dose reduction of up to 50%. (Minor) Patients taking benzodiazepines for insomnia should not use caffeine-containing products prior to going to bed as these products may antagonize the sedative effects of the benzodiazepine.
    Carbamazepine: (Moderate) Carbamazepine is a hepatic enzyme inducer and may potentially accelerate the hepatic metabolism of alprazolam leading to lower alprazolam serum concentrations. Concomitant administration of alprazolam with CNS-depressant drugs, including anticonvulsants, can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent.
    Carbetapentane; Chlorpheniramine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination. (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including benzodiazepines.
    Carbetapentane; Chlorpheniramine; Phenylephrine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination. (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including benzodiazepines. (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Carbetapentane; Diphenhydramine; Phenylephrine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination. (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including benzodiazepines. (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Carbetapentane; Guaifenesin: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including benzodiazepines.
    Carbetapentane; Guaifenesin; Phenylephrine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including benzodiazepines. (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Carbetapentane; Phenylephrine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including benzodiazepines. (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Carbetapentane; Phenylephrine; Pyrilamine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination. (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including benzodiazepines. (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Carbetapentane; Pseudoephedrine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including benzodiazepines.
    Carbetapentane; Pyrilamine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination. (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including benzodiazepines.
    Carbinoxamine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Carbinoxamine; Dextromethorphan; Pseudoephedrine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If hydrocodone is initiated in a patient taking a benzodiazepine, reduce initial dosage and titrate to clinical response; for hydrocodone extended-release products, initiate hydrocodone at 20% to 30% of the usual dosage. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid opiate cough medications in patients taking benzodiazepines. (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination. (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If hydrocodone is initiated in a patient taking a benzodiazepine, reduce initial dosage and titrate to clinical response; for hydrocodone extended-release products, initiate hydrocodone at 20% to 30% of the usual dosage. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid opiate cough medications in patients taking benzodiazepines. (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Carbinoxamine; Phenylephrine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination. (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Carbinoxamine; Pseudoephedrine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Cariprazine: (Moderate) Due to the CNS effects of cariprazine, caution should be used when cariprazine is given in combination with other centrally-acting medications including benzodiazepines and other anxiolytics, sedatives, and hypnotics.
    Ceritinib: (Major) Avoid coadministration of ceritinib with alprazolam due to increased alprazolam exposure. If coadministration is unavoidable, monitor for alprazolam-related adverse reactions including sedation and respiratory depression. Ceritinib is a CYP3A4 inhibitor and alprazolam is primarily metabolized by CYP3A4.
    Cetirizine: (Moderate) Additive drowsiness may occur if cetirizine/levocetirizine is administered with other drugs that depress the CNS, including benzodiazepines.
    Cetirizine; Pseudoephedrine: (Moderate) Additive drowsiness may occur if cetirizine/levocetirizine is administered with other drugs that depress the CNS, including benzodiazepines.
    Chlophedianol; Dexchlorpheniramine; Pseudoephedrine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Chlophedianol; Guaifenesin; Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Chloramphenicol: (Major) Coadministration of alprazolam and chloramphenicol is not recommended. If coadministration cannot be avoided, a dosage reduction of alprazolam should be considered. Chloramphenicol is a potent CYP3A4 inhibitor. The initial step in alprazolam metabolism is hydroxylation catalyzed by cytochrome CYP3A. Drugs that inhibit this metabolic pathway may profoundly decrease alprazolam clearance, resulting in increased potential for serious alprazolam-related adverse events, such as respiratory depression and prolonged sedation. Consequently, alprazolam should be avoided in patients receiving very potent inhibitors of CYP3A isoenzymes.
    Chlorcyclizine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Chlordiazepoxide: (Moderate) Concomitant administration of alprazolam with CNS-depressant drugs can potentiate the CNS effects of either agent.
    Chlordiazepoxide; Clidinium: (Moderate) Concomitant administration of alprazolam with CNS-depressant drugs can potentiate the CNS effects of either agent.
    Chlorpheniramine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Chlorpheniramine; Codeine: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opiate cough medications in patients taking benzodiazepines. (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Chlorpheniramine; Dextromethorphan: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination. (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opiate cough medications in patients taking benzodiazepines. (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination. (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opiate cough medications in patients taking benzodiazepines. (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If hydrocodone is initiated in a patient taking a benzodiazepine, reduce initial dosage and titrate to clinical response; for hydrocodone extended-release products, initiate hydrocodone at 20% to 30% of the usual dosage. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid opiate cough medications in patients taking benzodiazepines. (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Chlorpheniramine; Hydrocodone: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If hydrocodone is initiated in a patient taking a benzodiazepine, reduce initial dosage and titrate to clinical response; for hydrocodone extended-release products, initiate hydrocodone at 20% to 30% of the usual dosage. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid opiate cough medications in patients taking benzodiazepines. (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If hydrocodone is initiated in a patient taking a benzodiazepine, reduce initial dosage and titrate to clinical response; for hydrocodone extended-release products, initiate hydrocodone at 20% to 30% of the usual dosage. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid opiate cough medications in patients taking benzodiazepines. (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination. (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If hydrocodone is initiated in a patient taking a benzodiazepine, reduce initial dosage and titrate to clinical response; for hydrocodone extended-release products, initiate hydrocodone at 20% to 30% of the usual dosage. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid opiate cough medications in patients taking benzodiazepines. (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Chlorpheniramine; Phenylephrine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination. (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Chlorpheniramine; Pseudoephedrine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Chlorthalidone; Clonidine: (Moderate) Clonidine has CNS depressive effects and can potentiate the actions of other CNS depressants including benzodiazepines.
    Cimetidine: (Moderate) Coadministration of alprazolam should be avoided with potent CYP3A4 inhibitors such as cimetidine. In patients taking drugs that inhibit CYP3A isoenzymes to a significant but lesser degree, use alprazolam with caution and consider alprazolam dose reduction (up to 50% dose reduction).
    Ciprofloxacin: (Moderate) A decrease in the alprazolam dose may be needed. Ciprofloxacin is a CYP3A4 inhibitor and may reduce the metabolism of alprazolam and increase the potential for benzodiazepine toxicity.
    Cisapride: (Moderate) Cisapride may enhance the sedative effects of benzodiazepines. Patients should not drive or operate heavy machinery until they know how the combination affects them. Patient counseling is important, as cisapride alone does not cause drowsiness or affect psychomotor function.
    Cisatracurium: (Moderate) Concurrent use of benzodiazepines and other CNS active medications including neuromuscular blockers, can potentiate the CNS effects of either agent. Lower doses of one or both agents may be required. The severity of this interaction may be increased when additional CNS depressants are given.
    Clarithromycin: (Moderate) Clarithromycin inhibits CYP3A4 and may profoundly decrease alprazolam clearance. Use this combination with caution and consider a dose reduction of alprazolam of up to 50%.
    Clemastine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Clobazam: (Major) Concomitant administration of clobazam with other CNS depressant drugs including anxiolytics, sedatives, and hypnotics, can potentiate the CNS effects (i.e., increased sedation or respiratory depression) of either agent. In addition, concurrent use of clobazam and other benzodiazepines should generally be avoided since this may represent duplicative therapy, and centrally-mediated adverse effects may be potentiated. Results of one pharmacokinetic study indicated that clobazam decreased the AUC and Cmax of midazolam by 27% and 24%, respectively, and increased the AUC and Cmax of the active metabolite of midazolam by 4-fold and 2-fold, respectively. Midazolam is a substrate of CYP3A4 and clobazam is a mild inducer of this isoenzyme. According to the manufacturer, dosage adjustments of CYP3A4 substrates are not considered necessary.
    Clonazepam: (Moderate) Concomitant administration of alprazolam with CNS-depressant drugs can potentiate the CNS effects of either agent.
    Clonidine: (Moderate) Clonidine has CNS depressive effects and can potentiate the actions of other CNS depressants including benzodiazepines.
    Clorazepate: (Moderate) Concomitant administration of alprazolam with CNS-depressant drugs can potentiate the CNS effects of either agent.
    Clozapine: (Moderate) If concurrent therapy with clozapine and a benzodiazepine is necessary, it is advisable to begin with the lowest possible benzodiazepine dose and closely monitor the patient, particularly at initiation of treatment and following dose increases. Although the combination has been used safely, adverse reactions such as confusion, ataxia, somnolence, delirium, collapse, cardiac arrest, respiratory arrest, and death have occurred rarely in patients receiving clozapine concurrently or following benzodiazepine therapy. Several benzodiazepines, including clonazepam, oxazepam, flurazepam, diazepam, clobazam, flunitrazepam, and lorazepam have been implicated in these reactions. At least one case of sudden death was reported following intravenous administration of lorazepam to a patient receiving clozapine.
    Cobicistat: (Moderate) The plasma concentrations of alprazolam may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as drowsiness or dizziness, is recommended during coadministration. Cobicistat is a CYP3A4 inhibitor and alprazolam is a CYP3A4 substrate.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: (Moderate) The plasma concentrations of alprazolam may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as drowsiness or dizziness, is recommended during coadministration. Cobicistat is a CYP3A4 inhibitor and alprazolam is a CYP3A4 substrate.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) The plasma concentrations of alprazolam may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as drowsiness or dizziness, is recommended during coadministration. Cobicistat is a CYP3A4 inhibitor and alprazolam is a CYP3A4 substrate.
    Codeine: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opiate cough medications in patients taking benzodiazepines.
    Codeine; Guaifenesin: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opiate cough medications in patients taking benzodiazepines.
    Codeine; Phenylephrine; Promethazine: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opiate cough medications in patients taking benzodiazepines. (Moderate) Because promethazine causes pronounced sedation, an enhanced CNS depressant effect or additive drowsiness may occur when it is combined with other CNS depressants including benzodiazepines. (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Codeine; Promethazine: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opiate cough medications in patients taking benzodiazepines. (Moderate) Because promethazine causes pronounced sedation, an enhanced CNS depressant effect or additive drowsiness may occur when it is combined with other CNS depressants including benzodiazepines.
    COMT inhibitors: (Moderate) Concomitant administration of benzodiazepines with CNS-depressant drugs, including COMT inhibitors, can potentiate the CNS effects of either agent.
    Conivaptan: (Major) Coadministration of alprazolam and conivaptan is not recommended. Subsequent treatment with CYP3A substrates, such as alprazolam, may be initiated no sooner than 1 week after completion of conivaptan therapy. Conivaptan is a potent CYP3A4 inhibitor. 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. The initial step in alprazolam metabolism is hydroxylation catalyzed by cytochrome CYP3A. Drugs that inhibit this metabolic pathway may profoundly decrease alprazolam clearance, resulting in increased potential for serious alprazolam-related adverse events, such as respiratory depression and prolonged sedation. Consequently, alprazolam should be avoided in patients receiving very potent inhibitors of CYP3A isoenzymes.
    Crizotinib: (Moderate) Monitor for an increase in alprazolam-related adverse reactions including sedation and respiratory depression if coadministration with crizotinib is necessary; consider reducing the dose of alprazolam as clinically appropriate. Crizotinib is a moderate CYP3A substrate and alprazolam is a CYP3A substrate. Drugs inhibiting this metabolic pathway may have a profound effect on the clearance of alprazolam. Coadministration with a strong CYP3A4 inhibitor increased plasma alprazolam concentrations by 3.98-fold.
    Cyclizine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Cyclosporine: (Moderate) In patients taking drugs that inhibit CYP3A isoenzymes, use alprazolam with caution and consider alprazolam dose reduction (up to 50% dose reduction may be needed). Other drugs that may theoretically inhibit CYP3A4 metabolism of alprazolam include cyclosporine.
    Cyproheptadine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Dalfopristin; Quinupristin: (Major) Coadministration of alprazolam and dalfopristin; quinupristin is not recommended. If coadministration cannot be avoided, a dosage reduction of alprazolam should be considered. Dalfopristin; quinupristin is a potent CYP3A4 inhibitor. The initial step in alprazolam metabolism is hydroxylation catalyzed by cytochrome CYP3A. Drugs that inhibit this metabolic pathway may profoundly decrease alprazolam clearance, resulting in increased potential for serious alprazolam-related adverse events, such as respiratory depression and prolonged sedation. Consequently, alprazolam should be avoided in patients receiving very potent inhibitors of CYP3A isoenzymes.
    Danazol: (Moderate) Danazol is a CYP3A4 inhibitor and can decrease the hepatic metabolism of CYP3A4 substrates, including alprazolam.
    Darunavir: (Major) Coadministration of alprazolam and darunavir is not recommended. If coadministration cannot be avoided, a dosage reduction of alprazolam should be considered. Darunavir is a potent CYP3A4 inhibitor. The initial step in alprazolam metabolism is hydroxylation catalyzed by cytochrome CYP3A. Drugs that inhibit this metabolic pathway may profoundly decrease alprazolam clearance, resulting in increased potential for serious alprazolam-related adverse events, such as respiratory depression and prolonged sedation. Consequently, alprazolam should be avoided in patients receiving very potent inhibitors of CYP3A isoenzymes.
    Darunavir; Cobicistat: (Major) Coadministration of alprazolam and darunavir is not recommended. If coadministration cannot be avoided, a dosage reduction of alprazolam should be considered. Darunavir is a potent CYP3A4 inhibitor. The initial step in alprazolam metabolism is hydroxylation catalyzed by cytochrome CYP3A. Drugs that inhibit this metabolic pathway may profoundly decrease alprazolam clearance, resulting in increased potential for serious alprazolam-related adverse events, such as respiratory depression and prolonged sedation. Consequently, alprazolam should be avoided in patients receiving very potent inhibitors of CYP3A isoenzymes. (Moderate) The plasma concentrations of alprazolam may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as drowsiness or dizziness, is recommended during coadministration. Cobicistat is a CYP3A4 inhibitor and alprazolam is a CYP3A4 substrate.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Coadministration of alprazolam and ritonavir or lopinavir; ritonavir is not recommended. If coadministration cannot be avoided, a dosage reduction of alprazolam should be considered. Lopinavir and ritonavir are potent CYP3A4 inhibitors. The initial step in alprazolam metabolism is hydroxylation catalyzed by cytochrome CYP3A. Drugs that inhibit this metabolic pathway may profoundly decrease alprazolam clearance, resulting in increased potential for serious alprazolam-related adverse events, such as respiratory depression and prolonged sedation. Consequently, alprazolam should be avoided in patients receiving very potent inhibitors of CYP3A isoenzymes.
    Delavirdine: (Severe) According to the manufacturer of delavirdine, coadministration of alprazolam and delavirdine is contraindicated. Delavirdine is a potent CYP3A4 inhibitor. The initial step in alprazolam metabolism is hydroxylation catalyzed by cytochrome CYP3A. Drugs that inhibit this metabolic pathway may profoundly decrease alprazolam clearance, resulting in increased potential for serious alprazolam-related adverse events, such as respiratory depression and prolonged sedation.
    Desflurane: (Moderate) Concurrent use with benzodiazepines can decrease the minimum alveolar concentration (MAC) of desflurane needed to produce anesthesia.
    Desloratadine: (Minor) Although loratadine is considered a 'non-sedating' antihistamine, dose-related sedation has been noted. For this reason, it would be prudent to monitor for drowsiness when used concurrently with other CNS depressants such as benzodiazepines.
    Desloratadine; Pseudoephedrine: (Minor) Although loratadine is considered a 'non-sedating' antihistamine, dose-related sedation has been noted. For this reason, it would be prudent to monitor for drowsiness when used concurrently with other CNS depressants such as benzodiazepines.
    Deutetrabenazine: (Moderate) Advise patients that concurrent use of deutetrabenazine and drugs that can cause CNS depression, such as alprazolam, may have additive effects and worsen drowsiness or sedation.
    Dexchlorpheniramine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Dexmedetomidine: (Moderate) Co-administration of dexmedetomidine with benzodiazepines is likely to lead to an enhancement of CNS depression.
    Dextromethorphan; Diphenhydramine; Phenylephrine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination. (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Dextromethorphan; Promethazine: (Moderate) Because promethazine causes pronounced sedation, an enhanced CNS depressant effect or additive drowsiness may occur when it is combined with other CNS depressants including benzodiazepines.
    Diazepam: (Moderate) Concomitant administration of alprazolam with CNS-depressant drugs can potentiate the CNS effects of either agent.
    Dicyclomine: (Moderate) Dicyclomine can cause drowsiness, so it should be used cautiously in patients receiving CNS depressants like benzodiazepines.
    Digoxin: (Moderate) Digoxin toxicity may occur in patients 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. Patients receiving alprazolam or diazepam and digoxin concurrently should be monitored for increased serum digoxin levels.
    Dihydrocodeine; Guaifenesin; Pseudoephedrine: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opiate cough medications in patients taking benzodiazepines.
    Diltiazem: (Moderate) Consider a reduced dose of alprazolam is concurrent use of diltiazem is necessary. Coadministration of alprazolam, a CYP3A4 substrate, with diltiazem, a moderate CYP3A4 inhibitor, may result in increased alprazolam exposure.
    Dimenhydrinate: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Diphenhydramine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If hydrocodone is initiated in a patient taking a benzodiazepine, reduce initial dosage and titrate to clinical response; for hydrocodone extended-release products, initiate hydrocodone at 20% to 30% of the usual dosage. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid opiate cough medications in patients taking benzodiazepines. (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination. (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Diphenhydramine; Ibuprofen: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Diphenhydramine; Naproxen: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Diphenhydramine; Phenylephrine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination. (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Disulfiram: (Moderate) Disulfiram can decrease the hepatic oxidative metabolism of alprazolam if administered concomitantly. Patients receiving alprazolam therapy should be monitored for signs of altered benzodiazepine response when disulfiram is initiated or discontinued.
    Doxacurium: (Moderate) Concurrent use of benzodiazepines and other CNS active medications including neuromuscular blockers, can potentiate the CNS effects of either agent. Lower doses of one or both agents may be required. The severity of this interaction may be increased when additional CNS depressants are given.
    Doxylamine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Doxylamine; Pyridoxine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Dronabinol, THC: (Moderate) Use caution if the use of benzodiazepines are necessary with dronabinol, and monitor for additive dizziness, confusion, somnolence, and other CNS effects.
    Dronedarone: (Moderate) Dronedarone is metabolized by and is an inhibitor of CYP3A. Alprazolam is a substrate for CYP3A4. The concomitant administration of dronedarone and CYP3A substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    Droperidol: (Major) Droperidol administration is associated with an established risk for QT prolongation and torsades de pointes. In December 2001, the FDA issued a black box warning regarding the use of droperidol and its association with QT prolongation and potential for cardiac arrhythmias based on post-marketing surveillance data. Risk factors for the development of prolonged QT syndrome may include the use of benzodiazepines. Also, droperidol and benzodiazepines can both cause CNS depression. If used with a benzodiazepine, droperidol should be initiated at a low dose and adjusted upward, with caution, as needed to achieve the desired effect.
    Drospirenone; Ethinyl Estradiol: (Minor) Oral contraceptives can increase the effects of alprazolam because oral contraceptives 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 alprazolam.
    Drospirenone; Ethinyl Estradiol; Levomefolate: (Minor) Oral contraceptives can increase the effects of alprazolam because oral contraceptives 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 alprazolam.
    Efavirenz: (Moderate) In vivo, efavirenz has been shown to induce hepatic enzymes CYP3A4 and CYP2B6. Patients receiving benzodiazepines that are metabolized by these isoenzymes may experience decreased benzodiazepine serum concentrations if administered concurrently with efavirenz. Efavirenz should be used with caution with oxidized benzodiazepines including alprazolam. Monitor patients closely for excessive side effects.
    Efavirenz; Emtricitabine; Tenofovir: (Moderate) In vivo, efavirenz has been shown to induce hepatic enzymes CYP3A4 and CYP2B6. Patients receiving benzodiazepines that are metabolized by these isoenzymes may experience decreased benzodiazepine serum concentrations if administered concurrently with efavirenz. Efavirenz should be used with caution with oxidized benzodiazepines including alprazolam. Monitor patients closely for excessive side effects.
    Elbasvir; Grazoprevir: (Moderate) Administering alprazolam with elbasvir; grazoprevir may result in elevated alprazolam plasma concentrations. Alprazolam is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
    Enflurane: (Moderate) Concomitant administration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent.
    Enzalutamide: (Major) Monitor for withdrawal symptoms or lack of alprazolam efficacy if coadministration with enzalutamide is necessary. Alprazolam is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer.
    Ergotamine: (Moderate) Drugs that may inhibit CYP3A4, such as ergotamine, may reduce the metabolism of alprazolam. Use alprazolam and ergotamine with caution and consider alprazolam dose reduction of up to 50%.
    Erythromycin: (Moderate) Drugs that may inhibit CYP3A4, such as erythromycin, may inhibit the metabolism of alprazolam. Use alprazolam and erythromycin with caution and consider alprazolam dose reduction.
    Erythromycin; Sulfisoxazole: (Moderate) Drugs that may inhibit CYP3A4, such as erythromycin, may inhibit the metabolism of alprazolam. Use alprazolam and erythromycin with caution and consider alprazolam dose reduction.
    Eslicarbazepine: (Moderate) Concomitant administration of alprazolam with CNS-depressant drugs, including anticonvulsants, can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Additionally, eslicarbazepine is an inducer of the hepatic CYP3A4 isoenzyme thereby having the potential to lower the plasma levels of medications metabolized through these pathways. The effectiveness of medications such as alprazolam could theoretically be decreased.
    Estazolam: (Moderate) Concomitant administration of alprazolam with CNS-depressant drugs can potentiate the CNS effects of either agent.
    Eszopiclone: (Moderate) Concomitant administration of benzodiazepines with eszopiclone can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. The concurrent use of eszopiclone with other anxiolytics, sedatives, and hypnotics at bedtime or in the middle of the night is not recommended. In addition, the risk of next-day psychomotor impairment is increased during co-administration of eszopiclone and other CNS depressants, which may decrease the ability to perform tasks requiring full mental alertness such as driving. If used together, a reduction in the dose of one or both drugs may be needed.
    Ethanol: (Major) Alcohol is associated with CNS depression. The combined use of alcohol and CNS depressants can lead to additive CNS depression, which could be dangerous in tasks requiring mental alertness and fatal in overdose. Alcohol taken with other CNS depressants can lead to additive respiratory depression, hypotension, profound sedation, or coma. Consider the patient's use of alcohol or illicit drugs when prescribing CNS depressant medications. In many cases, the patient should receive a lower dose of the CNS depressant initially if the patient is not likely to be compliant with avoiding alcohol.
    Ethinyl Estradiol: (Minor) Oral contraceptives can increase the effects of alprazolam because oral contraceptives 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 alprazolam.
    Ethinyl Estradiol; Desogestrel: (Minor) Oral contraceptives can increase the effects of alprazolam because oral contraceptives 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 alprazolam.
    Ethinyl Estradiol; Ethynodiol Diacetate: (Minor) Oral contraceptives can increase the effects of alprazolam because oral contraceptives 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 alprazolam.
    Ethinyl Estradiol; Etonogestrel: (Minor) Oral contraceptives can increase the effects of alprazolam because oral contraceptives 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 alprazolam.
    Ethinyl Estradiol; Levonorgestrel: (Minor) Oral contraceptives can increase the effects of alprazolam because oral contraceptives 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 alprazolam.
    Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (Minor) Oral contraceptives can increase the effects of alprazolam because oral contraceptives 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 alprazolam.
    Ethinyl Estradiol; Norelgestromin: (Minor) Oral contraceptives can increase the effects of alprazolam because oral contraceptives 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 alprazolam.
    Ethinyl Estradiol; Norethindrone Acetate: (Minor) Oral contraceptives can increase the effects of alprazolam because oral contraceptives 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 alprazolam.
    Ethinyl Estradiol; Norethindrone Acetate; Ferrous fumarate: (Minor) Oral contraceptives can increase the effects of alprazolam because oral contraceptives 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 alprazolam.
    Ethinyl Estradiol; Norethindrone: (Minor) Oral contraceptives can increase the effects of alprazolam because oral contraceptives 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 alprazolam.
    Ethinyl Estradiol; Norethindrone; Ferrous fumarate: (Minor) Oral contraceptives can increase the effects of alprazolam because oral contraceptives 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 alprazolam.
    Ethinyl Estradiol; Norgestimate: (Minor) Oral contraceptives can increase the effects of alprazolam because oral contraceptives 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 alprazolam.
    Ethinyl Estradiol; Norgestrel: (Minor) Oral contraceptives can increase the effects of alprazolam because oral contraceptives 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 alprazolam.
    Ethosuximide: (Moderate) Concomitant administration of alprazolam with CNS-depressant drugs, including anticonvulsants, can potentiate the CNS effects of either agent.
    Etomidate: (Moderate) Concomitant administration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent.
    Felbamate: (Moderate) Concomitant administration of alprazolam with CNS-depressant drugs, including anticonvulsants, can potentiate the CNS effects of either agent.
    Fentanyl: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Fluconazole: (Moderate) Drugs that inhibit the CYP3A metabolic pathway, such as fluconazole, may profoundly decrease alprazolam clearance. Consequently, alprazolam should be avoided in patients receiving very potent inhibitors of CYP3A isoenzymes. In patients taking drugs that inhibit CYP3A isoenzymes to a significant but lesser degree, use alprazolam with caution and consider alprazolam dose reduction (up to 50% dosage reduction).
    Flumazenil: (Major) Flumazenil competes with benzodiazepines for binding at the GABA/benzodiazepine-receptor complex, the specific binding site of benzodiazepines. Because binding at the receptor is competitive and flumazenil has a much shorter duration of action than do most benzodiazepines, it is possible for the effects of flumazenil to dissipate sooner than the effects of the benzodiazepine. Flumazenil does not affect the pharmacokinetics of the benzodiazepines. Abrupt awakening can cause dysphoria, agitation, and possibly increased adverse effects. If administered to patients who have received a benzodiazepine chronically, abrupt interruption of benzodiazepine agonism by flumazenil can induce benzodiazepine withdrawal including seizures. Flumazenil has minimal effects on benzodiazepine-induced respiratory depression; suitable ventilatory support should be available, especially in treating acute benzodiazepine overdose. Flumazenil does not reverse the actions of barbiturates, opiate agonists, or tricyclic antidepressants.
    Fluoxetine: (Moderate) Clinical study results suggest that the interaction between alprazolam, a CYP3A4 substrate fluoxetine, a CYP3A4 inhibitor may be of clinical significance, and caution is recommended during co-administration. Concurrent use of fluoxetine with alprazolam increased the maximum plasma concentration of alprazolam by 46%, decreased clearance by 21%, increased the half-life by 17%, and decreased measured psychomotor performance. Monitor patients closely for excessive alprazolam-related side effects.
    Fluoxetine; Olanzapine: (Moderate) Although oral formulations of olanzapine and benzodiazepines may be used together, additive effects on respiratory depression and/or CNS depression are possible. Drugs that can cause CNS depression, if used concomitantly with olanzapine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension. Besides ethanol, clinicians should use other anxiolytics, sedatives, and hypnotics cautiously with olanzapine. (Moderate) Clinical study results suggest that the interaction between alprazolam, a CYP3A4 substrate fluoxetine, a CYP3A4 inhibitor may be of clinical significance, and caution is recommended during co-administration. Concurrent use of fluoxetine with alprazolam increased the maximum plasma concentration of alprazolam by 46%, decreased clearance by 21%, increased the half-life by 17%, and decreased measured psychomotor performance. Monitor patients closely for excessive alprazolam-related side effects.
    Flurazepam: (Moderate) Concomitant administration of alprazolam with CNS-depressant drugs can potentiate the CNS effects of either agent.
    Fluvoxamine: (Major) Caution is advisable during co-administration of alprazolam, a CYP3A4 substrate, and fluvoxamine, a moderate CYP3A4 inhibitor. Monitor patients closely for excessive alprazolam-related side effects. A reduction in alprazolam dose may be needed in some patients. In vivo study results indicate that fluvoxamine approximately doubled the maximum plasma concentration of alprazolam, decreased clearance by 49%, increased half-life by 71%, and decreased measured psychomotor performance.
    Food: (Major) Coadministration of marijuana with benzodiazepines may result in an exaggerated sedative effect. Instruct patients receiving these medications concurrently not to drive or operate machinery.
    Fosamprenavir: (Major) Coadministration of alprazolam and fosamprenavir is not recommended. If coadministration cannot be avoided, a dosage reduction of alprazolam should be considered. Fosamprenavir is a potent CYP3A4 inhibitor. The initial step in alprazolam metabolism is hydroxylation catalyzed by cytochrome CYP3A. Drugs that inhibit this metabolic pathway may profoundly decrease alprazolam clearance, resulting in increased potential for serious alprazolam-related adverse events, such as respiratory depression and prolonged sedation. Consequently, alprazolam should be avoided in patients receiving very potent inhibitors of CYP3A isoenzymes.
    Fospropofol: (Moderate) Concomitant administration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent.
    Gabapentin: (Moderate) Concomitant administration of alprazolam with CNS-depressant drugs, including anticonvulsants, can potentiate the CNS effects of either agent.
    General anesthetics: (Moderate) Concomitant administration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent.
    Grapefruit juice: (Major) Grapefruit juice has been shown to significantly increase peak serum concentrations and AUC of triazolam and oral midazolam. According to the manufacturer, a similar interaction may theoretically occur with alprazolam; however, one in-vivo pharmacokinetic study demonstrated that the bioavailability of alprazolam is unlikely to be effected by coadministration with grapefruit juice. Use with caution.
    Green Tea: (Minor) Patients taking benzodiazepines for insomnia should not use caffeine-containing products, such as green tea, prior to going to bed as these products may antagonize the sedative effects of the benzodiazepine.
    Guaifenesin; Hydrocodone: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If hydrocodone is initiated in a patient taking a benzodiazepine, reduce initial dosage and titrate to clinical response; for hydrocodone extended-release products, initiate hydrocodone at 20% to 30% of the usual dosage. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid opiate cough medications in patients taking benzodiazepines.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If hydrocodone is initiated in a patient taking a benzodiazepine, reduce initial dosage and titrate to clinical response; for hydrocodone extended-release products, initiate hydrocodone at 20% to 30% of the usual dosage. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid opiate cough medications in patients taking benzodiazepines.
    Guaifenesin; Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Guanabenz: (Moderate) Guanabenz is associated with sedative effects. Guanabenz can potentiate the effects of CNS depressants such as benzodiazepines, when administered concomitantly.
    Guanfacine: (Moderate) Guanfacine has been associated with sedative effects and can potentiate the actions of other CNS depressants including benzodiazepines.
    Guarana: (Minor) Caffeine, an active constituent of guarana, is a CNS stimulant associated with heightened attentiveness and insomnia, and is used to treat or prevent drowsiness or fatigue; patients taking benzodiazepines for insomnia should not use guarana-containing products prior to going to bed as these products may antagonize the sedative effects of the benzodiazepine or zolpidem.
    Haloperidol: (Moderate) Mild to moderate increases in haloperidol plasma concentrations have been reported during concurrent use of haloperidol and CYP3A4 substrates such as alprazolam. Until more data are available, it is advisable to closely monitor for adverse events when alprazolam is coadministered with haloperidol. Concomitant administration of alprazolam with CNS-depressant drugs including antipsychotics can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent.
    Halothane: (Moderate) Concomitant administration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent.
    Homatropine; Hydrocodone: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If hydrocodone is initiated in a patient taking a benzodiazepine, reduce initial dosage and titrate to clinical response; for hydrocodone extended-release products, initiate hydrocodone at 20% to 30% of the usual dosage. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid opiate cough medications in patients taking benzodiazepines.
    Hydantoins: (Moderate) Hydantoin anticonvulsants can theoretically add to the CNS-depressant effects of other CNS depressants including the benzodiazepines. In addition, potential hepatic enzyme inducers such as hydantoins can theoretically increase the clearance of benzodiazepines metabolized by oxidative metabolism, leading to lower benzodiazepine concentrations.
    Hydrochlorothiazide, HCTZ; Methyldopa: (Moderate) Methyldopa is associated with sedative effects. Methyldopa can potentiate the effects of CNS depressants such as barbiturates, benzodiazepines, opiate agonists, or phenothiazines when administered concomitantly.
    Hydrocodone: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If hydrocodone is initiated in a patient taking a benzodiazepine, reduce initial dosage and titrate to clinical response; for hydrocodone extended-release products, initiate hydrocodone at 20% to 30% of the usual dosage. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid opiate cough medications in patients taking benzodiazepines.
    Hydrocodone; Ibuprofen: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If hydrocodone is initiated in a patient taking a benzodiazepine, reduce initial dosage and titrate to clinical response; for hydrocodone extended-release products, initiate hydrocodone at 20% to 30% of the usual dosage. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid opiate cough medications in patients taking benzodiazepines.
    Hydrocodone; Phenylephrine: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If hydrocodone is initiated in a patient taking a benzodiazepine, reduce initial dosage and titrate to clinical response; for hydrocodone extended-release products, initiate hydrocodone at 20% to 30% of the usual dosage. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid opiate cough medications in patients taking benzodiazepines. (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Hydrocodone; Potassium Guaiacolsulfonate: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If hydrocodone is initiated in a patient taking a benzodiazepine, reduce initial dosage and titrate to clinical response; for hydrocodone extended-release products, initiate hydrocodone at 20% to 30% of the usual dosage. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid opiate cough medications in patients taking benzodiazepines.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If hydrocodone is initiated in a patient taking a benzodiazepine, reduce initial dosage and titrate to clinical response; for hydrocodone extended-release products, initiate hydrocodone at 20% to 30% of the usual dosage. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid opiate cough medications in patients taking benzodiazepines.
    Hydrocodone; Pseudoephedrine: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If hydrocodone is initiated in a patient taking a benzodiazepine, reduce initial dosage and titrate to clinical response; for hydrocodone extended-release products, initiate hydrocodone at 20% to 30% of the usual dosage. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid opiate cough medications in patients taking benzodiazepines.
    Hydromorphone: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If hydromorphone is initiated in a patient taking a benzodiazepine, reduce the initial dosage of hydromorphone and titrate to clinical response; for hydromorphone extended-release tablets, use 1/3 to 1/2 of the estimated hydromorphone starting dose. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Hydroxyzine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Ibuprofen; Oxycodone: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If oxycodone is initiated in a patient taking a benzodiazepine, reduce dosages and titrate to clinical response. For acetaminophen; oxycodone extended-release tablets, start with 1 tablet PO every 12 hours, and for other oxycodone products, use an initial dose of oxycodone at one-third to one-half the usual dosage. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Idelalisib: (Major) Coadministration of alprazolam and idelalisib is not recommended. If coadministration cannot be avoided, a dosage reduction of alprazolam should be considered. Idealalisib is a potent CYP3A4 inhibitor. The initial step in alprazolam metabolism is hydroxylation catalyzed by cytochrome CYP3A. Drugs that inhibit this metabolic pathway may profoundly decrease alprazolam clearance, resulting in increased potential for serious alprazolam-related adverse events, such as respiratory depression and prolonged sedation. Consequently, alprazolam should be avoided in patients receiving very potent inhibitors of CYP3A isoenzymes.
    Iloperidone: (Moderate) Drugs that can cause CNS depression, if used concomitantly with iloperidone, may increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness. Caution should be used when iloperidone is given in combination with other centrally-acting medications including anxiolytics, sedatives, and hypnotics.
    Imatinib: (Major) In patients taking CYP3A inhibitors such as imatinib, STI-571 use alprazolam with caution and consider alprazolam dose reduction (up to 50% dose reduction may be needed).
    Indinavir: (Severe) Coadministration of indinavir with alprazolam is contraindicated. Indinavir is expected to significantly inhibit the CYP3A4 metabolism of alprazolam, producing large increases in the plasma concentrations which may lead to excessive sedation and potentially respiratory depression. Consider an alternative benzodiazepine that does not undergo oxidative metabolism, such as lorazepam, oxazepam, or temazepam.
    Isavuconazonium: (Moderate) Concomitant use of isavuconazonium with alprazolam may result in increased serum concentrations of alprazolam. Alprazolam is primarily metabolized by the hepatic isoenzyme CYP3A4; isavuconazole, the active moiety of isavuconazonium, is a moderate inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are used together.
    Isoflurane: (Moderate) Concomitant administration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent.
    Isoniazid, INH: (Moderate) Isoniazid can decrease the hepatic oxidative metabolism of benzodiazepines if administered concomitantly. Patients receiving alprazolam therapy should be monitored for signs of altered benzodiazepine response when alprazolam is initiated or discontinued.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Moderate) Isoniazid can decrease the hepatic oxidative metabolism of benzodiazepines if administered concomitantly. Patients receiving alprazolam therapy should be monitored for signs of altered benzodiazepine response when alprazolam is initiated or discontinued. (Moderate) Rifampin is a potent inducer of the cytochrome P-450 hepatic enzyme system. Rifampin could induce the CYP3A4-mediated metabolism of oxidized benzodiazepines, such as alprazolam.
    Isoniazid, INH; Rifampin: (Moderate) Isoniazid can decrease the hepatic oxidative metabolism of benzodiazepines if administered concomitantly. Patients receiving alprazolam therapy should be monitored for signs of altered benzodiazepine response when alprazolam is initiated or discontinued. (Moderate) Rifampin is a potent inducer of the cytochrome P-450 hepatic enzyme system. Rifampin could induce the CYP3A4-mediated metabolism of oxidized benzodiazepines, such as alprazolam.
    Itraconazole: (Severe) Coadministration of itraconazole and alprazolam is contraindicated. Itraconazole significantly impairs the CYP3A4 metabolism of alprazolam, resulting in elevated alprazolam concentrations, which may cause prolonged sedation and respiratory depression. When a single dose of alprazolam was administered to healthy patients receiving itraconazole, the mean AUC and half-live of alprazolam were increased 2.7 fold. Lorazepam, oxazepam, or temazepam may be safer alternatives if a benzodiazepine must be administered in combination with itraconazole, as these benzodiazepines are not oxidatively metabolized.
    Ivacaftor: (Moderate) Use caution when administering ivacaftor and alprazolam concurrently because patients are at increased risk for adverse effects from alprazolam. Ivacaftor is a CYP3A inhibitor, and alprazolam is a CYP3A substrate. Co-administration of ivacaftor with midazolam, another CYP3A substrate, increased midazolam exposure by 1.5-fold.
    Kava Kava, Piper methysticum: (Major) 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.
    Ketamine: (Moderate) Concomitant administration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent.
    Ketoconazole: (Severe) Coadministration of ketoconazole and alprazolam is contraindicated. Ketoconazole significantly impairs the CYP3A4 metabolism of alprazolam, resulting in elevated alprazolam concentrations. Lorazepam, oxazepam, or temazepam may be safer alternatives if a benzodiazepine must be administered in combination with ketoconazole, as these benzodiazepines are not oxidatively metabolized.
    Lacosamide: (Moderate) Concomitant administration of alprazolam with CNS-depressant drugs, including anticonvulsants, can potentiate the CNS effects of either agent.
    Lamotrigine: (Moderate) Concomitant administration of alprazolam with CNS-depressant drugs, including anticonvulsants, can potentiate the CNS effects of either agent.
    Levetiracetam: (Moderate) Concomitant administration of alprazolam with CNS-depressant drugs, including anticonvulsants, can potentiate the CNS effects of either agent.
    Levocetirizine: (Moderate) Additive drowsiness may occur if cetirizine/levocetirizine is administered with other drugs that depress the CNS, including benzodiazepines.
    Levomethadyl: (Moderate) Concomitant administration of benzodiazepines with CNS-depressant drugs, including opiate agonists, can potentiate the CNS effects of either agent.
    Levomilnacipran: (Moderate) Concurrent use of many CNS active drugs, including benzodiazepines, with levomilnacipran has not been evaluated by the manufacturer. Therefore, caution is advisable when combining anxiolytics, sedatives, and hypnotics or other psychoactive medications with levomilnacipran.
    Levorphanol: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If levorphanol is initiated in a patient taking a benzodiazepine, reduce the initial dose of levorphanol by approximately 50% or more. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Lithium: (Moderate) Because lithium has the potential to impair cognitive and motor skills, caution is advisable during concurrent use of other medications with centrally-acting effects including anxiolytics, sedatives, and hypnotics.
    Lomitapide: (Major) Concomitant use of lomitapide and alprazolam may significantly increase the serum concentration of lomitapide. Therefore, the lomitapide dose should not exceed 30 mg/day PO during concurrent use. Alprazolam is a weak CYP3A4 inhibitor; the exposure to lomitapide is increased by approximately 2-fold in the presence of weak CYP3A4 inhibitors.
    Lopinavir; Ritonavir: (Major) Coadministration of alprazolam and lopinavir; ritonavir is not recommended. If coadministration cannot be avoided, a dosage reduction of alprazolam should be considered. Lopinavir and ritonavir are potent CYP3A4 inhibitors. The initial step in alprazolam metabolism is hydroxylation catalyzed by cytochrome CYP3A. Drugs that inhibit this metabolic pathway may profoundly decrease alprazolam clearance, resulting in increased potential for serious alprazolam-related adverse events, such as respiratory depression and prolonged sedation. Consequently, alprazolam should be avoided in patients receiving very potent inhibitors of CYP3A isoenzymes. (Major) Coadministration of alprazolam and ritonavir or lopinavir; ritonavir is not recommended. If coadministration cannot be avoided, a dosage reduction of alprazolam should be considered. Lopinavir and ritonavir are potent CYP3A4 inhibitors. The initial step in alprazolam metabolism is hydroxylation catalyzed by cytochrome CYP3A. Drugs that inhibit this metabolic pathway may profoundly decrease alprazolam clearance, resulting in increased potential for serious alprazolam-related adverse events, such as respiratory depression and prolonged sedation. Consequently, alprazolam should be avoided in patients receiving very potent inhibitors of CYP3A isoenzymes.
    Loratadine: (Minor) Although loratadine is considered a 'non-sedating' antihistamine, dose-related sedation has been noted. For this reason, it would be prudent to monitor for drowsiness when used concurrently with other CNS depressants like benzodiazepines.
    Loratadine; Pseudoephedrine: (Minor) Although loratadine is considered a 'non-sedating' antihistamine, dose-related sedation has been noted. For this reason, it would be prudent to monitor for drowsiness when used concurrently with other CNS depressants like benzodiazepines.
    Lorazepam: (Moderate) Concomitant administration of alprazolam with CNS-depressant drugs can potentiate the CNS effects of either agent.
    Loxapine: (Moderate) Concomitant administration of alprazolam with CNS-depressant drugs, including antipsychotics, can potentiate the CNS effects of either agent.
    Lumacaftor; Ivacaftor: (Moderate) Lumacaftor; ivacaftor may decrease the systemic exposure and therapeutic efficacy of alprazolam. If used together, alprazolam dosages may need to be adjusted. Alprazolam is a CYP3A substrate. Lumacaftor is a strong CYP3A inducer. When alprazolam (0.8 mg as a single dose) was given with carbamazepine (300 mg/day for 10 days), another strong CYP3A inducer, alprazolam clearance more than doubled and elimination half-life decreased from 17.1 +/- 4.9 hours to 7.7 +/- 1.7 hours.
    Lumacaftor; Ivacaftor: (Moderate) Use caution when administering ivacaftor and alprazolam concurrently because patients are at increased risk for adverse effects from alprazolam. Ivacaftor is a CYP3A inhibitor, and alprazolam is a CYP3A substrate. Co-administration of ivacaftor with midazolam, another CYP3A substrate, increased midazolam exposure by 1.5-fold.
    Lurasidone: (Moderate) Due to the CNS effects of lurasidone, caution should be used when lurasidone is given in combination with other centrally acting medications such as anxiolytics, sedatives, and hypnotics, including benzodiazepines. In one study, co-administration of lurasidone and midazolam increased the Cmax and AUC of midazolam by about 21% and 44%, respectively, compared to midazolam alone; however, dosage adjustment of midazolam based upon pharmacokinetic parameters is not required during concurrent use of lurasidone.
    Magnesium Salts: (Minor) Because of the CNS-depressant effects of magnesium sulfate, additive central-depressant effects can occur following concurrent administration with CNS depressants such as benzodiazepines. Caution should be exercised when using these agents concurrently.
    Maprotiline: (Moderate) Benzodiazepines or other CNS depressants should be combined cautiously with maprotiline because they could cause additive depressant effects and possible respiratory depression or hypotension. The combination of benzodiazepines and maprotiline is commonly used clinically and is considered to be safe as long as patients are monitored for excessive adverse effects from either agent. Maprotiline may lower the seizure threshold, so when benzodiazepines are used for anticonvulsant effects the patient should be monitored for desired clinical outcomes.
    Meclizine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Melatonin: (Major) Use caution when combining melatonin with the benzodiazepines; when the benzodiazepine is used for sleep, co-use of melatonin should be avoided. In animal studies, melatonin has been shown to increase benzodiazepine binding to receptor sites. In one case report, a benzodiazepine-dependent woman with an 11 year history of insomnia weaned and discontinued her benzodiazepine prescription within a few days without rebound insomnia or apparent benzodiazepine withdrawal when melatonin was given. In another case report, the ingestion of excessive melatonin along with normal doses of chlordiazepoxide and an antidepressant resulted in lethargy and short-term amnestic responses. Both cases suggest additive pharmacodynamic effects. In a clinical trial, there was clear evidence for a transitory pharmacodynamic interaction between melatonin and another hypnotic agent one hour following co-dosing. Concomitant administration resulted in increased impairment of attention, memory and coordination compared to the hypnotic agent alone. Use of more than one agent for hypnotic purposes may increase the risk for over-sedation, CNS effects, or sleep-related behaviors. Be alert for unusual changes in moods or behaviors.Patients reporting unusual sleep-related behaviors likely should discontinue melatonin use.
    Meperidine: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Meperidine; Promethazine: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. (Moderate) Because promethazine causes pronounced sedation, an enhanced CNS depressant effect or additive drowsiness may occur when it is combined with other CNS depressants including benzodiazepines.
    Mephobarbital: (Major) Additive CNS depression may occur with concomitant use of benzodiazepines and barbiturates. Barbiturates may also induce the metabolism of some benzodiazepines. Monitor for alterations in response to therapy.
    Meprobamate: (Moderate) Concomitant administration of benzodiazepines with meprobamate can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. If used together, a reduction in the dose of one or both drugs may be needed.
    Mestranol; Norethindrone: (Minor) Oral contraceptives can increase the effects of alprazolam because oral contraceptives 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 alprazolam.
    Methadone: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If methadone is initiated in a patient taking a benzodiazepine, reduced dosages are recommended; in opioid-naive adults, use an initial dose of methadone 2.5 mg PO every 12 hours. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Methocarbamol: (Moderate) Concurrent use of benzodiazepines and other CNS active medications including skeletal muscle relaxants, can potentiate the CNS effects of either agent. Lower doses of one or both agents may be required. The severity of this interaction may be increased when additional CNS depressants are given.
    Methohexital: (Major) Additive CNS depression may occur with concomitant use of benzodiazepines and barbiturates. Barbiturates may also induce the metabolism of some benzodiazepines. Monitor for alterations in response to therapy.
    Methscopolamine: (Moderate) CNS depression can be increased when methscopolamine is combined with other CNS depressants such as any anxiolytics, sedatives, and hypnotics.
    Methsuximide: (Moderate) Concomitant administration of alprazolam with CNS-depressant drugs, including anticonvulsants, can potentiate the CNS effects of either agent.
    Methyldopa: (Moderate) Methyldopa is associated with sedative effects. Methyldopa can potentiate the effects of CNS depressants such as barbiturates, benzodiazepines, opiate agonists, or phenothiazines when administered concomitantly.
    Metoclopramide: (Minor) Combined use of metoclopramide and other CNS depressants, such as anxiolytics, sedatives, and hypnotics, can increase possible sedation.
    Metyrapone: (Moderate) Metyrapone may cause dizziness and/or drowsiness. Other drugs that may also cause drowsiness, such as benzodiazepines, should be used with caution. Additive drowsiness and/or dizziness is possible.
    Metyrosine: (Moderate) The concomitant administration of metyrosine with benzodiazepines can result in additive sedative effects.
    Midazolam: (Moderate) Concomitant administration of alprazolam with CNS-depressant drugs can potentiate the CNS effects of either agent.
    Mifepristone, RU-486: (Moderate) Mifepristone inhibits CYP3A4. Coadministration of mifepristone may lead to an increase in serum levels of drugs that are CYP3A4 substrates, such as alprazolam. Due to the slow elimination of mifepristone from the body, such interactions may be observed for a prolonged period after mifepristone administration.
    Milnacipran: (Moderate) Concurrent use of many CNS-active drugs with milnacipran or levomilnacipran has not been evaluated by the manufacturer. Therefore, caution is advisable when combining anxiolytics, sedatives, and hypnotics or other psychoactive medications with these medications.
    Minocycline: (Minor) Injectable minocycline contains magnesium sulfate heptahydrate. Because of the CNS-depressant effects of magnesium sulfate, additive central-depressant effects can occur following concurrent administration with CNS depressants such as benzodiazepines. Caution should be exercised when using these agents concurrently.
    Mirtazapine: (Moderate) Consistent with the pharmacology of mirtazapine and the drug's side effect profile, additive effects may occur with other CNS-active agents, including benzodiazepines.
    Mitotane: (Moderate) Avoid the concomitant use of mitotane with alprazolam; if coadministration cannot be avoided, monitor for decreased efficacy of alprazolam. Mitotane is a strong CYP3A4 inducer and alprazolam is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of alprazolam. Additionally, mitotane can cause sedation, lethargy, vertigo, and other CNS adverse reactions; additive CNS effects may occur initially when mitotane is given concurrently with alprazolam.
    Mivacurium: (Moderate) Concurrent use of benzodiazepines and other CNS active medications including neuromuscular blockers, can potentiate the CNS effects of either agent. Lower doses of one or both agents may be required. The severity of this interaction may be increased when additional CNS depressants are given.
    Molindone: (Moderate) Concomitant administration of alprazolam with CNS-depressant drugs, including antipsychotics, can potentiate the CNS effects of either agent.
    Monoamine oxidase inhibitors: (Moderate) The CNS-depressant effects of MAOIs can be potentiated with concomitant administration of other drugs known to cause CNS depression including benzodiazepines. MAOIs can cause a variable change in seizure patterns, so careful monitoring of the patient with epilepsy is required when benzodiazepines are used in the treatment of epilepsy.
    Morphine: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If morphine is initiated in a patient taking a benzodiazepine, reduce initial dosages and titrate to clinical response. For extended-release tablets, start with morphine 15 mg PO every 12 hours, and for extended-release capsules, start with 30 mg PO every 24 hours or less. Use an initial morphine; naltrexone dose of 20 mg/0.8 mg PO every 24 hours. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Morphine; Naltrexone: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If morphine is initiated in a patient taking a benzodiazepine, reduce initial dosages and titrate to clinical response. For extended-release tablets, start with morphine 15 mg PO every 12 hours, and for extended-release capsules, start with 30 mg PO every 24 hours or less. Use an initial morphine; naltrexone dose of 20 mg/0.8 mg PO every 24 hours. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Nabilone: (Moderate) Concomitant use of nabilone with other CNS depressants can potentiate the effects of nabilone on respiratory depression.
    Nalbuphine: (Major) Concomitant use of mixed opiate agonists/antagonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of mixed opiate agonists/antagonists with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If a mixed opiate agonist/antagonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the mixed opiate agonist/antagonist and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking a mixed opiate agonist/antagonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Nefazodone: (Major) In general, nefazodone is not recommended for use with alprazolam in most patients. The initial dose of alprazolam should be reduced by 50% when concurrent use cannot be avoided. Nefazodone inhibits the hepatic CYP3A4 isoenzyme and substantially increases the plasma concentrations of alprazolam. Alprazolam AUC and half-life are increased 2-fold by the addition of nefazodone.
    Nelfinavir: (Major) Coadministration of alprazolam and nelfinavir is not recommended. If coadministration cannot be avoided, a dosage reduction of alprazolam should be considered. Nelfinavir is a potent CYP3A4 inhibitor. The initial step in alprazolam metabolism is hydroxylation catalyzed by cytochrome CYP3A. Drugs that inhibit this metabolic pathway may profoundly decrease alprazolam clearance, resulting in increased potential for serious alprazolam-related adverse events, such as respiratory depression and prolonged sedation. Consequently, alprazolam should be avoided in patients receiving very potent inhibitors of CYP3A isoenzymes.
    Netupitant; Palonosetron: (Major) Netupitant is a moderate inhibitor of CYP3A4 and should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4, such as alprazolam. The plasma concentrations of CYP3A4 substrates can increase when co-administered with netupitant. The inhibitory effect on CYP3A4 can last for multiple days. When midazolam, another benzodiazepine metabolized via CYP3A4, was administered with netupitant, the systemic exposure to midazolam was significantly increased. Increased benzodiazepine exposure may lead to increased sedation or respiratory depression. Monitor patients closely who receive concurrent therapy.
    Neuromuscular blockers: (Moderate) Concurrent use of benzodiazepines and other CNS active medications including neuromuscular blockers, can potentiate the CNS effects of either agent. Lower doses of one or both agents may be required. The severity of this interaction may be increased when additional CNS depressants are given.
    Nevirapine: (Moderate) Nevirapine may induce the metabolism of certain benzodiazepines that are metabolized through the cytochrome P450 system including alprazolam. Patients should be monitored closely for loss of clinical effects.
    Nicardipine: (Moderate) Nicardipine is an inhibitor of CYP3A4 isoenzymes. Co-administration with nicardipine may lead to an increase in serum levels of drugs that are CYP3A4 substrates including alprazolam.
    Nifedipine: (Moderate) In patients taking drugs that inhibit CYP3A isoenzymes, use alprazolam with caution and consider alprazolam dose reduction (up to 50% dose reduction may be needed). Niifedipine may theoretically inhibit CYP3A4 metabolism of alprazolam.
    Nilotinib: (Major) Nilotinib is a competitive inhibitor of CYP3A4. Alprazolam is a CYP3A4 substrate. Coadminister these drugs with caution. Increased alprazolam serum concentrations may occur, leading to an increased risk of alprazolam-related adverse reactions. Monitor patients carefully, as the alprazolam dosage may need to be decreased.
    Nitroglycerin: (Minor) Nitroglycerin can cause hypotension. This action may be additive with other agents that can cause hypotension such as benzodiazepines. Patients should be monitored more closely for hypotension if nitroglycerin is used concurrently with benzodiazepines.
    Obeticholic Acid: (Moderate) Obeticholic acid may increase the exposure to concomitant drugs that are CYP1A2 substrates, such as alprazolam. Therapeutic monitoring is recommended with coadministration.
    Olanzapine: (Moderate) Although oral formulations of olanzapine and benzodiazepines may be used together, additive effects on respiratory depression and/or CNS depression are possible. Drugs that can cause CNS depression, if used concomitantly with olanzapine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension. Besides ethanol, clinicians should use other anxiolytics, sedatives, and hypnotics cautiously with olanzapine.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) Coadministration of alprazolam and ritonavir or lopinavir; ritonavir is not recommended. If coadministration cannot be avoided, a dosage reduction of alprazolam should be considered. Lopinavir and ritonavir are potent CYP3A4 inhibitors. The initial step in alprazolam metabolism is hydroxylation catalyzed by cytochrome CYP3A. Drugs that inhibit this metabolic pathway may profoundly decrease alprazolam clearance, resulting in increased potential for serious alprazolam-related adverse events, such as respiratory depression and prolonged sedation. Consequently, alprazolam should be avoided in patients receiving very potent inhibitors of CYP3A isoenzymes.
    Omeprazole: (Moderate) Omeprazole inhibits CYP2C19. There have been some case reports describing an interaction between omeprazole and benzodiazepines metabolized via the cytochrome P450 system, such as alprazolam. Patients should be monitored to determine if it is necessary to adjust the dosage of the benzodiazepine when taken concomitantly with omeprazole.
    Omeprazole; Sodium Bicarbonate: (Moderate) Omeprazole inhibits CYP2C19. There have been some case reports describing an interaction between omeprazole and benzodiazepines metabolized via the cytochrome P450 system, such as alprazolam. Patients should be monitored to determine if it is necessary to adjust the dosage of the benzodiazepine when taken concomitantly with omeprazole.
    Oritavancin: (Moderate) Alprazolam is metabolized by CYP3A4; oritavancin is a weak CYP3A4 inducer. Plasma concentrations and efficacy of alprazolam may be reduced if these drugs are administered concurrently.
    Oxazepam: (Moderate) Concomitant administration of alprazolam with CNS-depressant drugs can potentiate the CNS effects of either agent.
    Oxcarbazepine: (Moderate) Oxcarbazepine and its active metabolite, MHD, are dose-dependent inducers of the hepatic CYP3A4/5 isoenzymes thereby having the potential to lower the plasma levels of medications metabolized through these pathways. The effectiveness of medications such as alprazolam could theoretically be decreased. In addition, concomitant administration of alprazolam with CNS-depressant drugs, including anticonvulsants, can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent.
    Oxybutynin: (Moderate) Additive CNS depression may occur when oxybutynin is used concomitantly with other CNS-depressant drugs, including anxiolytics, sedatives, and hypnotics.
    Oxycodone: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If oxycodone is initiated in a patient taking a benzodiazepine, reduce dosages and titrate to clinical response. For acetaminophen; oxycodone extended-release tablets, start with 1 tablet PO every 12 hours, and for other oxycodone products, use an initial dose of oxycodone at one-third to one-half the usual dosage. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Oxymorphone: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If oxymorphone is initiated in a patient taking a benzodiazepine, use an initial dose of oxymorphone at 1/3 to 1/2 the usual dosage and titrate to clinical response. If the extended-release oxymorphone tablets are used concurrently with a CNS depressant, use an initial dosage of 5 mg PO every 12 hours. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Paliperidone: (Moderate) Drugs that can cause CNS depression, if used concomitantly with paliperidone, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness. Caution should be used when paliperidone is given in combination with other centrally-acting medications including anxiolytics, sedatives, and hypnotics, buprenorphine, butorphanol, dronabinol, THC, ethanol, nabilone, nalbuphine, opiate agonists, and pentazocine.
    Pancuronium: (Moderate) Concurrent use of benzodiazepines and other CNS active medications including neuromuscular blockers, can potentiate the CNS effects of either agent. Lower doses of one or both agents may be required. The severity of this interaction may be increased when additional CNS depressants are given.
    Papaverine: (Moderate) Concurrent use of papaverine with potent CNS depressants such as benzodiazepines could lead to enhanced sedation.
    Paroxetine: (Minor) The manufacturer of alprazolam states that in vitro studies suggest paroxetine may inhibit the metabolism of alprazolam via inhibition of CYP3A4. However, paroxetine is typically considered a major inhibitor of CYP2D6, for which alprazolam is not a substrate. The potential for clinical interaction is uncertain. Be alert for any change in psychomotor performance or other benzodiazepine-related side effects when paroxetine is combined with alprazolam.
    Pazopanib: (Moderate) Pazopanib is a weak inhibitor of CYP3A4. Coadministration of pazopanib and alprazolam, a CYP3A4 substrate, may cause an increase in systemic concentrations of alprazolam. Use caution when administering these drugs concomitantly.
    Pentazocine: (Major) Concomitant use of mixed opiate agonists/antagonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of mixed opiate agonists/antagonists with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If a mixed opiate agonist/antagonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the mixed opiate agonist/antagonist and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking a mixed opiate agonist/antagonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Pentazocine; Naloxone: (Major) Concomitant use of mixed opiate agonists/antagonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of mixed opiate agonists/antagonists with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If a mixed opiate agonist/antagonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the mixed opiate agonist/antagonist and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking a mixed opiate agonist/antagonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Pentobarbital: (Major) Additive CNS depression may occur with concomitant use of benzodiazepines and barbiturates. Barbiturates may also induce the metabolism of some benzodiazepines. Monitor for alterations in response to therapy.
    Perampanel: (Moderate) Patients taking benzodiazepines with perampanel may experience increased CNS depression. Monitor patients for adverse effects; dose adjustment of either drug may be necessary. Use of midazolam in healthy subjects who received perampanel 6 mg once daily for 20 days decreased the AUC and Cmax of midazolam by 13% and 15%, respectively, possibly due to weak induction of CYP3A4 by perampanel; the specific clinical significance of this interaction is unknown.
    Phenobarbital: (Major) Additive CNS depression may occur with concomitant use of benzodiazepines and barbiturates. Barbiturates may also induce the metabolism of some benzodiazepines. Monitor for alterations in response to therapy.
    Phenothiazines: (Moderate) Phenothiazines are CNS depressant drugs that may have cumulative effects when administered concurrently and they should be used cautiously with anxiolytic, sedative, and hypnotic type drugs, such as the benzodiazepines. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension. Additionally, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of other CNS depressants than with sedatives alone. Monitor for additive effects, unusual moods or behaviors, and warn about the potential effects to driving and other activities.
    Phentermine; Topiramate: (Moderate) Topiramate has the potential to cause CNS depression as well as other cognitive and/or neuropsychiatric adverse reactions. The CNS depressant effects of topiramate can be potentiated pharmacodynamically by concurrent use of CNS depressant agents such as the benzodiazepines. Concurrent use of topiramate and benzodiazepines associated with thrombocytopenia (e.g., clonazepam, lorazepam, and clobazam), may also increase the risk of bleeding; monitor patients appropriately during benzodiazepine therapy.
    Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Phenylephrine; Promethazine: (Moderate) Because promethazine causes pronounced sedation, an enhanced CNS depressant effect or additive drowsiness may occur when it is combined with other CNS depressants including benzodiazepines. (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Pimozide: (Moderate) Due to the effects of pimozide on cognition, it should be used cautiously with other CNS depressants including benzodiazepines.
    Posaconazole: (Major) Coadministration of posaconazole and alprazolam is not recommended. If coadministration cannot be avoided, a dosage reduction of alprazolam should be considered. Posaconazole is a potent inhibitor of CYP3A4. The initial step in alprazolam metabolism is hydroxylation catalyzed by cytochrome CYP3A. Drugs that inhibit this metabolic pathway may profoundly decrease alprazolam clearance. Consequently, alprazolam should be avoided in patients receiving very potent inhibitors of CYP3A isoenzymes.
    Pramipexole: (Major) Concomitant administration of benzodiazepines with CNS-depressant drugs, including pramipexole, can potentiate the CNS effects.
    Prasterone, Dehydroepiandrosterone, DHEA (Dietary Supplements): (Major) Prasterone, dehydroepiandrosterone, DHEA may inhibit the metabolism of benzodiazepines (e.g., alprazolam, estazolam, midazolam) which undergo CYP3A4-mediated metabolism. In one study of elderly volunteers, half of the patients received DHEA 200 mg/day PO for 2 weeks, followed by a single dose of triazolam 0.25 mg. Triazolam clearance was reduced by close to 30% in the DHEA-pretreated patients vs. the control group; however, the effect of DHEA on CYP3A4 metabolism appeared to vary widely among subjects. While more study is needed, benzodiazepine-induced CNS sedation and other adverse effects might be increased in some individuals if DHEA is co-administered.
    Prasterone, Dehydroepiandrosterone, DHEA (FDA-approved): (Major) Prasterone, dehydroepiandrosterone, DHEA may inhibit the metabolism of benzodiazepines (e.g., alprazolam, estazolam, midazolam) which undergo CYP3A4-mediated metabolism. In one study of elderly volunteers, half of the patients received DHEA 200 mg/day PO for 2 weeks, followed by a single dose of triazolam 0.25 mg. Triazolam clearance was reduced by close to 30% in the DHEA-pretreated patients vs. the control group; however, the effect of DHEA on CYP3A4 metabolism appeared to vary widely among subjects. While more study is needed, benzodiazepine-induced CNS sedation and other adverse effects might be increased in some individuals if DHEA is co-administered.
    Pregabalin: (Moderate) Pregabalin can potentiate the CNS-depressant action of other drugs such as benzodiazepines. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension.
    Primidone: (Major) Additive CNS depression may occur with concomitant use of benzodiazepines and barbiturates. Barbiturates may also induce the metabolism of some benzodiazepines. Monitor for alterations in response to therapy.
    Probenecid: (Moderate) Probenecid may inhibit the metabolism of the benzodiazepines, including those which are metabolized by conjugation (e.g., lorazepam) or oxidation (e.g., midazolam). Probenecid has been shown to decrease lorazepam clearance by about 50% and increase its elimination half-life. In addition, pretreatment with probenecid shortened the induction time (85 vs. 109 seconds) of midazolam in presurgical patients. Patients receiving alprazolam therapy should be monitored for signs of altered benzodiazepine response when probenecid is initiated or discontinued.
    Procarbazine: (Minor) CNS depressants benzodiazepines can potentiate the CNS depression caused by procarbazine therapy, so these drugs should be used together cautiously.
    Promethazine: (Moderate) Because promethazine causes pronounced sedation, an enhanced CNS depressant effect or additive drowsiness may occur when it is combined with other CNS depressants including benzodiazepines.
    Propofol: (Moderate) Concomitant administration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent.
    Propoxyphene: (Moderate) Coadministration 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.
    Quazepam: (Moderate) Concomitant administration of alprazolam with CNS-depressant drugs can potentiate the CNS effects of either agent.
    Quetiapine: (Moderate) Somnolence is a commonly reported adverse effect of quetiapine; coadministration of quetiapine with anxiolytics, sedatives, and hypnotics, or other CNS depressants may result in additive sedative effects.
    Ramelteon: (Moderate) Ramelteon is a sleep-promoting agent; therefore, additive pharmacodynamic effects are possible when combining ramelteon with benzodiazepines or other miscellaneous anxiolytics, sedatives, and hypnotics. Pharmacokinetic interactions have been observed with the use of zolpidem. Use of ramelteon 8 mg/day for 11 days and a single dose of zolpidem 10 mg resulted in an increase in the median Tmax of zolpidem of about 20 minutes; exposure to zolpidem was unchanged. Ramelteon use with hypnotics of any kind is considered duplicative therapy and these drugs are generally not co-administered.
    Ranolazine: (Moderate) In patients taking drugs that inhibit CYP3A isoenzymes, use alprazolam with caution and consider alprazolam dose reduction (up to 50% dose reduction may be needed). Ranolazine may theoretically inhibit CYP3A4 metabolism of alprazolam.
    Rapacuronium: (Moderate) Concurrent use of benzodiazepines and other CNS active medications including neuromuscular blockers, can potentiate the CNS effects of either agent. Lower doses of one or both agents may be required. The severity of this interaction may be increased when additional CNS depressants are given.
    Rasagiline: (Moderate) The CNS-depressant effects of MAOIs can be potentiated with concomitant administration of other drugs known to cause CNS depression including buprenorphine, butorphanol, dronabinol, THC, nabilone, nalbuphine, and anxiolytics, sedatives, and hypnotics. Use these drugs cautiously with MAOIs; warn patients to not drive or perform other hazardous activities until they know how a particular drug combination affects them. In some cases, the dosages of the CNS depressants may need to be reduced.
    Remifentanil: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Benzodiazepine doses may need to be reduced up to 75% during coadministration with remifentanil. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Ribociclib: (Moderate) Use caution if coadministration of ribociclib with alprazolam is necessary, as the systemic exposure of alprazolam may be increased resulting in an increase in alprazolam-related adverse reactions; adjust the dose of alprazolam if necessary. Ribociclib is a moderate CYP3A4 inhibitor and alprazolam is a CYP3A4 substrate.
    Ribociclib; Letrozole: (Moderate) Use caution if coadministration of ribociclib with alprazolam is necessary, as the systemic exposure of alprazolam may be increased resulting in an increase in alprazolam-related adverse reactions; adjust the dose of alprazolam if necessary. Ribociclib is a moderate CYP3A4 inhibitor and alprazolam is a CYP3A4 substrate.
    Rifabutin: (Moderate) Rifabutin could induce the CYP3A4-mediated metabolism of oxidized benzodiazepines, such as alprazolam.
    Rifampin: (Moderate) Rifampin is a potent inducer of the cytochrome P-450 hepatic enzyme system. Rifampin could induce the CYP3A4-mediated metabolism of oxidized benzodiazepines, such as alprazolam.
    Rifapentine: (Moderate) Rifapentine could induce the CYP3A4-mediated metabolism of oxidized benzodiazepines, such as alprazolam.
    Risperidone: (Moderate) Due to the primary CNS effects of risperidone, caution should be used when risperidone is given in combination with other centrally acting medications including anxiolytics, sedatives, and hypnotics.
    Ritonavir: (Major) Coadministration of alprazolam and ritonavir or lopinavir; ritonavir is not recommended. If coadministration cannot be avoided, a dosage reduction of alprazolam should be considered. Lopinavir and ritonavir are potent CYP3A4 inhibitors. The initial step in alprazolam metabolism is hydroxylation catalyzed by cytochrome CYP3A. Drugs that inhibit this metabolic pathway may profoundly decrease alprazolam clearance, resulting in increased potential for serious alprazolam-related adverse events, such as respiratory depression and prolonged sedation. Consequently, alprazolam should be avoided in patients receiving very potent inhibitors of CYP3A isoenzymes.
    Rocuronium: (Moderate) Concurrent use of benzodiazepines and other CNS active medications including neuromuscular blockers, can potentiate the CNS effects of either agent. Lower doses of one or both agents may be required. The severity of this interaction may be increased when additional CNS depressants are given.
    Ropinirole: (Moderate) Concomitant use of ropinirole with other CNS depressants, such as alprazolam, can potentiate the sedation effects of ropinirole.
    Rotigotine: (Major) Concomitant use of rotigotine with other CNS depressants, such as benzodiazepines, can potentiate the sedative effects of rotigotine.
    Rufinamide: (Minor) Rufinamide is not metabolized through hepatic CYP isozymes; however, it is a weak inducer of CYP3A4. In theory, decreased exposure of drugs that are extensively metabolized by CYP3A4, such as alprazolam, may occur during concurrent use with rufinamide.
    Safinamide: (Moderate) Dopaminergic medications, including safinamide, may cause a sudden onset of somnolence which sometimes has resulted in motor vehicle accidents. Patients may not perceive warning signs, such as excessive drowsiness, or they may report feeling alert immediately prior to the event. Because of possible additive effects, advise patients about the potential for increased somnolence during concurrent use of safinamide with other sedating medications, such as benzodiazepines.
    Saquinavir: (Major) Coadministration of alprazolam and saquinavir boosted with ritonavir is not recommended. If coadministration cannot be avoided, a dosage reduction of alprazolam should be considered. Saquinavir boosted with ritonavir is a potent CYP3A4 inhibitor. The initial step in alprazolam metabolism is hydroxylation catalyzed by cytochrome CYP3A. Drugs that inhibit this metabolic pathway may profoundly decrease alprazolam clearance, resulting in increased potential for serious alprazolam-related adverse events, such as respiratory depression and prolonged sedation. Consequently, alprazolam should be avoided in patients receiving very potent inhibitors of CYP3A isoenzymes.
    Scopolamine: (Moderate) Scopolamine may cause dizziness and drowsiness. Concurrent use of scopolamine and CNS depressants can adversely increase the risk of CNS depression.
    Secobarbital: (Major) Additive CNS depression may occur with concomitant use of benzodiazepines and barbiturates. Barbiturates may also induce the metabolism of some benzodiazepines. Monitor for alterations in response to therapy.
    Sedating H1-blockers: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Sertraline: (Minor) The manufacturer of alprazolam states that in vitro studies suggest sertraline may inhibit the metabolism of alprazolam via inhibition of CYP3A4. The potential for clinical interaction is uncertain. Be alert for any change in psychomotor performance or other benzodiazepine-related side effects when sertraline is combined with alprazolam.
    Sevoflurane: (Moderate) Concomitant administration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent.
    Simeprevir: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of alprazolam, which is a CYP3A4 substrate. Monitor patients for adverse effects of alprazolam, such as sedation.
    Sincalide: (Moderate) Sincalide-induced gallbladder ejection fraction may be affected by benzodiazepines. False study results are possible in patients with drug-induced hyper- or hypo-responsiveness; thorough patient history is important in the interpretation of procedure results.
    Skeletal Muscle Relaxants: (Moderate) Concomitant use of skeletal muscle relaxants with benzodiazepines can result in additive CNS depression. The severity of this interaction may be increased when additional CNS depressants are given.
    Sodium Oxybate: (Severe) Sodium oxybate should not be used in combination with CNS depressant anxiolytics, sedatives, and hypnotics or other sedative CNS depressant drugs. Specifically, sodium oxybate use is contraindicated in patients being treated with sedative hypnotic drugs. Sodium oxybate (GHB) has the potential to impair cognitive and motor skills. For example, the concomitant use of barbiturates and benzodiazepines increases sleep duration and may contribute to rapid onset, pronounced CNS depression, respiratory depression, or coma when combined with sodium oxybate.
    St. John's Wort, Hypericum perforatum: (Major) St. John's Wort may induce the hepatic CYP3A4 metabolism of alprazolam which is metabolized by oxidation. It would be prudent to avoid coadministration of St. John's Wort with alprazolam. Benzodiazepines that are not metabolized by CYP3A4 such as oxazepam or lorazepam may be alternatives if a benzodiazepine is required in combination with St. John's Wort.
    Streptogramins: (Major) Coadministration of alprazolam and dalfopristin; quinupristin is not recommended. If coadministration cannot be avoided, a dosage reduction of alprazolam should be considered. Dalfopristin; quinupristin is a potent CYP3A4 inhibitor. The initial step in alprazolam metabolism is hydroxylation catalyzed by cytochrome CYP3A. Drugs that inhibit this metabolic pathway may profoundly decrease alprazolam clearance, resulting in increased potential for serious alprazolam-related adverse events, such as respiratory depression and prolonged sedation. Consequently, alprazolam should be avoided in patients receiving very potent inhibitors of CYP3A isoenzymes.
    Succinimides: (Moderate) Concomitant administration of alprazolam with CNS-depressant drugs, including anticonvulsants, can potentiate the CNS effects of either agent.
    Succinylcholine: (Moderate) Concurrent use of benzodiazepines and other CNS active medications including neuromuscular blockers, can potentiate the CNS effects of either agent. Lower doses of one or both agents may be required. The severity of this interaction may be increased when additional CNS depressants are given.
    Sufentanil: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Suvorexant: (Moderate) CNS depressant drugs may have cumulative effects when administered concurrently and they should be used cautiously with suvorexant. A reduction in dose of the CNS depressant may be needed in some cases. These agents include the benzodiazepines.
    Tapentadol: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If tapentadol is initiated in a patient taking a benzodiazepine, a reduced initial dosage of tapentadol is recommended. If the extended-release tapentadol tablets are used concurrently with a benzodiazepine, use an initial tapentadol dose of 50 mg PO every 12 hours. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Tasimelteon: (Moderate) Concomitant administration of alprazolam with CNS-depressant drugs can potentiate the CNS effects of either agent.
    Teduglutide: (Moderate) Teduglutide may increase absorption of benzodiazepines or other psychotropic agents because of it's pharmacodynamic effect of improving intestinal absorption. In studies with teduglutide, one of the subjects was receiving concomitant treatment with prazepam and experienced dramatic deterioration in mental status progressing to coma during her first week of teduglutide therapy. Upon admission to the ICU, her benzodiazepine level was reported as >300 mcg/L. Both drugs were discontinued, and the coma resolved 5 days later. Careful monitoring and possible dose adjustment of the psychotropic agent is recommended.
    Telaprevir: (Moderate) Close clinical monitoring is advised when administering alprazolam with telaprevir due to an increased potential for serious alprazolam-related adverse events. If alprazolam dose adjustments are made, re-adjust the dose upon completion of telaprevir treatment. Predictions about the interaction can be made based on the metabolic pathway of alprazolam. Alprazolam is metabolized by the hepatic isoenzyme CYP3A4; telaprevir inhibits this isoenzyme. Coadministration may result in elevated alprazolam plasma concentrations.
    Telithromycin: (Major) Coadministration of alprazolam and telithromycin is not recommended. If coadministration cannot be avoided, a dosage reduction of alprazolam should be considered. Telithromycin is a potent CYP3A4 inhibitor. The initial step in alprazolam metabolism is hydroxylation catalyzed by cytochrome CYP3A. Drugs that inhibit this metabolic pathway may profoundly decrease alprazolam clearance, resulting in increased potential for serious alprazolam-related adverse events, such as respiratory depression and prolonged sedation. Consequently, alprazolam should be avoided in patients receiving very potent inhibitors of CYP3A isoenzymes.
    Telotristat Ethyl: (Moderate) Use caution if coadministration of telotristat ethyl and alprazolam is necessary, as the systemic exposure of alprazolam may be decreased resulting in reduced efficacy. If these drugs are used together, monitor patients for suboptimal efficacy of alprazolam; consider increasing the dose of alprazolam if necessary. Alprazolam is a CYP3A4 substrate. The mean Cmax and AUC of another sensitive CYP3A4 substrate was decreased by 25% and 48%, respectively, when coadministered with telotristat ethyl; the mechanism of this interaction appears to be that telotristat ethyl increases the glucuronidation of the CYP3A4 substrate.
    Temazepam: (Moderate) Concomitant administration of alprazolam with CNS-depressant drugs can potentiate the CNS effects of either agent.
    Tetrabenazine: (Moderate) Concurrent use of tetrabenazine and drugs that can cause CNS depression, such as benzodiazepines, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension.
    Thalidomide: (Major) The use of benzodiazepine anxiolytics, sedatives, or hypnotics with thalidomide may cause an additive sedative effect and should be avoided. Thalidomide frequently causes drowsiness and somnolence. Dose reductions may be required. Patients should be instructed to avoid situations where drowsiness may be a problem and not to take other medications that may cause drowsiness without adequate medical advice. Advise patients as to the possible impairment of mental and/or physical abilities required for the performance of hazardous tasks, such as driving a car or operating other complex or dangerous machinery.
    Theophylline, Aminophylline: (Moderate) Aminophylline has been reported to counteract the pharmacodynamic effects of diazepam. A proposed mechanism is competitive binding of aminophylline to adenosine receptors in the brain. Whether a similar interaction occurs with other benzodiazepines is not known. If aminophylline therapy is initiated or discontinued, monitor the clinical response to benzodiazepines. (Moderate) Theophylline has been reported to counteract the pharmacodynamic 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.
    Thiopental: (Major) Additive CNS depression may occur with concomitant use of benzodiazepines and barbiturates. Barbiturates may also induce the metabolism of some benzodiazepines. Monitor for alterations in response to therapy.
    Thiothixene: (Moderate) Thiothixene can potentiate the CNS-depressant action of other drugs such as benzodiazepines. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension.
    Tiagabine: (Moderate) Because of the possible additive effects of drugs that depress the central nervous system, benzodiazepines should be used with caution in patients receiving tiagabine.
    Tipranavir: (Major) Coadministration of alprazolam and tipranavir is not recommended. If coadministration cannot be avoided, a dosage reduction of alprazolam should be considered. Tipranavir is a potent CYP3A4 inhibitor. The initial step in alprazolam metabolism is hydroxylation catalyzed by cytochrome CYP3A. Drugs that inhibit this metabolic pathway may profoundly decrease alprazolam clearance, resulting in increased potential for serious alprazolam-related adverse events, such as respiratory depression and prolonged sedation. Consequently, alprazolam should be avoided in patients receiving very potent inhibitors of CYP3A isoenzymes.
    Tizanidine: (Moderate) Concurrent use of tizanidine and CNS depressants like the benzodiazepines can cause additive CNS depression. The severity of this interaction may be increased when additional CNS depressants are given.
    Tobacco: (Moderate) The clinical significance of the pharmacokinetic effect of tobacco smoking on alprazolam clearance is unclear. According to the manufacturer, alprazolam concentrations may be reduced by up to 50% in tobacco smokers vs. non-smokers. In one small study (n = 10), the mean half-life of alprazolam was significantly (p < 0.01) shorter in smokers ( > 10 cigarettes/day) than nonsmokers. No significant differences between groups were found in the Cmax or AUC. A bioavailability study (n = 17) evaluating the immediate-release and controlled-release formulations of alprazolam found that cigarette smokers had a 100% increase in clearance of alprazolam compared with nonsmokers. Polycyclic aromatic hydrocarbons (PAHs) found in tobacco smoke are potent inducers of CYP1A1, CYP1A2, and possibly CYP2E1. Because alprazolam is a primary substrate of CYP3A4, further evaluation of this potential interaction is needed in order to determine its clinical impact to patients.
    Topiramate: (Moderate) Topiramate has the potential to cause CNS depression as well as other cognitive and/or neuropsychiatric adverse reactions. The CNS depressant effects of topiramate can be potentiated pharmacodynamically by concurrent use of CNS depressant agents such as the benzodiazepines. Concurrent use of topiramate and benzodiazepines associated with thrombocytopenia (e.g., clonazepam, lorazepam, and clobazam), may also increase the risk of bleeding; monitor patients appropriately during benzodiazepine therapy.
    Tramadol: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Trandolapril; Verapamil: (Moderate) Consider a reduced dose of alprazolam is concurrent use of verapamil is necessary. Coadministration of alprazolam, a CYP3A4 substrate, with verapamil, a moderate CYP3A4 inhibitor, may result in increased alprazolam exposure.
    Trazodone: (Moderate) CNS depressants should be used cautiously in patients receiving trazodone because of additive CNS-depressant effects, including possible respiratory depression or hypotension. A dose reduction of one or both drugs may be warranted.
    Triazolam: (Moderate) Concomitant administration of alprazolam with CNS-depressant drugs can potentiate the CNS effects of either agent.
    Tricyclic antidepressants: (Moderate) Concomitant administration of benzodiazepines with CNS-depressant drugs, such as tricyclic antidepressants, can potentiate the CNS effects of either agent. Tricyclic antidepressants may also lower the seizure threshold leading to pharmacodynamic interactions with anticonvulsant benzodiazepines (i.e., clobazam, clonazepam, diazepam, and lorazepam). The plasma concentrations of imipramine and desipramine may increase an average of 31% and 20%, respectively, when administered concurrently with alprazolam. The significance of this interaction has not been described; therefore, patients should be monitored closely for symptoms of tricyclic toxicity during coadministration of these agents with alprazolam.
    Trihexyphenidyl: (Moderate) CNS depressants, such as anxiolytics, sedatives, and hypnotics, can increase the sedative effects of trihexyphenidyl.
    Trimethobenzamide: (Moderate) The concurrent use of trimethobenzamide with other medications that cause CNS depression, like the benzodiazepines, may potentiate the effects of either trimethobenzamide or the benzodiazepine.
    Triprolidine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
    Tubocurarine: (Moderate) Concurrent use of benzodiazepines and other CNS active medications including neuromuscular blockers, can potentiate the CNS effects of either agent. Lower doses of one or both agents may be required. The severity of this interaction may be increased when additional CNS depressants are given.
    Valerian, Valeriana officinalis: (Major) Any substances that act on the CNS, including psychoactive drugs and drugs used as anesthetic adjuvants (e.g., barbiturates, benzodiazepines), may theoretically interact with valerian, Valeriana officinalis. The valerian derivative, dihydrovaltrate, binds at barbiturate binding sites; valerenic acid has been shown to inhibit enzyme-induced breakdown of GABA in the brain; the non-volatile monoterpenes (valepotriates) have sedative activity. These interactions are probably pharmacodynamic in nature. There is a possibility of interaction with valerian at normal prescription dosages of anxiolytics, sedatives, and hypnotics (including barbiturates and benzodiazepines). Patients who are taking barbiturates or other sedative/hypnotic drugs should avoid concomitant administration of valerian. Patients taking medications such as tricyclic antidepressants, lithium, MAOIs, skeletal muscle relaxants, SSRIs and serotonin norepinephrine reuptake inhibitors (e.g., duloxetine, venlafaxine) should discuss the use of herbal supplements with their health care professional prior to consuming valerian; combinations should be approached with caution in the absence of clinical data. Patients should not abruptly stop taking their prescribed psychoactive medications.
    Valproic Acid, Divalproex Sodium: (Moderate) Concomitant administration of alprazolam with CNS-depressant drugs, including anticonvulsants, can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent.
    Vecuronium: (Moderate) Concurrent use of benzodiazepines and other CNS active medications including neuromuscular blockers, can potentiate the CNS effects of either agent. Lower doses of one or both agents may be required. The severity of this interaction may be increased when additional CNS depressants are given.
    Verapamil: (Moderate) Consider a reduced dose of alprazolam is concurrent use of verapamil is necessary. Coadministration of alprazolam, a CYP3A4 substrate, with verapamil, a moderate CYP3A4 inhibitor, may result in increased alprazolam exposure.
    Vigabatrin: (Moderate) Vigabatrin may cause somnolence and fatigue. Drugs that can cause CNS depression, if used concomitantly with vigabatrin, may increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness. Caution should be used when vigabatrin is given in combination with benzodiazepines.
    Vilazodone: (Moderate) Due to the CNS effects of vilazodone, caution should be used when vilazodone is given in combination with other centrally acting medications such as the benzodiazepines.
    Voriconazole: (Severe) Coadministration of voriconazole and alprazolam is contraindicated. Voriconazole is a strong CYP3A4 inhibitor and significantly impairs the CYP3A4 metabolism of alprazolam, resulting in elevated alprazolam concentrations. Lorazepam, oxazepam, or temazepam may be safer alternatives if a benzodiazepine must be administered in combination with voriconazole, as these benzodiazepines are not oxidatively metabolized.
    Zafirlukast: (Moderate) Alprazolam is metabolized by cytochrome CYP3A. Zafirlukast inhibits CYP3A isoenzymes to a significant but lesser degree, and use with alprazolam should be done with caution and consider alprazolam dose reduction up to 50%.
    Zaleplon: (Moderate) In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. Other drugs that may have additive CNS effects with zaleplon but have not been studied include benzodiazepines. If used together, a reduction in the dose of one or both drugs may be needed.
    Zileuton: (Moderate) Zileuton may inhbit the CYP3A isoenzymes and reduce the metabolism of alprazolam, potentially increasing the risk for benzodiazepine toxicity. Consider alprazolam dose reduction of up to 50%. Monitor for an increase in CNS and/or respiratory depression.
    Ziprasidone: (Moderate) Ziprasidone has the potential to impair cognitive and motor skills. Additive CNS depressant effects are possible when ziprasidone is used concurrently with any CNS depressant.
    Zolpidem: (Moderate) Concomitant administration of benzodiazepines with zolpidem can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. If used together, a reduction in the dose of one or both drugs may be needed. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. Concurrent use of zolpidem with other sedative-hypnotics, including other zolpidem products, at bedtime or the middle of the night is not recommended. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone.
    Zonisamide: (Moderate) Concomitant administration of alprazolam with CNS-depressant drugs, including anticonvulsants, can potentiate the CNS effects of either agent.

    PREGNANCY AND LACTATION

    Pregnancy

    Many benzodiazepines distribute into breast milk. Because of the potential for adverse effects in the nursing infant, such as sedation, feeding difficulties, and weight loss, alprazolam generally is not recommended during breast-feeding. The estimated dose that a breast-feeding infant would receive based on breat milk concentrations after single oral doses of 0.5 mg has been reported to be 0.5—5 mcg/kg/day or approximately 3% of the maternal weight-adjusted dose. Irritability and withdrawal symptoms have been reported in babies exposed to alprazolam through breast milk upon discontinuation of either breast-feeing or alprazolam. Alprazolam is listed by the American Academy of Pediatrics as a drug whose effect on the nursing infant is not known but may be of concern, particularly with prolonged exposure. If occasional maternal therapy with a benzodiazepine is required, a shorter-acting agent such as lorazepam may be considered. Some experts have concluded that occasional maternal treatment with usual doses of lorazepam would pose little risk to a nursing infant. If any benzodiazepine is used by a breast-feeding mother, monitor the infant for adverse effects, such as sedation. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding baby experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    Benzodiazepines act at the level of the limbic, thalamic, and hypothalamic regions of the CNS and can produce any level of CNS depression required including sedation, hypnosis, skeletal muscle relaxation, and anticonvulsant activity. Recent evidence indicates that benzodiazepines exert their effects through enhancement of the gamma-aminobutyric acid (GABA)-benzodiazepine receptor complex. GABA is an inhibitory neurotransmitter that exerts its effects at specific receptor subtypes designated GABA-A and GABA-B. GABA-A is the primary receptor subtype in the CNS and is thought to be involved in the actions of anxiolytics and sedatives.
     
    Specific benzodiazepine receptor subtypes are thought to be coupled to GABA-A receptors. Three types of BNZ receptors are located in the CNS and other tissues; the BNZ-1 receptors are located in the cerebellum and cerebral cortex, the BNZ-2 receptors in the cerebral cortex and spinal cord, and the BNZ-3 receptors in peripheral tissues. Activation of the BNZ-1 receptor is thought to mediate sleep while the BNZ-2 receptor affects muscle relaxation, anticonvulsant activity, motor coordination, and memory. Benzodiazepines bind nonspecifically to BNZ-1 and BNZ-2 which ultimately enhances the effects of GABA. Unlike barbiturates which augment GABA responses by increasing the length of time that chloride channels are open, benzodiazepines enhance the effects of GABA by increasing GABA affinity for the GABA receptor. Binding of GABA to the site opens the chloride channel resulting in a hyperpolarized cell membrane that prevents further excitation of the cell.
     
    Benzodiazepines alleviate insomnia by decreasing the latency to sleep and increasing sleep continuity and total sleep time through their effects on GABA. Preliminary evidence suggests that alprazolam decreases cerebral blood flow and plasma epinephrine concentrations.

    PHARMACOKINETICS

    Alprazolam is administered orally.
     
    Alprazolam is widely distributed and is 90% plasma protein-bound, primarily to serum albumin. Alprazolam may cross the placenta and distributes into breast milk (see Contraindications). Alprazolam undergoes oxidative metabolism in the liver through CYP3A4, producing metabolites with little or no activity. The alpha-hydroxy-alprazolam metabolite is approximately one half as potent as the parent compound while the benzophenone derivative is inactive. Both metabolites are excreted primarily in the urine. The half-life of alprazolam immediate-release tablets is 11.2 hours (range 6.3—26.9 hours). The half-life of alprazolam extended-release ranges from roughly 11 to 16 hours.

    Oral Route

    Alprazolam is rapidly absorbed following oral administration. Peak plasma concentrations are attained within 1—2 hours of administration of the immediate-release tablets. The onset of action usually occurs within 15—30 minutes. The pharmacokinetics of alprazolam extended-release tablets are similar to the immediate-release tablets, except that the extended-release tablets have a slower rate of absorption and yield a constant concentration maintained between 5 and 11 hours after dosing. Although elevations up to 25% in the Cmax have been observed when extended-release tablets were given following a high-fat meal, the AUC and T1/2 were not affected by consumption of food. Additionally, alprazolam extended-release given at night (vs. the morning) results in a 30% higher Cmax and a reduction in Tmax by 1 hour. The rate of metabolism of alprazolam extended-release is not effected by the slower rate of absorption.