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. 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 P 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. This list is not inclusive of all agents that may potently inhibit CYP3A4.
Reduced elimination of alprazolam has also been reported in obesity. 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. The mean half-life of alprazolam is prolonged to 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: 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.
Specific criteria for anxiolytics must be met, including 1 limiting use to indications specified in the OBRA guidelines e. 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. 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. 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.
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. Additionally, the oral clearance of alprazolam 0. Alprazolam is a CYP3A4 substrate. Barbiturates are CYP3A4 inducers. Acetaminophen; Butalbital; Caffeine; 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; Caffeine; Magnesium Salicylate; Phenyltoloxamine: Moderate Coadministration can potentiate the CNS effects e. Use caution with this combination. Acetaminophen; Caffeine; Phenyltoloxamine; Salicylamide: Acetaminophen; Chlorpheniramine; 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; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: Acetaminophen; Chlorpheniramine; Phenylephrine; Phenyltoloxamine: Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: Moderate The CNS depressant effects of dichloralphenazone can be potentiated by benzodiazepines.
Avoid opiate cough medications in patients taking benzodiazepines. 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.
The dose of any opiate agonist administered with parenteral diazepam should be reduced by at least one-third. Moderate Concomitant administration of alprazolam with CNS-depressant drugs, including anticonvulsants, can potentiate the CNS effects of either agent. Therefore, psychotropic pharmacodynamic interactions could occur following concomitant administration of drugs with significant CNS activity. 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. There have been some case reports describing an interaction between omeprazole and benzodiazepines metabolized via the cytochrome P 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. 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.
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. Moderate Monitor for withdrawal symptoms or lack of alprazolam efficacy if coadministration with apalutamide is necessary. Moderate Apomorphine causes significant somnolence. Concomitant administration of apomorphine and CNS depressants could result in additive depressant effects.
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. 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. Consider selection of an agent that is not metabolized via CYP3A4 isoenzymes e. As a single mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions.
However, as a single mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant mg IV as a single dose increased the AUC of midazolam given on days 1 and 4 by approximately 1. Less than a 2-fold increase in the midazolam AUC is not considered clinically important. 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. 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.
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. 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; Hyoscyamine; Phenobarbital; Scopolamine: Moderate Scopolamine may cause dizziness and drowsiness. Belladonna Alkaloids; Ergotamine; Phenobarbital: Moderate CNS depressants, such as anxiolytics, sedatives, and hypnotics, can increase the sedative effects of benztropine.
Major Coadministration of alprazolam and boceprevir is not recommended. Boceprevir is a potent CYP3A4 inhibitor. Moderate Bosentan is an inducer of cytochrome P enzymes, specifically the CYP2C9 and CYP3A4 isoenzymes, and may decrease concentrations of drugs metabolized by these enzymes, including alprazolam. 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.
Moderate Monitor for decreased efficacy of alprazolam if coadministration with brigatinib is necessary. 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. 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.
In patients treated with buprenorphine for opioid use disorder, cessation of benzodiazepines or other CNS depressants is preferred in most cases. Consider alternatives to benzodiazepines for conditions such as anxiety or insomnia in patients receiving buprenorphine maintenance treatment. 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. 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.
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. 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. Major Coadministration of alprazolam and chloramphenicol is not recommended.
Chloramphenicol is a potent CYP3A4 inhibitor. Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: Moderate Coadministration of alprazolam should be avoided with potent CYP3A4 inhibitors such as cimetidine. 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.
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. Major Concomitant administration of clobazam with other CNS depressant drugs including anxiolytics, sedatives, and hypnotics, can potentiate the CNS effects i.
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. 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.
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; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: 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.
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. 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.
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. Other drugs that may theoretically inhibit CYP3A4 metabolism of alprazolam include cyclosporine. Major Coadministration of alprazolam and dalfopristin; quinupristin is not recommended. Dalfopristin; quinupristin is a potent CYP3A4 inhibitor. Major Coadministration of alprazolam and darunavir is not recommended.
Darunavir is a potent CYP3A4 inhibitor. Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: Major Coadministration of alprazolam and ritonavir or lopinavir; ritonavir is not recommended. Lopinavir and ritonavir are potent CYP3A4 inhibitors. Severe According to the manufacturer of delavirdine, coadministration of alprazolam and delavirdine is contraindicated. Delavirdine is a potent CYP3A4 inhibitor.
Moderate Concurrent use with benzodiazepines can decrease the minimum alveolar concentration MAC of desflurane needed to produce anesthesia. 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. Moderate Co-administration of dexmedetomidine with benzodiazepines is likely to lead to an enhancement of CNS depression.
Moderate Dicyclomine can cause drowsiness, so it should be used cautiously in patients receiving CNS depressants like benzodiazepines. Moderate Digoxin toxicity may occur in patients receiving alprazolam and digoxin. Patients receiving alprazolam or diazepam and digoxin concurrently should be monitored for increased serum digoxin levels.
Moderate Consider a reduced dose of alprazolam is concurrent use of diltiazem is necessary. 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. Moderate Use caution if the use of benzodiazepines are necessary with dronabinol, and monitor for additive dizziness, confusion, somnolence, and other CNS effects.
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. Major Droperidol administration is associated with an established risk for QT prolongation and torsades de pointes. In December , 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. 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: 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; Lamivudine; Tenofovir Disoproxil Fumarate: Moderate Administering alprazolam with elbasvir; grazoprevir may result in elevated alprazolam plasma concentrations. If these drugs are used together, closely monitor for signs of adverse events. Moderate Concomitant administration can potentiate the CNS effects e.
Major Monitor for withdrawal symptoms or lack of alprazolam efficacy if coadministration with enzalutamide is necessary. 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. Moderate Concomitant administration of alprazolam with CNS-depressant drugs, including anticonvulsants, can potentiate the CNS effects e.
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. Moderate Concomitant administration of benzodiazepines with eszopiclone can potentiate the CNS effects e.
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. 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; Ethynodiol Diacetate: Ethinyl Estradiol; Norethindrone Acetate: Ethinyl Estradiol; Norethindrone Acetate; Ferrous fumarate: Ethinyl Estradiol; Norethindrone; Ferrous fumarate: Moderate Drugs that inhibit the CYP3A metabolic pathway, such as fluconazole, may profoundly decrease alprazolam clearance.
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. 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.
Monitor patients closely for excessive alprazolam-related side effects. 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.
A reduction in alprazolam dose may be needed in some patients. 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. Major Coadministration of alprazolam and fosamprenavir is not recommended. Fosamprenavir is a potent CYP3A4 inhibitor. 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. 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.
Moderate Guanabenz is associated with sedative effects. Guanabenz can potentiate the effects of CNS depressants such as benzodiazepines, when administered concomitantly. Moderate Guanfacine has been associated with sedative effects and can potentiate the actions of other CNS depressants including benzodiazepines. 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.
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. 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. 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; Potassium Guaiacolsulfonate; Pseudoephedrine: Major Coadministration of alprazolam and idelalisib is not recommended. Idealalisib is a potent CYP3A4 inhibitor. 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. 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. 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. 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 hepatic enzyme system. Rifampin could induce the CYP3A4-mediated metabolism of oxidized benzodiazepines, such as alprazolam. 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. 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. Moderate Use caution when administering ivacaftor and alprazolam concurrently because patients are at increased risk for adverse effects from alprazolam.
Co-administration of ivacaftor with midazolam, another CYP3A substrate, increased midazolam exposure by 1. 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.
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. 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.
Moderate A clinically relevant increase in the plasma concentration of alprazolam may occur if given with letermovir. Coadministration is not recommended if the patient is also receiving cyclosporine, because the magnitude of the interaction may be increased. If coadministration of all 3 drugs cannot be avoided, a dosage reduction of alprazolam should be considered.
Alprazolam is primarily metabolized by CYP3A4. Concurrent administration with other moderate to strong inhibitors increased alprazolam exposure by 1. Moderate Concomitant administration of benzodiazepines with CNS-depressant drugs, including opiate agonists, can potentiate the CNS effects of either agent. 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. 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.
Major Concomitant use of lomitapide and alprazolam may significantly increase the serum concentration of lomitapide. Major Coadministration of alprazolam and lopinavir; ritonavir is not recommended. 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.
Moderate Concomitant administration of alprazolam with CNS-depressant drugs, including antipsychotics, can potentiate the CNS effects of either agent. 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.
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. 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. 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. 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. Moderate Concomitant administration of benzodiazepines with meprobamate can potentiate the CNS effects e. Major Concurrent use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. If concurrent use is necessary, use the lowest effective dose and minimum duration possible.
If methadone is initiated for pain in an opioid-naive patient taking a benzodiazepine, use an initial methadone dose of 2. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial benzodiazepine dose and titrate to response. In patients treated with methadone for opioid use disorder, cessation of benzodiazepines or other CNS depressants is preferred in most cases.
Concomitant use of benzodiazepines, including alprazolam extended-release, and opioids may result in profound sedation, respiratory depression, coma, and death. Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioids alone.
If a decision is made to prescribe alprazolam extended-release concomitantly with opioids, prescribe the lowest effective dosages and minimum durations of concomitant use, and follow patients closely for signs and symptoms of respiratory depression and sedation. In patients already receiving an opioid analgesic, prescribe a lower initial dose of alprazolam extended-release than indicated in the absence of an opioid and titrate based on clinical response. If an opioid is initiated in a patient already taking alprazolam extended-release, prescribe a lower initial dose of the opioid and titrate based upon clinical response.
Advise both patients and caregivers about the risks of respiratory depression and sedation when alprazolam extended-release is used with opioids. Advise patients not to drive or operate heavy machinery until the effects of concomitant use with the opioid have been determined see Drug Interactions. Certain adverse clinical events, some life-threatening, are a direct consequence of physical dependence to alprazolam.
However, in a controlled postmarketing discontinuation study of panic disorder patients who received alprazolam tablets, the duration of treatment 3 months compared to 6 months had no effect on the ability of patients to taper to zero dose. Relapse or return of illness was defined as a return of symptoms characteristic of panic disorder primarily panic attacks to levels approximately equal to those seen at baseline before active treatment was initiated.
Rebound refers to a return of symptoms of panic disorder to a level substantially greater in frequency, or more severe in intensity than seen at baseline. Withdrawal symptoms were identified as those which were generally not characteristic of panic disorder and which occurred for the first time more frequently during discontinuation than at baseline.
The rate of relapse, rebound, and withdrawal in patients with panic disorder who received alprazolam extended-release tablets has not been systematically studied. Experience in randomized placebo-controlled discontinuation studies of patients with panic disorder who received alprazolam tablets showed a high rate of rebound and withdrawal symptoms compared to placebo treated patients. In a controlled clinical trial in which 63 patients were randomized to alprazolam tablets and where withdrawal symptoms were specifically sought, the following were identified as symptoms of withdrawal: Other symptoms, such as anxiety and insomnia, were frequently seen during discontinuation, but it could not be determined if they were due to return of illness, rebound, or withdrawal.
In a controlled postmarketing discontinuation study of panic disorder patients treated with alprazolam tablets, the duration of treatment 3 months compared to 6 months had no effect on the ability of patients to taper to zero dose. Seizures were reported for three patients in panic disorder clinical trials with alprazolam extended-release tablets. In one case, the patient abruptly discontinued alprazolam extended-release, and in both cases, alcohol intake was implicated.
All three patients recovered without sequelae. Seizures have also been observed in association with dose reduction or discontinuation of alprazolam tablets, the immediate-release form of alprazolam. Five of these cases clearly occurred during abrupt dose reduction, or discontinuation from daily doses of 2 mg to 10 mg. Three cases occurred in situations where there was not a clear relationship to abrupt dose reduction or discontinuation.
In one instance, seizure occurred after discontinuation from a single dose of 1 mg after tapering at a rate of 1 mg every three days from 6 mg daily. In two other instances, the relationship to taper is indeterminate; in both of these cases the patients had been receiving doses of 3 mg daily prior to seizure. The duration of use in the above 8 cases ranged from 4 to 22 weeks.
There have been occasional voluntary reports of patients developing seizures while apparently tapering gradually from alprazolam. The medical event voluntary reporting system shows that withdrawal seizures have been reported in association with the discontinuation of alprazolam tablets. In most cases, only a single seizure was reported; however, multiple seizures and status epilepticus were reported as well.
Early morning anxiety and emergence of anxiety symptoms between doses of alprazolam tablets have been reported in patients with panic disorder taking prescribed maintenance doses. These symptoms may reflect the development of tolerance or a time interval between doses which is longer than the duration of clinical action of the administered dose.
In either case, it is presumed that the prescribed dose is not sufficient to maintain plasma levels above those needed to prevent relapse, rebound, or withdrawal symptoms over the entire course of the interdosing interval. Withdrawal reactions may occur when dosage reduction occurs for any reason. This includes purposeful tapering, but also inadvertent reduction of dose e. Because of its CNS depressant effects, patients receiving alprazolam extended-release tablets should be cautioned against engaging in hazardous occupations or activities requiring complete mental alertness such as operating machinery or driving a motor vehicle.
For the same reason, patients should be cautioned about the simultaneous ingestion of alcohol and other CNS depressant drugs during treatment with alprazolam extended-release tablets. Benzodiazepines can potentially cause fetal harm when administered to pregnant women. If alprazolam is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.
Because of experience with other members of the benzodiazepine class, alprazolam is assumed to be capable of causing an increased risk of congenital abnormalities when administered to a pregnant woman during the first trimester. Because use of these drugs is rarely a matter of urgency, their use during the first trimester should almost always be avoided.
The possibility that a woman of childbearing potential may be pregnant at the time of institution of therapy should be considered. Patients should be advised that if they become pregnant during therapy or intend to become pregnant they should communicate with their physicians about the desirability of discontinuing the drug. Drugs that inhibit this metabolic pathway may have a profound effect on the clearance of alprazolam. Consequently, alprazolam should be avoided in patients receiving very potent inhibitors of CYP3A.
With drugs inhibiting CYP3A to a lesser but still significant degree, alprazolam should be used only with caution and consideration of appropriate dosage reduction. The coadministration of alprazolam with these agents is not recommended. Drugs demonstrated to be CYP3A inhibitors on the basis of clinical studies involving alprazolam caution and consideration of appropriate alprazolam dose reduction are recommended during coadministration with the following drugs. Nefazodone - Coadministration of nefazodone increased alprazolam concentration two-fold.
As with other psychotropic medications, the usual precautions with respect to administration of the drug and size of the prescription are indicated for severely depressed patients or those in whom there is reason to expect concealed suicidal ideation or plans. Panic disorder has been associated with primary and secondary major depressive disorders and increased reports of suicide among untreated patients. Episodes of hypomania and mania have been reported in association with the use of alprazolam tablets in patients with depression.
Alprazolam has a weak uricosuric effect. Although other medications with weak uricosuric effect have been reported to cause acute renal failure, there have been no reported instances of acute renal failure attributable to therapy with alprazolam. The usual precautions in treating patients with impaired renal, hepatic, or pulmonary function should be observed. There have been rare reports of death in patients with severe pulmonary disease shortly after the initiation of treatment with alprazolam tablets.
A decreased systemic alprazolam elimination rate e. To assure safe and effective use of alprazolam extended-release, the physician should provide the patient with the following guidance. Laboratory tests are not ordinarily required in otherwise healthy patients. However, when treatment is protracted, periodic blood counts, urinalysis, and blood chemistry analyses are advisable in keeping with good medical practice.
The concomitant use of benzodiazepines and opioids increases the risk of respiratory depression because of actions at different receptor sites in the CNS that control respiration. When benzodiazepines and opioids are combined, the potential for benzodiazepines to significantly worsen opioid-related respiratory depression exists. Limit dosage and duration of concomitant use of benzodiazepines and opioids, and monitor patients closely for respiratory depression and sedation.
If alprazolam extended-release tablets are to be combined with other psychotropic agents or anticonvulsant drugs, careful consideration should be given to the pharmacology of the agents to be employed, particularly with compounds which might potentiate the action of benzodiazepines. The benzodiazepines, including alprazolam, produce additive CNS depressant effects when coadministered with other psychotropic medications, anticonvulsants, antihistaminics, ethanol and other drugs which themselves produce CNS depression.
The clinical significance of these changes is unknown. Drugs demonstrated to be CYP3A inhibitors of possible clinical significance on the basis of clinical studies involving alprazolam caution is recommended during coadministration with alprazolam. Drugs and other substances demonstrated to be CYP3A inhibitors on the basis of clinical studies involving benzodiazepines metabolized similarly to alprazolam or on the basis of in vitro studies with alprazolam or other benzodiazepines caution is recommended during coadministration with alprazolam.
Available data from clinical studies of benzodiazepines other than alprazolam suggest a possible drug interaction with alprazolam for the following: Data from in vitro studies of alprazolam suggest a possible drug interaction with alprazolam for the following: Data from in vitro studies of benzodiazepines other than alprazolam suggest a possible drug interaction for the following: Carbamazepine can increase alprazolam metabolism and therefore can decrease plasma levels of alprazolam.
Although interactions between benzodiazepines and commonly employed clinical laboratory tests have occasionally been reported, there is no consistent pattern for a specific drug or specific test. It should be considered that the child born of a mother who is receiving benzodiazepines may be at some risk for withdrawal symptoms from the drug during the postnatal period. Also, neonatal flaccidity and respiratory problems have been reported in children born of mothers who have been receiving benzodiazepines.
Benzodiazepines are known to be excreted in human milk. It should be assumed that alprazolam is as well. Chronic administration of diazepam to nursing mothers has been reported to cause their infants to become lethargic and to lose weight. As a general rule, nursing should not be undertaken by mothers who must use alprazolam.
Safety and effectiveness of alprazolam in individuals below 18 years of age have not been established. The elderly may be more sensitive to the effects of benzodiazepines. They exhibit higher plasma alprazolam concentrations due to reduced clearance of the drug as compared with a younger population receiving the same doses. The information included in the subsection on Adverse Events Observed in Short-Term, Placebo-Controlled Trials with alprazolam extended-release tablets is based on pooled data of five 6- and 8-week placebo-controlled clinical studies in panic disorder.
Adverse event reports were elicited either by general inquiry or by checklist, and were recorded by clinical investigators using terminology of their own choosing. The stated frequencies of adverse events represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse event of the type listed. An event was considered treatment emergent if it occurred for the first time or worsened during therapy following baseline evaluation.
In the tables and tabulations that follow, standard MedDRA terminology version 4. The most common events leading to discontinuation and considered to be drug-related i. The prescriber should be aware that adverse event incidence cannot be used to predict the incidence of adverse events in the course of usual medical practice where patient characteristics and other factors differ from those which prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with event incidence obtained from other clinical investigations involving different treatments, uses, and investigators.
The cited values, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and non-drug factors to the adverse event incidence rate in the population studied. Following is a list of MedDRA terms that reflect treatment-emergent adverse events reported by patients with panic disorder treated with alprazolam extended-release. All potentially important reported events are included except those already listed in the above table or elsewhere in labeling, those events for which a drug cause was remote, those event terms that were so general as to be uninformative, and those events that occurred at rates similar to background rates in the general population.
It is important to emphasize that, although the events reported occurred during treatment with alprazolam extended-release, they were not necessarily caused by the drug. Events are further categorized by body system and listed in order of decreasing frequency according to the following definitions: Ear and Labyrinth Disorders: General Disorders and Administration Site Conditions: Musculoskeletal and Connective Tissue Disorders: Renal and Urinary Disorders: Respiratory, Thoracic, and Mediastinal Disorders: Skin and Subcutaneous Tissue Disorders: The categories of adverse events reported in the clinical development program for alprazolam tablets in the treatment of panic disorder differ somewhat from those reported for alprazolam extended-release tablets because the clinical trials with alprazolam tablets and alprazolam extended-release tablets used different standard medical nomenclature for reporting the adverse events.
Nevertheless, the types of adverse events reported in the clinical trials with alprazolam tablets were generally the same as those reported in the clinical trials with alprazolam extended-release tablets. To discontinue treatment in patients taking alprazolam extended-release tablets, the dosage should be reduced slowly in keeping with good medical practice.
It is suggested that the daily dosage of alprazolam extended-release tablets be decreased by no more than 0. Some patients may benefit from an even slower dosage reduction. In a controlled postmarketing discontinuation study of panic disorder patients which compared this recommended taper schedule with a slower taper schedule, no difference was observed between the groups in the proportion of patients who tapered to zero dose; however, the slower schedule was associated with a reduction in symptoms associated with a withdrawal syndrome.
As with all benzodiazepines, paradoxical reactions such as stimulation, increased muscle spasticity, sleep disturbances, hallucinations, and other adverse behavioral effects such as agitation, rage, irritability, and aggressive or hostile behavior have been reported rarely. Should any of the above events occur, alprazolam should be discontinued. Isolated published reports involving small numbers of patients have suggested that patients who have borderline personality disorder, a prior history of violent or aggressive behavior, or alcohol or substance abuse may be at risk for such events.
Instances of irritability, hostility, and intrusive thoughts have been reported during discontinuation of alprazolam in patients with posttraumatic stress disorder. Various adverse drug reactions have been reported in association with the use of alprazolam tablets since market introduction. The majority of these reactions were reported through the medical event voluntary reporting system.
Because of the spontaneous nature of the reporting of medical events and the lack of controls, a causal relationship to the use of alprazolam tablets cannot be readily determined. The symptoms can range from mild dysphoria and insomnia to a major syndrome that may include abdominal and muscle cramps, vomiting, sweating, tremors, and convulsions.
Distinguishing between withdrawal emergent signs and symptoms and the recurrence of illness is often difficult in patients undergoing dose reduction. The long-term strategy for treatment of these phenomena will vary with their cause and the therapeutic goal. When necessary, immediate management of withdrawal symptoms requires re-institution of treatment at doses of alprazolam sufficient to suppress symptoms. There have been reports of failure of other benzodiazepines to fully suppress these withdrawal symptoms.
These failures have been attributed to incomplete cross-tolerance but may also reflect the use of an inadequate dosing regimen of the substituted benzodiazepine or the effects of concomitant medications. While it is difficult to distinguish withdrawal and recurrence for certain patients, the time course and the nature of the symptoms may be helpful. A withdrawal syndrome typically includes the occurrence of new symptoms, tends to appear toward the end of taper or shortly after discontinuation, and will decrease with time.
In recurring panic disorder, symptoms similar to those observed before treatment may recur either early or late, and they will persist. While the severity and incidence of withdrawal phenomena appear to be related to dose and duration of treatment, withdrawal symptoms, including seizures, have been reported after only brief therapy with alprazolam at doses within the recommended range for the treatment of anxiety e.
Signs and symptoms of withdrawal are often more prominent after rapid decrease of dosage or abrupt discontinuance. Patients, especially individuals with a history of seizures or epilepsy, should not be abruptly discontinued from any CNS depressant agent, including alprazolam. Psychological dependence is a risk with all benzodiazepines, including alprazolam. Some patients have experienced considerable difficulty in tapering and discontinuing from alprazolam, especially those receiving higher doses for extended periods.