Short-acting anxiolytic benzodiazepine
Alprazolam is a benzodiazepine used for short-term treatment of generalised anxiety and panic attacks. It is effective, but can cause dependence, drowsiness and impair driving — use the lowest dose for the shortest time.
Also known as: Xanax
Combining Alprazolam with Clarithromycin increases Alprazolam concentrations, with a risk of excessive sedation.
Alprazolam is metabolised by CYP3A4; clarithromycin, a potent inhibitor of this enzyme, can raise its concentrations and potentiate sedation, ataxia and the risk of respiratory depression, especially in the elderly and in patients with respiratory or liver disease. Reduce the alprazolam dose (up to 50%) during the combination, avoid it in patients with sleep apnoea or severe COPD and monitor sedation; prefer a non-interacting antibiotic (e.g. azithromycin, which has less effect) when possible.
Alprazolam + clarithromycin: clarithromycin inhibits CYP3A4 and may double alprazolam levels, with sedation and respiratory depression. Monitor and reduce the alprazolam dose.
Clarithromycin, a CYP3A4 inhibitor, reduces Alprazolam metabolism, raising its serum levels.
Watch for sedation and central nervous system depression.
Marked sedation or confusion require dose reduction and reassessment.
Consider reducing the Alprazolam dose during Clarithromycin use.
DailyMed/FDA (NIH/NLM) — approved Alprazolam label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0cf8b567-201b-44fa-8fd3-c74023aff44f ; approved Clarithromycin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d836ae7e-fdbf-4dcb-a90d-ede1dcbc3e67 — with additional reference: Prontuário Terapêutico do INFARMED, INFARMED (11th ed., 2012)
Combining Alprazolam with Ketoconazole increases Alprazolam concentrations, with a risk of excessive sedation.
Alprazolam is metabolised by CYP3A4, and ketoconazole is a potent inhibitor of this enzyme, potentially raising benzodiazepine concentrations and effects markedly (sedation, drowsiness, ataxia, respiratory depression), especially in the elderly. The ketoconazole label considers co-administration with alprazolam (like oral midazolam and triazolam) contraindicated, because the elevated concentrations can potentiate and prolong hypnotic and sedative effects. Do not combine; consider an alternative benzodiazepine or anxiolytic not metabolised by CYP3A4.
Alprazolam + ketoconazole: the azole inhibits CYP3A4 and can greatly raise alprazolam levels, with sedation and respiratory depression. Contraindicated (ketoconazole label).
Ketoconazole, a CYP3A4 inhibitor, reduces Alprazolam metabolism, raising its levels.
Marked sedation, confusion or respiratory depression require immediate intervention.
Marked sedation or respiratory depression require immediate intervention.
Reduce the Alprazolam dose or avoid the combination; monitor sedation.
DailyMed/FDA (NIH/NLM) — approved Alprazolam label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0cf8b567-201b-44fa-8fd3-c74023aff44f ; approved Ketoconazole label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f162e616-21b4-49b1-b437-15e21001a6f0 — with additional reference: Prontuário Terapêutico do INFARMED, INFARMED (11th ed., 2012)
Combining morphine with alprazolam increases the risk of profound sedation, respiratory depression, coma and death.
Morphine and alprazolam depress the central nervous system and the respiratory centre through complementary mechanisms (mu opioid receptor agonism and GABA potentiation at the GABA-A receptor). The FDA issued a boxed warning for the combination of opioids with benzodiazepines: a substantial proportion of overdose deaths involves both groups together. Whenever possible, avoid co-administration; if clinically unavoidable, use the lowest effective doses for the shortest time, inform the patient and family, and monitor sedation, respiratory rate and oxygen saturation. Naloxone should be available when the opioid is used at a relevant dose.
Benzodiazepine + opioid: additive CNS and respiratory depression, with risk of deep sedation, coma and death. Avoid the combination; if unavoidable, use the lowest effective doses and monitor sedation and breathing closely.
Additive effect of opioids and benzodiazepines on central nervous system and respiratory depression.
Respiratory rate, oxygen saturation, level of sedation and pupillary response.
Respiratory depression (rate < 10/min), deep sedation or coma require urgent assessment and reversal with naloxone.
Avoid the combination whenever possible; if unavoidable, use the lowest effective doses and monitor closely.
DailyMed/FDA (NIH/NLM) — approved Morphine label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=57ee014e-744e-65e1-e063-6394a90a8c93 ; approved Alprazolam label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0cf8b567-201b-44fa-8fd3-c74023aff44f — with additional reference: Prontuário Terapêutico do INFARMED (11th ed., 2012)
Codeine with alprazolam increases the risk of sedation, respiratory depression and death; codeine is contraindicated in children.
Codeine is converted to morphine by CYP2D6 and, together with alprazolam, the two drugs add their central nervous system and respiratory depressant effects, with risk of deep sedation, coma and death — the same FDA boxed warning that applies to all opioids with benzodiazepines. In ultrarapid CYP2D6 metabolisers, conversion to morphine is exaggerated and the risk is even higher; codeine is therefore contraindicated in children and should be avoided during breastfeeding. Management is the same as for other opioids: avoid the combination whenever possible, and if unavoidable, minimal doses, short duration and monitoring of sedation, respiratory rate and oxygen saturation.
Benzodiazepine + opioid: additive CNS and respiratory depression. Codeine is a prodrug of morphine (CYP2D6) and is contraindicated in children. Avoid; if unavoidable, lowest doses and close monitoring.
Additive CNS depression; codeine is metabolised to morphine by CYP2D6 and the central depression adds to the benzodiazepine.
Respiratory pattern, sedation, pupils and signs of opioid toxicity.
Deep sedation, bradypnoea or hypoxia require urgent reversal (naloxone).
Avoid the combination; if required, use minimum doses and monitor the patient closely.
DailyMed/FDA (NIH/NLM) — approved Codeine label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=4c966d73-77c6-4514-954e-57aa06a080c6 ; approved Alprazolam label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0cf8b567-201b-44fa-8fd3-c74023aff44f — with additional reference: Prontuário Terapêutico do INFARMED (11th ed., 2012)
Hydromorphone with alprazolam potentiates CNS and respiratory depression and may be fatal.
Hydromorphone is a potent opioid (mu agonist) and alprazolam a benzodiazepine: their central nervous system and respiratory centre depressant effects add up, and the risk of deep sedation, coma and death from respiratory depression is substantial — the reason for the FDA boxed warning for opioids with benzodiazepines. The combination should be avoided whenever possible; if clinically indispensable, use the lowest effective doses, limit the duration, inform the patient and family, and monitor sedation, respiratory rate and oxygen saturation, with naloxone available.
Benzodiazepine + opioid: additive CNS and respiratory depression, with risk of deep sedation, coma and death. Avoid; if unavoidable, lowest doses and close monitoring of breathing.
Additive opioid-benzodiazepine action on respiratory and CNS depression.
Respiratory rate, SpO2, sedation and pupil size.
Bradypnoea or unresponsiveness require naloxone and ventilatory support.
Avoid coadministration; if unavoidable, reduce doses and ensure supervision.
DailyMed/FDA (NIH/NLM) — approved Hydromorphone label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=4c5c1cc8-c42b-46e3-ad68-8e22f57101f2 ; approved Alprazolam label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0cf8b567-201b-44fa-8fd3-c74023aff44f — with additional reference: Prontuário Terapêutico do INFARMED (11th ed., 2012)
Grapefruit juice inhibits CYP3A4, the enzyme that metabolises alprazolam, potentially raising its concentrations and sedative effects.
Avoid grapefruit juice during alprazolam treatment.
DailyMed/FDA (NIH/NLM) — approved Alprazolam label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0cf8b567-201b-44fa-8fd3-c74023aff44f
Alcohol potentiates the central nervous system depression caused by benzodiazepines, with a risk of excessive sedation and respiratory depression.
Avoid alcohol intake during treatment.
DailyMed/FDA (NIH/NLM) — approved Alprazolam label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0cf8b567-201b-44fa-8fd3-c74023aff44f
Benzodiazepines can depress the respiratory centre, with an increased risk in severe lung disease (COPD, sleep apnoea).
Use with caution and consider lower doses in patients with respiratory disease.
DailyMed/FDA (NIH/NLM) — approved Alprazolam label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0cf8b567-201b-44fa-8fd3-c74023aff44f
Alprazolam is metabolised in the liver; hepatic impairment reduces its elimination and increases the risk of accumulation.
Reduce the dose and monitor sedation in patients with hepatic impairment.
DailyMed/FDA (NIH/NLM) — approved Alprazolam label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0cf8b567-201b-44fa-8fd3-c74023aff44f
Benzodiazepines cross the placenta; first-trimester use is associated with malformations and third-trimester use with neonatal sedation and withdrawal syndrome.
Avoid in the first trimester; use only if the benefit clearly outweighs the risk in the 2nd/3rd.
Present in breast milk; avoid breastfeeding or the drug.
No specific contraception required; the decision should be individualised.
DailyMed/FDA (NIH/NLM) — approved Alprazolam label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0cf8b567-201b-44fa-8fd3-c74023aff44f
Clinical and educational support tool. The information does not replace a medical prescription or the opinion of a qualified healthcare professional.
Benzodiazepine (1,4-benzodiazepine). Plasma levels increase proportionally to the dose (0.5 to 3 mg). Peak plasma concentrations 1 to 2 hours after dosing; serum protein binding of 80% (mostly albumin). Half-life is prolonged in the elderly, obese and patients with liver disease.
It exerts its anxiolytic and antipanic effect by binding to the benzodiazepine site of GABA-A receptors in the brain, potentiating GABA-mediated synaptic inhibition.
Peak plasma concentrations 1 to 2 hours after oral administration; levels proportional to the dose over the range of 0.5 to 3 mg. Concentrations may be reduced by up to 50% in smokers.
Extensively metabolised, mainly by CYP3A4, to two active metabolites (4-hydroxyalprazolam and α-hydroxyalprazolam), which circulate at concentrations below 4% of the parent compound; the low concentrations and potencies indicate a reduced contribution to the effect. Excretion mainly urinary. CYP3A4 inhibitors (ketoconazole, itraconazole, nefazodone, fluvoxamine, erythromycin) increase AUC.
Mean plasma half-life of about 11.2 hours (6.3 to 26.9) in healthy adults; 16.3 hours in the elderly; 21.8 hours in obese patients; 19.7 hours in patients with alcoholic liver disease. CYP3A4 inducers (e.g. carbamazepine) shorten the half-life.
Medicines from the same therapeutic group (ATC classification) or the same pharmacological class.
