Alprazolam Contraindications
Alprazolam is absolutely contraindicated in patients with known hypersensitivity to benzodiazepines, acute narrow-angle glaucoma, and concurrent use with ketoconazole or itraconazole. 1
Absolute Contraindications
The FDA-approved labeling establishes three clear absolute contraindications 1:
Known sensitivity to alprazolam or other benzodiazepines - Any documented allergic reaction or hypersensitivity to this drug class precludes use 1
Acute narrow-angle glaucoma - The drug is strictly contraindicated in this condition, though patients with open-angle glaucoma receiving appropriate therapy may use alprazolam 1
Concurrent use with ketoconazole or itraconazole - These azole antifungals significantly impair CYP3A-mediated oxidative metabolism of alprazolam, leading to dangerous drug accumulation 1
Strong Relative Contraindications
While not absolute contraindications per FDA labeling, several clinical situations warrant extreme caution or avoidance:
History of substance abuse or dependence - Alprazolam has particularly high misuse liability among benzodiazepines due to its rapid onset and short half-life (12-15 hours), making it prone to abuse and dependence 2, 3, 4. The drug should be avoided in patients with current or recent stimulant drug abuse, though history of other substance use (alcohol, opiates, cigarettes) may not represent absolute contraindication with careful monitoring 5
Pregnancy and lactation - Caution is warranted during pregnancy, requiring careful risk-benefit assessment 5. Benzodiazepines carry risks during pregnancy and should be used only when benefits clearly outweigh risks 5
Severe respiratory insufficiency - Benzodiazepines can cause respiratory depression, making them dangerous in patients with severe pulmonary disease or COPD 5
Severe liver disease - Alprazolam clearance is significantly reduced in cirrhosis, leading to drug accumulation 6. Dose reduction is mandatory if use cannot be avoided 5
Myasthenia gravis - Benzodiazepines can worsen muscle weakness and should be avoided unless the patient is imminently dying 5
Important Drug Interactions
Beyond the absolute contraindication with azole antifungals, several medications significantly impair alprazolam clearance 6:
Cimetidine, fluoxetine, fluvoxamine, and propoxyphene - These drugs significantly reduce alprazolam metabolism, requiring dose adjustment or alternative therapy 6
MAO inhibitors - While not specifically mentioned for alprazolam, concomitant use of MAO inhibitors with benzodiazepines requires extreme caution given potential for severe interactions 5
High-dose olanzapine - Fatalities have been reported with concurrent benzodiazepine and high-dose olanzapine use due to oversedation and respiratory depression 5
Clinical Considerations
Elderly patients require dose reduction even when apparently healthy, as alprazolam clearance is reduced with age 6. Renal disease causes reduced protein binding (increased free fraction) and potentially reduced clearance, necessitating dose adjustment 6.
The drug's pharmacokinetics show dose-independent kinetics with 80-100% oral bioavailability and steady-state concentrations changing by 10-12 mcg/L for each 1 mg/day dosage change 6. Peak levels occur 0.7-1.8 hours post-dose, contributing to its high misuse potential 6.
Alprazolam withdrawal is particularly challenging to treat compared to other benzodiazepines, making it a poor choice for long-term use 3, 4. The drug should be reserved for short-term use in carefully selected patients without substance abuse history and with close monitoring 3.