4. Drug-Drug Interactions
Patient profiles will be assessed to identify those drug regimens which may result in clinically significant drug-drug interactions. Drug-drug interactions considered clinically relevant for nonsedative/hypnotic benzodiazepines are summarized in Table 4. Only those drug-drug interactions identified as clinical significance of contraindicated or those considered life-threatening which have not yet been classified will be reviewed:
| Target Drug | Interacting Drug | Interaction | Recommendation | Clinical Significance Level* |
|---|---|---|---|---|
| alprazolam | CYP3A4 inhibitors (e.g., azole anti-fungals, macro-lides, NNRT inhibitors, protease inhibitors) | adjunctive administration may result in enhanced oxidized BZD pharmacologic effects and/or toxicity, including significant sedation and/or respiratory depression, as alprazolam is metabolized by CYP3A4 | avoid combined therapy with most CYP3A4 inhibitors, if possible | contraindicated |
| alprazolam | phenytoin | phenytoin is a strong CYP3A4 inducer and concomitant therapy may result in decreased alprazolam concentrations | monitor for reduced alprazolam clinical effects and adjust doses as necessary | moderate (CP) |
| benzodiazepines (BZDs) | central nervous system (CNS) depressants | concurrent administration may potentiate respiratory depression, especially with overdosage | monitor for respiratory depression; adjust doses as necessary | major (CP) |
| BZDs | sodium oxybate (Xyrem®) | combined use may lead to increased respiratory depression due to additive CNS/ respiratory depressive effects | adjunctive use should be avoided; if concurrent use necessary, closely monitor for respiratory depression; dosage reductions for one or both medications may be needed | contraindicated |
| clobazam | drugs metabolized by CYP2C19 (e.g., clopidogrel, cimetidine, fluconazole) | co-administration may result in increased clobazam serum levels and increased pharmacologic and/or adverse effects as clobazam is partially metabolized by CYP2C19 | monitor for enhanced clobazam pharmacologic/adverse effects; adjust clobazam dose as necessary | moderate (CP) |
| drugs metabolized by and substrates of CYP2D6 (diphenhydramine, tricyclic antidepressants) | Clobazam may be a CYP2D6 inhibitor that could increase serum concentrations of drugs metabolized by or substrates for CYP2D6 | monitor for enhanced pharmacologic/adverse effects; adjust doses as necessary | contraindicated (thioridazine) moderate | |
| other oxidized BZDs (chlor-diazepoxide, clonazepam, diazepam) | CYP3A4 inhibitors [e.g., azole antifungals, macrolides, non-nucleoside reverse transcriptase (NNRT) inhibitors, protease inhibitors] | adjunctive administration may result in enhanced oxidized BZD pharmacologic effects and/or toxicity, including significant sedation and/or respiratory depression, as oxidized BZDs are metabolized by CYP3A4 | avoid combined therapy, if possible; if concurrent with BZD necessary, monitor for increased sedation, respiratory depression, or consider a BZD metabolized by glucuronidation (e.g., oxazepam) | major (protease inhibitors) moderate (azoles, macrolides, NNRT inhibitors) |
| oxidized BZDs (e.g., alprazolam, chlordiazepoxide, clonazepam, diazepam) | CYP3A4 inducers (e.g., carbamazepine, rifamycins) | combined use may result in increased oxidized BZD clearance, reduced oxidized BZD serum levels, and decreased pharmacologic effects; oxidized BZDs are metabolized by CYP3A4 | monitor oxidized BZD clinical response and adjust dose as needed; may also consider substituting a BZD metabolized by glucuronidation (e.g., oxazepam) | major (barbiturates) moderate |
| select BZDs (chlordiazepoxide, diazepam) | phenytoin | concomitant use may result in unpredictable effects on serum phenytoin levels (may increase, decrease, or not change) due to unknown effect on phenytoin metabolism; phenytoin may induce BZD metabolism, reduce BZD serum levels, and decrease BZD pharmacologic effects | closely monitor serum phenytoin levels and observed for altered pharmacologic effects (reduced efficacy, increased toxicity); monitor for reduced BZD clinical effects and adjust doses as necessary | moderate |
| chlordiazepoxide/amitriptyline | amphetamines | combined administration may increase potential for serotonin syndrome as both medications target the serotonin neurotransmitter system | if adjunctive therapy is necessary, start with lower doses and monitor for signs/ symptoms of serotonin syndrome; discontinue both medications if serotonin syndrome develops | moderate |
| chlordiazepoxide/amitriptyline | monoamine oxidase inhibitors | increased risk of serotonin syndrome with amitriptyline (e.g., mental status changes, hyperpyrexia, restless, shivering, hypertonia, tremor) due to serotonin metabolism inhibition by monoamine oxidase | allow 14 days after MAOI discontinuation before initiating other tricyclic antidepressant therapy | contraindicated |
| chlordiazepoxide/amitriptyline | QT interval-prolonging drugs | co-administration with QT interval-prolonging drugs may increase risk of QT interval prolongation and torsades de pointes as amitriptyline also prolongs the QT interval | avoid concurrent use; if adjunctive use necessary, monitor for increased pharmacologic/toxic effects; adjust dose as necessary or discontinue therapy | major (CP) |
| midazolam | CYP3A4 inhibitors | midazolam is a CYP3A substrate and concomitant therapy may result in prolonged sedation because of a decreased clearance of midazolam | Avoid co-administration of midazolam with moderate or strong CYP3A4 inhibitors. Use with caution with co-administered with mild CYP3A4 inhibitors | contraindicated (strong CYP3A4 inhibitors) major (moderate CYP3A4 inhibitors) |
| Opioids | Concomitant use increases the risk of respiratory depression | Reserve concomitant prescribing for use in patients for whom alternative treatment options are inadequate. Minimize dosages and durations to the minimum required | Major | |
| central nervous system depressants | Concomitant use may increase the risk of hypoventilation, airway obstruction, desaturation, or apnea and may contribute to profound and/or prolonged drug effect | Reserve concomitant use for patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required | major (tricyclic antidepressants, melatonin) moderate (baclofen, cyclobenzaprine) |
Legend:
- *CP = Clinical Pharmacology