Alprazolam (Page 4 of 9)
6.2 Postmarketing Experience
The following adverse reactions have been identified during postapproval use of alprazolam. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Endocrine disorders
Hyperprolactinemia
General disorders and administration site conditions
Edema peripheral
Hepatobiliary disorders
Hepatitis, hepatic failure
Investigations
Liver enzyme elevations
Psychiatric disorders
Hypomania, mania
Reproductive system and breast disorders
Gynecomastia, galactorrhea
Skin and subcutaneous tissue disorders
Photosensitivity reaction, angioedema, Stevens-Johnson syndrome
7 DRUG INTERACTIONS
7.1 Drugs Having Clinically Important Interactions with Alprazolam
Table 4 includes clinically significant drug interactions with alprazolam [see Clinical Pharmacology (12.3)].
| Opioids | |
| Clinical implication | 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. Benzodiazepines interact at gammaaminobutyric acid(GABAA ) sites and opioids interact primarily at mu receptors. When benzodiazepines and opioids are combined, the potential for benzodiazepines to significantly worsen opioid-related respiratory depression exists. |
| Prevention or management | Limit dosage and duration of concomitant use of alprazolam and opioids, and monitor patients closely for respiratory depression and sedation [see Warnings and Precautions ( 5.1)]. |
| Examples | Morphine, buprenorphine, hydromorphone, oxymorphone, oxycodone, fentanyl, methadone, alfentanil, butorpenol, codeine, dihydrocodeine, meperidine, pentazocine, remifentanil, sufentanil, tapentadol, tramadol. |
| CNS Depressants | |
| Clinical implication | The benzodiazepines, including alprazolam, produce additive CNS depressant effects when coadministered with other CNS depressants. |
| Prevention or management | Limit dosage and duration of alprazolam during concomitant use with CNS depressants [see Warnings and Precautions (5.3)]. |
| Examples | Psychotropic medications, anticonvulsants, antihistaminics, ethanol, and other drugs which themselves produce CNS depression. |
| Strong Inhibitors of CYP3A (except ritonavir) | |
| Clinical implication | Concomitant use of alprazolam with strong CYP3A inhibitors has a profound effect on the clearance of alprazolam, resulting in increased concentrations of alprazolam and increased risk of adverse reactions [see Clinical Pharmacology (12.3)]. |
| Prevention or management | Concomitant use of alprazolam with a strong CYP3A4 inhibitor (except ritonavir) is contraindicated [see Contraindications (4), Warnings and Precautions (5.5)]. |
| Examples | Ketoconazole, itraconazole, clarithromycin |
| Moderate or Weak Inhibitors of CYP3A | |
| Clinical implication | Concomitant use of alprazolam with CYP3A inhibitors may increase the concentrations of alprazolam, resulting in increased risk of adverse reactions of alprazolam [see Clinical Pharmacology (12.3)]. |
| Prevention or management | Avoid use and consider appropriate dose reduction when alprazolam is coadministered with a moderate or weak CYP3A inhibitor [see Warnings and Precautions (5.5)]. |
| Examples | Nefazodone, fluvoxamine, cimetidine, erythromycin |
| CYP3A Inducers | |
| Clinical implication | Concomitant use of CYP3A inducers can increase alprazolam metabolism and therefore can decease plasma levels of alprazolam [see Clinical Pharmacology (12.3)]. |
| Prevention or management | Caution is recommended during coadministration with alprazolam. |
| Examples | Carbamazepine, phenytoin |
| Ritonavir | |
| Clinical implication | Interactions involving ritonavir and alprazolam are complex and time dependent. Short term administration of ritonavir increased alprazolam exposure due to CYP3A4 inhibition. Following long term treatment of ritonavir (>10 to 14 days), CYP3A4 induction offsets this inhibition. Alprazolam exposure was not meaningfully affected in the presence of ritonavir. |
| Prevention or management | Reduce alprazolam dosage when ritonavir and alprazolam are initiated concomitantly, or when ritonavir is added to a regimen where alprazolam is stabilized. Increase alprazolam dosage to the target dosage after 10 to 14 days of dosing ritonavir and alprazolam concomitantly. No dosage adjustment of alprazolam is necessary in patients receiving ritonavir for more than 10 to14 days [see Dosage and Administration (2.6)]. Concomitant use of alprazolam with a strong CYP3A inhibitor, except ritonavir, is contraindicated [see Contraindications (4), Warnings and Precautions (5.5)]. |
| Digoxin | |
| Clinical implication | Increased digoxin concentrations have been reported when alprazolam was given, especially in geriatric patients( >65 years of age). |
| Prevention or management | In patients on digoxin therapy, measure serum digoxin concentrations before initiating alprazolam. Continue monitoring digoxin serum concentration and toxicity frequently. Reduce the digoxin dose if necessary. |
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