Zylam Drug Interactions

Midazolam is metabolized almost exclusively by other 3A4 of the cytochrome P450 (CYP450). The inhibitors and the inducers of CYP3A4, but also other active ingredients, may interact with midazolam.
As midazolam has a significant first-step effect, parenterally administered midazolam would theoretically be subject to less metabolic interactions and the relevant clinical responses would be limited.
ITRACONAZOLE, FLUCONAZOLE AND KETOCONAZOLE: When midazolam was administered as a single dose by bolus injection for short-term sedation, the effect of midazolam was neither increased nor extended by itraconazole at a clinically significant level, so there is no need to reduce the dosage. However, the administration of high doses on long-term infusions of midazolam to patients treated itraconazole, fluconazole or ketoconazole, for example, during their stay at ICU, may cause long-term hypnotic effects, delay recover and produce respiratory depression, which requires to adapt the doses.
VERAPAMIL AND DILTIAZEM: No in vivo interaction studies have been made with intravenous midazolam and verapamil or diltiazem. Although one cannot expect clinically significant interactions when using midazolam for short-term sedation, one must be cautious when administering midazolam concomitantly with verapamil or diltiazem by the intravenous route.
MACROLIDE ANTIBIOTICS: ERYTHROMYCIN AND CLARITHROMYCIN: When midazolam was administered as a single dose by bolus injection for short-term sedation, the effect of midazolam was neither increased nor extended by erythromycin at a clinically significant level, although there was a significant reduction of the plasma clearance. Caution is recommended when midazolam is given concomitantly with erythromycin or clarithromycin by the intravenous route. No clinically significant interactions have been shown of midazolam with other macrolide antibiotics.
CIMETIDINE AND RANITIDINE: The co-administration of cimetidine (in doses equal to or higher than 800 mg/day) and intravenous midazolam slightly increased the plasma concentration of midazolam –in a state of balance- which could delay recovery, whereas co-administration of ranitidine had no effect. Cimetidine and ranitidine did not affect the pharmacokinetics of oral midazolam. These data suggest that midazolam may be administered intravenously with the standard dosage of cimetidine (that is, 400 mg/day) and ranitidine without titrating their dosage.
SAQINAVIR: Co-administration of a single intravenous dose of 0.05 mg/kg of midazolam after 3 or 5 days of saquinavir administration (1,200 mg three times per day) to 12 healthy volunteers reduced midazolam elimination by 56% and increased the elimination half-life from 4.1 to 9.5 hours. Saquinavir intensified only the subjective effects of midazolam (visual analog scale with the item “global effect” of the medicine).
Thus, a single intravenous midazolam bolus dose can be given in combination with saquinavir. Nevertheless, during a prolonged infusion of midazolam, it is recommended to reduce the total dose so as not to delay the recovery.
OTHER PROTEASE INHIBITORS: RITONAVIR, INDINAVIR, NELFINAVIR AND AMPRENAVIR: No in vivo interaction studies have been made with intravenous midazolam and other protease inhibitors. Considering that saquinavir is characterized by the poorest inhibitory potency of CYP3A4 among all protease inhibitors, the midazolam dose must be systematically reduced during prolonged infusion when administered concomitantly with protease inhibitors other than saquinavir.
CNS DEPRESSANTS: Other sedative drugs may increase midazolam effects. The pharmacological groups of CNS depressants are the opiates (when used as analgesics, antitussives or replacement therapy), antipsychotics, other benzodiazepines used as anxiolytics or hypnotics, phenobarbital, sedative antidepressants, antihistamines and centrally antihypertensive drugs.
Additional sedation must be considered when midazolam is combined with other sedatives. Moreover, an additional increase of the respiratory depression should be monitored in case of concomitant treatment with opiates, phenobarbital or benzodiazepines.
Alcohol may considerably enhance the sedative effect of midazolam. Alcohol consumption must be avoided when midazolam is administered.
OTHER INTERACTIONS: IV administration of midazolam decreases the minimum alveolar concentration (MAC) of inhalational anesthetics required for general anesthetics.