Drug Interactions between MKO Melt Dose Pack and st. john's wort

MONITOR CLOSELY: Coadministration of ketamine with other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. In addition, opioid analgesics, barbiturates, and benzodiazepines may prolong the time to complete recovery from anesthesia.

MANAGEMENT: During concomitant use of ketamine with other CNS depressants, including alcohol, close monitoring of neurologic status and respiratory parameters, including respiratory rate and pulse oximetry, is recommended. Dosage adjustments should be considered according to the patient's clinical situation. Ambulatory patients should be counseled to avoid hazardous activities requiring mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.

MONITOR CLOSELY: Coadministration of ketamine with other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. In addition, opioid analgesics, barbiturates, and benzodiazepines may prolong the time to complete recovery from anesthesia.

MANAGEMENT: During concomitant use of ketamine with other CNS depressants, including alcohol, close monitoring of neurologic status and respiratory parameters, including respiratory rate and pulse oximetry, is recommended. Dosage adjustments should be considered according to the patient's clinical situation. Ambulatory patients should be counseled to avoid hazardous activities requiring mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.

MONITOR CLOSELY: Concomitant use of 5-HT3 receptor antagonists with agents that possess or enhance serotonergic activity such as selective serotonin reuptake inhibitors (SSRIs), selective serotonin-norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants (TCAs), 5-HT1 receptor agonists (triptans), ergot alkaloids, phenylpiperidine opioids, bupropion, dextromethorphan, linezolid, lithium, St. John's wort, tramadol, and tryptophan may potentiate the risk of serotonin syndrome, which is a rare but serious and potentially fatal condition thought to result from hyperstimulation of brainstem 5-HT1A and 2A receptors. According to the manufacturers, development of serotonin syndrome has been reported with 5-HT3 receptor antagonists, primarily during concomitant use of serotonergic drugs but also in overdose. Some of the reported cases were fatal. Symptoms of the serotonin syndrome may include mental status changes such as irritability, altered consciousness, confusion, hallucination, and coma; autonomic dysfunction such as tachycardia, hyperthermia, diaphoresis, shivering, blood pressure lability, and mydriasis; neuromuscular abnormalities such as hyperreflexia, myoclonus, tremor, rigidity, and ataxia; and gastrointestinal symptoms such as abdominal cramping, nausea, vomiting, and diarrhea.

MANAGEMENT: Caution is advised if 5-HT3 receptor antagonists are prescribed with other agents that affect the serotonergic neurotransmitter system. Patients should be closely monitored for symptoms of the serotonin syndrome during treatment. Particular caution is warranted when initiating or increasing the dosages of these agents. The potential risk for serotonin syndrome should be considered even when administering serotonergic agents sequentially, as some agents may demonstrate a prolonged elimination half-life. For example, a 5-week washout period is typically recommended following use of fluoxetine and 2 weeks following use of MAOIs before administering another serotonergic agent. If serotonin syndrome develops or is suspected during the course of therapy, all serotonergic agents should be discontinued immediately and supportive care rendered as necessary. Moderately ill patients may also benefit from the administration of a serotonin antagonist (e.g., cyproheptadine, chlorpromazine). Severe cases should be managed under consultation with a toxicologist and may require sedation, neuromuscular paralysis, intubation, and mechanical ventilation in addition to the other measures.

MONITOR: Long-term (10 days or more) administration of St. John's wort may significantly decrease the oral bioavailability and/or plasma concentrations of benzodiazepines that are exclusively metabolized by CYP450 3A4 such as alprazolam, midazolam, and triazolam. The proposed mechanism is induction of CYP450 3A4-mediated intestinal (first-pass) and hepatic metabolism by constituents of St. John's wort. In 12 healthy volunteers, pretreatment with St. John's wort (300 mg, containing 0.9 mg hypericin, orally 3 times a day for 2 weeks) decreased the mean peak plasma concentration (Cmax), area under the concentration-time curve (AUC) and bioavailability of oral midazolam (5 mg single dose) by 43%, 52% and 45%, respectively, compared to administration of midazolam alone. The oral clearance of midazolam approximately doubled with St. John's wort, while the elimination half-life was not significantly altered. In contrast, St. John's wort decreased the AUC of intravenous midazolam (0.05 mg/kg single dose) by only 21% and increased its clearance by 27% compared to control, and the difference was not statistically significant. Another study found that systemic clearance of IV midazolam increased by 44% while oral clearance increased by 168% after pretreatment with St. John's wort for 12 days. The interaction has also been reported with alprazolam. In 12 heathy volunteers, mean AUC and elimination half-life of alprazolam (2 mg single dose) reduced by approximately one-half and oral clearance more than doubled following treatment with St. John's wort for 2 weeks. However, effects of the interaction may be highly variable due to differences in composition of commercial St. John's wort products and deviation from labeled claims of many herbal products. A clinical study found no consistent effects on alprazolam with the use of recommended dosages of St. John's wort in seven healthy subjects.

MANAGEMENT: In general, patients should be advised to consult their healthcare provider before using any herbal or alternative medicines. If St. John's wort is prescribed with alprazolam, midazolam or triazolam, the possibility of a diminished therapeutic response to the benzodiazepine should be considered. Patients should be monitored more closely following the addition, withdrawal or change of dosage of St. John's wort, and the benzodiazepine dosage adjusted as necessary.