Drug Interactions between Akynzeo and Vanspar

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.

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MONITOR: Coadministration with netupitant or its prodrug, fosnetupitant, may increase the plasma concentrations of drugs that are primarily metabolized by CYP450 3A4. The mechanism is decreased clearance due to inhibition of CYP450 3A4 activity by netupitant and its desmethyl metabolite. When a single 7.5 mg oral dose of midazolam, a CYP450 3A4 probe substrate, was administered with netupitant 300 mg, mean midazolam peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 36% and 126%, respectively. When a 500 mg dose of erythromycin, another CYP450 3A4 substrate, was coadministered with netupitant 300 mg, the mean Cmax and AUC of erythromycin were increased by 92% and 56%, respectively, although the systemic exposure of erythromycin was highly variable.

MANAGEMENT: Caution is advised when netupitant or fosnetupitant is used concomitantly with drugs that undergo metabolism by CYP450 3A4, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever netupitant or fosnetupitant is added to or withdrawn from therapy. The inhibitory effect on CYP450 3A4 can last for 6 days after administration of a single dose of netupitant or fosnetupitant.

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