News Author: Yael Waknine
CME Author: Yael Waknine
The US Food and Drug Administration (FDA) has approved safety labeling revisions to advise of the risk for serotonin syndrome in patients receiving concomitant treatment with paroxetine mesylate and triptans, drug interactions between voriconazole and efavirenz requiring dose adjustments for both drugs when used concomitantly, and the risk for respiratory adverse events associated with use of desflurane in certain pediatric settings.
Concomitant Use of Paroxetine Mesylate (Pexeva) and Triptans Linked to Risk for Serotonin Syndrome
On December 9, 2006, the FDA approved safety labeling revisions for paroxetine mesylate (Pexeva tablets, made by Synthon Pharmaceuticals, Ltd) to advise of the potential increased risk for serotonin syndrome in patients receiving concomitant treatment with other serotonergic drugs (including 5-hydroxytryptamine-receptor agonists [triptans]) or drugs that impair serotonin metabolism (including monoamine oxidase inhibitors [MAOIs]).
Concurrent treatment with paroxetine and MAOIs is therefore contraindicated. Concomitant use of other selective serotonin reuptake inhibitors (SSRIs), serotonin/norepinephrine reuptake inhibitors (SNRIs), or the serotonin precursor tryptophan is not recommended. Caution is advised when using paroxetine in combination with other drugs or agents that can affect serotonergic neurotransmitter systems, such as the antibiotic linezolid (a reversible nonselective MAOI), lithium, tramadol, St. John's Wort, and triptans.
According to the FDA, rare postmarketing cases of serotonin syndrome have been reported with use of SSRIs and triptans. Associated symptoms may include changes in mental status (eg, agitation, hallucinations, and coma), autonomic instability (eg, tachycardia, labile blood pressure, and hyperthermia), neuromuscular aberrations (eg, hyperreflexia and incoordination), and/or gastrointestinal tract symptoms, such as nausea, vomiting, and diarrhea.
Paroxetine-treated patients in whom concomitant triptan therapy is clinically warranted should be carefully monitored, particularly during initiation of therapy, dose increases, or the addition of another serotonergic drug.
Triptans are used to treat migraines. The drug class includes naratriptan HCl (Amerge, made by GlaxoSmithKline), almotriptan malate (Axert, made by Ortho-McNeil Pharmaceutical, Inc), frovatriptan succinate (Frova, made by Endo Pharmaceuticals), sumatriptan/sumatriptan succinate (Imitrex, made by GlaxoSmithKline), rizatriptan benzoate (Maxalt and Maxalt-MLT, made by Merck and Co, Inc), eletriptan HBr (Relpax, made by Pfizer, Inc), and zolmitriptan (Zomig and Zomig ZMT, made by AstraZeneca Pharmaceuticals LP).
Paroxetine mesylate is indicated for the treatment of major depressive, obsessive-compulsive, panic, and generalized anxiety disorders. Although the risk for suicidal behavior/thoughts (suicidality) warrants monitoring of all patients regardless of the condition being treated, it is of particular importance in patients with a history of suicidality, those exhibiting a significant degree of suicidal ideation prior to treatment, and young adults.
FDA Warns of 2-Way Drug Interaction Between Voriconazole (Vfend) and Efavirenz
On December 1, 2006, the FDA approved safety labeling revisions for voriconazole (Vfend injection, tablets, and oral suspension, made by Pfizer, Inc) to advise of a 2-way drug interaction with coadministered efavirenz (Sustiva tablets and capsules, made by Bristol-Myers Squibb).
Standard doses of voriconazole are contraindicated with efavirenz because efavirenz significantly decreases voriconazole plasma concentrations while voriconazole significantly increases efavirenz plasma concentrations.
The warning was based on data from a pharmacokinetic study of healthy subjects, showing that systemic exposure of voriconazole (400 mg given orally every 12 hours for 1 day followed by 200 mg every 12 hours for 8 days) was significantly decreased (mean area under the curve [AUC], 61%; Cmax, 77%) when given concurrently with efavirenz (400 mg every 12 hours for 9 days). The AUC and Cmax for efavirenz increased by an average of 38% and 44%, respectively.
Concomitant therapy therefore requires dosage adjustments for both agents. Voriconazole maintenance dosing should be increased from 200 to 400 mg and given every 12 hours. The once-daily dose of efavirenz should be decreased from 600 to 300 mg using the capsule formulation.
Voriconazole is indicated for the treatment of fungal infections, including invasive aspergillosis, candidemia in nonneutropenic patients, esophageal candidiasis, and serious infections intolerant of or refractory to other therapy. It is marketed as 50- and 200-mg tablets and reconstituted as 40-mg/mL oral suspension and 200-mg vials.
Efavirenz is a nonnucleoside reverse transcriptase inhibitor indicated for use in combination with other antiretroviral agents for the treatment of HIV-1 infection. It is available in 50-, 100-, and 200-mg capsules and 600-mg tablets.
Desflurane (Suprane) Linked to Respiratory Adverse Events in Certain Pediatric Settings
On December 15, 2006, the FDA approved safety labeling revisions for desflurane volatile liquid for inhalation (Suprane, made by Baxter Healthcare Corp) to advise of the risk for respiratory adverse events associated with its use in certain pediatric settings.
The FDA warns that desflurane is not recommended for induction of general anesthesia via a mask in children because of the high incidence of moderate to severe respiratory adverse reactions, including laryngospasm (50%), coughing (72%), breath-holding (68%), increased secretions, (21%), and oxyhemoglobin desaturation (pulse oximetry [SpO2] of <90%, 26%) reported in clinical studies.
Also, desflurane is not approved for maintenance of anesthesia in nonintubated children because of the increased risk for respiratory adverse events relative to isoflurane observed in a clinical safety trial of 300 pediatric patients aged 2 to 16 years (mean, 7.4 years) who received desflurane via a face mask or laryngeal mask airway after induction with intravenous propofol or inhaled sevoflurane.
Study results showed that the overall rate of respiratory adverse events in the desflurane group was 39% and most commonly included coughing (26%), laryngospasm (13%), and secretions (12%); 5% of pediatric patients experienced severe laryngospasm (associated with SpO2 < 90% for > 15 seconds or requiring succinylcholine). The incidence rate for severe laryngospasm was higher in children aged 2 to 6 years (9%) than in those aged 7 to 11 years or 12 to 16 years (1% and 1%, respectively).
Removal of the laryngeal mask airway under deep anesthesia (minimum alveolar concentration [MAC] range, 0.6 – 2.3; mean, 1.12 MAC) was linked to further increases in the rate of respiratory adverse events compared with awake removal or removal under deep anesthesia with isoflurane. The frequency and severity of nonrespiratory adverse events were comparable between the 2 groups.
Desflurane is indicated as an inhalation agent for induction and/or maintenance anesthesia in adults undergoing inpatient or outpatient surgery. Although it is not recommended for anesthetic induction in pediatric patients because of the high risk for moderate to severe upper airway adverse events, it may be used for anesthesia maintenance in infants and children following induction with other agents and tracheal intubation.
