High-Dose Zofran Pulled From Market
The 32-mg dose of the anti-nausea drug ondansetron (Zofran) has been pulled from the market because of concerns about cardiac problems, the FDA announced Tuesday.
Ondansetron is approved for preventing chemotherapy-induced nausea and vomiting, and, in lower doses, for postoperative nausea and vomiting. The 32-mg formulation is given as a single intravenous dose.
"FDA does not anticipate that removal of the 32-mg intravenous dose of ondansetron currently sold as pre-mixed injections will contribute to a drug shortage of IV ondansetron, as the 32-mg dose makes up a very small percentage of the current market," the agency said in a statement.
In June, the FDA warned that the 32-mg dose should be avoided due to the risk of QT interval prolongation, which can lead to torsades de pointes, a potentially fatal arrhythmia.
"FDA continues to recommend the intravenous regimen of 0.15 mg/kg administered every 4 hours for three doses to prevent chemotherapy-induced nausea and vomiting," Tuesday's statement continued. "Oral dosing of ondansetron remains effective for the prevention of chemotherapy-induced nausea and vomiting. At this time, there is not enough information available for FDA to recommend an alternative single IV dose regimen."
Prior to the June warning, the FDA had indicated that it was investigating the arrhythmogenic potential of ondansetron in collaboration with the drug's maker, GlaxoSmithKline.
Preliminary results of a study ordered by the FDA found a maximum mean difference in QTcF of 20 msec after the 32-mg IV dose. An IV dose of 8 mg, on the other hand, led to a mean maximum QTcF difference of 6 msec.
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FDA : Abnormal heart rhythms associated with use of Anzemet (dolasetron mesylate)
On December 17, 2010, the Food and Drug Administration issued a Drug Safety Communication informing patients and healthcare professionals that the injection form of Anzemet (dolasetron mesylate) should no longer be used to prevent nausea and vomiting associated with cancer chemotherapy in pediatric and adult patients. New data demonstrate that Anzemet injection can increase the risk of developing an abnormal heart rhythm (torsade de pointes), which in some cases can be fatal. Patients at particular risk are those with underlying heart conditions or those who have existing heart rate or rhythm problems. Anzemet causes a dose-dependant prolongation in the QT, PR, and QRS intervals on an electrocardiogram, or ECG.A contraindication against this use in nausea and vomiting associated with cancer chemotherapy is being added to the product label for Anzemet injection. Anzemet injection may still be used for the prevention and treatment of postoperative nausea and vomiting because the lower doses used for postoperative nausea and vomiting are less likely to affect the electrical activity of the heart and result in abnormal heart rhythms.
Anzemet tablets may still be used to prevent nausea and vomiting associated with cancer chemotherapy because the risk of developing an abnormal heart rhythm with the oral form of this drug is less than that seen with the injection form. However, a stronger warning against this potential risk is being added to the Warnings and Precautions sections of the Anzemet tablet label. Anzemet tablets may also still be used for prevention of postoperative nausea and vomiting.
The FDA previously noted cardiovascular safety concerns which suggested Anzemet could cause QT prolongation, which can lead to a serious and sometimes fatal heart rhythm called torsade de pointes. Previous versions of the Anzemet labels included a warning on ECG interval changes (PR, QT, JT prolongation and QRS widening), a precaution to use with caution in patients who have or may develop prolongation of cardiac conduction intervals (particularly QT), and listed cardiovascular events in the "Adverse Events" section of the drug label. However, limitations of the previous data did not clearly establish the degree to which Anzemet may cause QT prolongation.
The FDA recommended that the drug sponsor conduct a thorough QT study in adults in order to determine the degree of the prolongation. A pediatric study was not recommended due to the wide variability in heart rate and, thus, QTc interval in the pediatric population.
The effect of intravenous Anzemet on the QTcF interval (i.e., the QT interval measurement corrected by using Fridericia's formula) was evaluated in a randomized, placebo- and active- (moxifloxacin 400 mg once daily) controlled crossover study in 80 healthy adults, with 14 measurements taken over 24 hours on Day 4. The maximum mean differences in QTcF from placebo after baseline-correction were 14.1 ms and 36.6 ms for 100 mg IV Anzemet and supratherapeutic doses of 300 mg IV Anzemet doses, respectively.
Prolongation of the PR and QRS interval was also noted in subjects receiving Anzemet in the same study on Day 4. The maximum mean difference in PR from placebo after baseline-correction was 9.8 ms and 33.1 ms for 100 mg IV Anzemet and 300 mg IV Anzemet doses, respectively. Based on exposure-response analyses, QT, QRS, and PR interval prolongations appear to be associated with higher concentrations of Anzemet's active metabolite, hydrodolasetron.
Patients at particular risk for serious abnormal rhythms are those with underlying structural heart disease and preexisting conduction system abnormalities, the elderly, patients with sick sinus syndrome, patients with atrial fibrillation with slow ventricular response, patients with myocardial ischemia or patients receiving drugs known to prolong the PR interval (such as verapamil) and QRS interval (such as flecainide or quinidine).
Overall, a significant QT prolongation was detected in this study in adults. The QT prolongation in pediatric patients was predicted based upon knowledge of the pharmacokinetics of Anzemet injection formulation in this population. Based on this modeling and simulation, the change in QTcF was significantly higher in pediatric patients being treated with intravenous Anzemet for nausea and vomiting associated with cancer chemotherapy. The predicted QTcF interval mean was 22.5 ms for the nausea and vomiting associated with cancer chemotherapy recommended dose (1.8 mg/kg). The elevation was less prominent in the postoperative nausea and vomiting population due to the lower prescribed dose (0.35mg/kg) in these patients. It is recognized in the International Conference on Harmonization E14 Guideline1 that drugs that prolong the mean QT/QTc interval by >20 ms have a substantially increased likelihood of being proarrhythmic. This study demonstrated that Anzemet can produce dose-dependent QT prolongation which can lead to an increased risk of a serious abnormal rhythm such as torsade de pointes.
In summary, Anzemet may affect the electrical activity of the heart through prolongation of the QT, QRS and PR intervals, which may result in abnormal heart rhythms. Due to the risk of QT prolongation from increased drug exposure, Anzemet injection should no longer be used to prevent nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy. This use is removed from the Anzemet injection label, and a contraindication has been added for both children and adults. Stronger warnings that both the tablet and injection formulations of Anzemet may affect the electrical activity of the heart and cause abnormal heart rhythms have been added to the drug labels. There are certain patients who should not use Anzemet because they are at higher risk for developing abnormal heart rhythms, such as patients with congenital long QT syndrome. Heart rhythm monitoring (e.g., ECG) should be used in patients with congestive heart failure, patients with slow heart rate, the elderly, and in patients who are renally impaired. Potassium and magnesium levels should be assessed and, if abnormal, corrected before initiating treatment with Anzemet. These electrolytes should be monitored after administration as clinically indicated. Patients at risk for developing hypokalemia or hypomagnesemia during Anzemet exposure should be monitored with ECG.
At this time, FDA advises that Healthcare Professionals be aware that:
- Torsade de pointes, an abnormal heart rhythm, has been reported in some patients receiving Anzemet injection.
- Anzemet should not be used in patients with congenital long-QT syndrome.
- Hypokalemia and hypomagnesemia should be corrected before administering Anzemet. These electrolytes should be monitored after administration as clinically indicated.
- ECG monitoring should be used in patients with congestive heart failure, patients with bradycardia, patients with underlying heart disease, the elderly and in patients who are renally impaired who are taking Anzemet.
- No dose adjustment is necessary for renal-impaired patients, hepatic-impaired patients, or the elderly.
- Anzemet also causes dose-dependent PR and QRS prolongation. Drugs known to prolong the PR interval (such as verapamil) or QRS interval (such as flecainide or quinidine) should be avoided in patients taking Anzemet.
- Patients should be advised to contact a healthcare professional immediately if they experience signs and symptoms of an abnormal heart rate or rhythm while taking Anzemet.
- Adverse events involving Anzemet should be reported to the FDA MedWatch program at www.fda.gov/medwatch.
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