FDA NewsPerspective

FDA issues safety alert for antifungal medication dosages, approves label revisions

The FDA issued a safety announcement today warning prescribers, pharmacists and patients that differences in dosing regimens between the two oral formulations of the antifungal Noxafil can lead to dosing errors.

Noxafil (posaconazole, Merck) is approved for the treatment of invasive fungal infections caused by Aspergillus and Candida in patients aged 13 years or older with weakened immune systems, according to the FDA. The drug is available in two oral formulations — delayed-release tablets and an oral suspension — as well as an IV solution. The oral suspension, approved in 2006, is also used to treat Candida infections in the mouth or throat.  

Oral Suspension Label

Figure 1. The outer carton label for the oral suspension of posaconazole.

Delayed-Release Tablet Label

Figure 2. The outer carton label for the delayed-release tablet formulation of posaconazole.

Source: FDA

Since the approval of the delayed-release tablets in November 2013, there were 11 dosing errors reported to the FDA, including one death.  In one case report, a pharmacy replaced delayed-release tablets with the oral suspension without changing the dose and frequency of administration, resulting in an underdose. The patient later died from a stroke related to an invasive Aspergillus infection, the FDA said. In the other case reports, several patients experienced adverse reactions such as nausea and vomiting.

The FDA reported that exact substitution (mg for mg) can result in drug levels that are lower or higher than needed to effectively treat infections due to variations in how the drug is absorbed and managed by the body.

“The delayed-release tablet has a higher bioavailability than the oral suspension,” the FDA said. “As a result, the dose and frequency of administration for [posaconazole] depend on the particular formulation used and the indication for use.”

To prevent future dosing errors, the outer cartons and labels for posaconazole were updated to clarify that the two formulations cannot be directly substituted for each other. Instead, a change in dose is required.

The FDA recommends that prescribers specify the dosage form, strength, and frequency of all posaconazole prescriptions, that pharmacists request prescribers to clarify the dosage form, strength, or frequency when it is not specified, and that patients talk to their health care professional before switching formulations.

Patients receiving posaconazole should seek medical care if they develop severe diarrhea or vomiting, notice swelling in an arm or leg, experience shortness of breath, or notice a change in heart rate or heart rhythm.

The FDA issued a safety announcement today warning prescribers, pharmacists and patients that differences in dosing regimens between the two oral formulations of the antifungal Noxafil can lead to dosing errors.

Noxafil (posaconazole, Merck) is approved for the treatment of invasive fungal infections caused by Aspergillus and Candida in patients aged 13 years or older with weakened immune systems, according to the FDA. The drug is available in two oral formulations — delayed-release tablets and an oral suspension — as well as an IV solution. The oral suspension, approved in 2006, is also used to treat Candida infections in the mouth or throat.  

Oral Suspension Label

Figure 1. The outer carton label for the oral suspension of posaconazole.

Delayed-Release Tablet Label

Figure 2. The outer carton label for the delayed-release tablet formulation of posaconazole.

Source: FDA

Since the approval of the delayed-release tablets in November 2013, there were 11 dosing errors reported to the FDA, including one death.  In one case report, a pharmacy replaced delayed-release tablets with the oral suspension without changing the dose and frequency of administration, resulting in an underdose. The patient later died from a stroke related to an invasive Aspergillus infection, the FDA said. In the other case reports, several patients experienced adverse reactions such as nausea and vomiting.

The FDA reported that exact substitution (mg for mg) can result in drug levels that are lower or higher than needed to effectively treat infections due to variations in how the drug is absorbed and managed by the body.

“The delayed-release tablet has a higher bioavailability than the oral suspension,” the FDA said. “As a result, the dose and frequency of administration for [posaconazole] depend on the particular formulation used and the indication for use.”

To prevent future dosing errors, the outer cartons and labels for posaconazole were updated to clarify that the two formulations cannot be directly substituted for each other. Instead, a change in dose is required.

The FDA recommends that prescribers specify the dosage form, strength, and frequency of all posaconazole prescriptions, that pharmacists request prescribers to clarify the dosage form, strength, or frequency when it is not specified, and that patients talk to their health care professional before switching formulations.

Patients receiving posaconazole should seek medical care if they develop severe diarrhea or vomiting, notice swelling in an arm or leg, experience shortness of breath, or notice a change in heart rate or heart rhythm.

    Perspective
    Edward A. Bell

    Edward A. Bell

    This drug safety communication on the appropriate use of posaconazole, a triazole antifungal agent, perhaps can be summarized best rather simply: when prescribing a drug product for a patient, write or electronically enter the characteristics that are essential for every prescribed product, including the dosage form, the strength, the dose, and the dosing schedule. Without this essential information, confusion and medication errors may ensue, potentially with significant consequences.

    Such confusion with posaconazole products has resulted in a patient’s death, according to the FDA. Posaconazole is commercially available as a delayed-release tablet, an oral liquid suspension and an intravenous liquid formulation. The delayed-release tablets and the oral suspension are not directly equivalent (interchangeable) on a mg-per-mg basis.

    Reasoning for this relates to differing pharmacokinetic variables among these dosage forms — differences in oral absorption and total body clearance, among other variables — and thus differences in dosing. Several other drugs products share similar precautions on dosage form/dosing differences, including Zithromax (azithromycin, Pfizer) and Augmentin (amoxicillin/clavulanate, Dr. Reddy’s Laboratories).

    With the commercial availability of so many drug products, and with new drug products and dosage forms introduced frequently, it is difficult not to be confused. When such confusion ensues, do not hesitate to call your institutional or community pharmacy and ask.

    Noxafil dosage form and dosing

    Delayed-release tablets – 100 mg

    Dose

    • Prophylaxis – invasive Aspergillus and Candida infection (≥13 years age)

    • Loading dose – 3 x 100 mg (300 mg) DR tablets twice daily x 1 day, then maintenance dose of 3 x 100 mg (300 mg) DR tablets once daily

    Oral suspension – 40 mg/mL

    Dose

    • Prophylaxis – invasive Aspergillus and Candida infection (≥13 years age)

    • Treatment – oropharyngeal Candida infection

    • 5 mL (200 mg) three times daily

    • Loading dose – 2.5 mL (100 mg) twice daily x 1 day, then maintenance dose of 2.5 mL (100 mg) once daily for 13 days

    • Edward A. Bell, PharmD, BCPS
    • Infectious Diseases in Children Editorial Board member Professor of pharmacy practice Drake University College of Pharmacy and Health Sciences Blank Children’s Hospital and Clinics

    Disclosures: Bell reports no relevant financial disclosures.