By Stan Deresinski, MD, FACP, FIDSA
Dr. Deresinski is Clinical Professor of Medicine, Stanford University
Dr. Deresinski reports no financial relationships relevant to this field of study.
SYNOPSIS: The availability of two different oral formulations of posacozaole (oral suspension, delayed release tablets) with differing bioavailability and dosing requires great care by both prescribers and dispensing pharmacists in their use.
SOURCE: FDA Drug Safety Communication: FDA cautions about dosing errors when switching between different oral formulations of antifungal Noxafil (posaconazole); label changes approved. www.fda.gov/drugs/drugsafety/ucm479352.htm.
In the United States, posaconazole (Noxafil) is available for intravenous administration, but also as two distinct oral formulations — an oral suspension and a delayed-release tablet. The former was approved in 2006, and the latter in November 2013. The recommended dosing differs. The formulations also differ in how they should be taken relative to food. The bioavailability of the oral suspension is improved when it is taken during or within 20 minutes of a full meal or liquid nutritional supplement; it can also be taken with an acidic carbonated beverage such as ginger ale. Although bioavailability is not significantly improved, taking the tablet with food reduces gastric irritation.
The tables list recommended dosing for FDA-approved indications, but higher doses are generally used for some unapproved indications, such as the treatment of infections due to filamentous fungi. Since the approval of the delayed-release tablet, the FDA has received 11 reports of errors due to prescription and/or dispensing of the wrong formulation, with one patient requiring hospitalization and another dying as a result.
The patient who died was receiving posaconazole delayed-release tablets for antifungal prophylaxis when the pharmacy substituted the oral suspension without attention to proper dosing. The bioavailability of the tablets is significantly superior and more reliable than that of the oral suspension. Presumably under-dosed, the patient died of a stroke “related” to Aspergillus infection.
In the other 10 cases, the switch was in the other direction, i.e., from the oral suspension to delayed-release tablets and also occurred without dose adjustment. One example was provided: A patient was given two 100-mg delayed-release tablets 3 times daily — twice the recommended prophylactic dose of three 100-mg tablets once daily. The most frequently reported adverse effects were nausea and vomiting, which, in one case, was associated with hypokalemia.
Available evidence indicated that the errors were due to a lack of knowledge among healthcare professionals that the oral formulations may not be substituted for each other without appropriate dose adjustment. As a consequence, the FDA has issued a caution about the potential for dosing errors occurring when the oral formulations of posaconazole are prescribed:
- Prescribers should specify the dosage form, strength, and frequency on all prescriptions they write for Noxafil.
- Pharmacists should request clarification from prescribers when the dosage form, strength, or frequency is not specified.
- Use caution when switching between Noxafil delayed-release tablets and Noxafil oral suspension, as the dosing is different for the two oral formulations. The delayed-release tablet has a higher bioavailability than the oral suspension. As a result, the dose and frequency of administration for Noxafil depend on the particular formulation used and the indication for use.
- Prescribers should follow the specific dosing instructions for each formulation. Incorrect dosage and administration can lead to subtherapeutic levels and potential for treatment failures, or higher levels and potential for adverse reactions.
-
Advise patients to seek medical attention right away if they:
- develop severe diarrhea or vomiting.
- notice a change in heart rate or heart rhythm, or have a heart condition or circulatory disease.
- have a potentially proarrhythmic condition, as posaconazole should be administered with caution in these patients.
- notice swelling in an arm or leg, or experience shortness of breath.
- have liver disease or develop itching, nausea or vomiting, their eyes or skin turn yellow, they feel more tired than usual, or feel like they have the flu.
Table 1. Dosage for Noxafil Delayed-release Tablets
|
Indication |
Dose and Duration of Therapy |
|
Prophylaxis of invasive Aspergillus and Candida infections |
Loading dose: 300 mg (three 100 mg delayed-release tablets) twice a day on the first day.
Maintenance dose: 300 mg (three 100 mg delayed-release tablets) once a day, starting on the second day. Duration of therapy is based on recovery from |
Table 2. Dosage for Noxafil Oral Suspension
|
Indication |
Dose and Duration of Therapy |
|
Prophylaxis of invasive Aspergillus and Candida infections |
200 mg (5 mL) three times a day. The duration of therapy is based on recovery from neutropenia and immunosuppression. |
|
Oropharyngeal Candidiasis |
Loading dose: 100 mg (2.5 mL) twice a day on the first day. Maintenance dose: 100 mg (2.5 mL) once a day for 13 days. |
|
Oropharyngeal Candidiasis Refractory to Itraconazole and/or Fluconazole |
400 mg (10 mL) twice a day. Duration of therapy should be based on the severity of the patient’s underlying disease and clinical response. |
The availability of two different oral formulations of posacozaole (oral suspension, delayed release tablets) with differing bioavailability and dosing requires great care by both prescribers and dispensing pharmacists in their use.
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