FDA Safety Changes: Levitra, Minocin, Zyvox
This activity is part of an ongoing CME/CE initiative to provide information on labeling changes reported by the FDA. Activities of this nature will be posted on Medscape on a weekly basis.
August 8, 2007 — The US Food and Drug Administration (FDA) has approved safety labeling revisions to advise of drug interactions with vardenafil and the additive effect on QT interval prolongation associated with concomitant use of certain medications, and the potential for development of Clostridium difficile-associated diarrhea more than 2 months after completion of therapy with minocycline HCl or linezolid.
Vardenafil (Levitra) Linked to Drug Interactions and Risk for Additive QT Effects
On April 6, the FDA approved safety labeling revisions for vardenafil (Levitra tablets, made by Bayer Pharmaceuticals Corp) to advise of drug interactions and the additive effect on QT interval prolongation associated with concomitant use of certain medications.
Because vardenafil is metabolized predominantly by the hepatic enzyme cytochrome P450 isoenzyme 3A4 (CYP3A4), serum levels can be significantly increased by concomitant use of indinavir, saquinavir, atazanavir, or other potent CYP3A4 inhibitors, such as clarithromycin, ketoconazole 400 mg daily, or itraconazole 400 mg daily. This can lead to an increased risk for adverse events such as hypotension, visual changes, and priapism.
Therefore, patients receiving treatment with these drugs or regimens should not exceed a dose of 2.5 mg vardenafil within a 24-hour period. For patients taking ketoconazole or itraconazole 200 mg daily, the vardenafil dose should not exceed 5 mg within a 24-hour period. The FDA notes that though the specific interactions have not been studied, other CYP3A4 inhibitors (eg, grapefruit juice) are also likely to increase vardenafil exposure.
The agency also warned of the risk for an additive effect on QT interval prolongation with concomitant use of other drugs known to exert this effect, as determined by data from a postmarketing study. A previous study of healthy men (n = 59) had revealed that the effect of 10 mg of vardenafil is similar to that of 400 mg of moxifloxacin.
These observations should be considered in clinical decisions when prescribing vardenafil for patients with a known history of QT prolongation or those taking medications known to prolong the QT interval. Patients taking class 1A (eg, quinidine, procainamide) or class III (eg, amiodarone, sotalol) antiarrhythmic medications or those with congenital QT prolongation should avoid using vardenafil.
Vardenafil is indicated for the treatment of erectile dysfunction. The recommended daily starting dose for most patients is 10 mg taken approximately 1 hour before sexual activity and then lowered to 5 mg or increased to a maximum of 20 mg based on efficacy and adverse events.
Minocycline HCl (Minocin) and Linezolid (Zyvox) Linked to Risk for Clostridium difficile-Associated Diarrhea
On April 2 and 26, the FDA approved safety labeling revisions for minocycline HCl (Minocin pellet-filled capsules, made by Triax Pharmaceuticals, LLC) and linezolid (Zyvox injection, tablets, and oral suspension, made by Pharmacia & Upjohn [a division of Pfizer, Inc]) to warn of the risk for Clostridium difficile-associated diarrhea (CDAD).
Treatment with antibacterial agents such as minocycline and linezolid can alter the colon’s normal flora, leading to overgrowth of C difficile and subsequent release of toxins A and B that contribute to the development of CDAD. Nearly all antibiotics have been implicated in CDAD, which may range in severity from mild diarrhea to fatal colitis.
Because hypertoxin-producing strains of C difficile can be refractory to antimicrobial therapy, they are associated with increased morbidity and mortality and may require colectomy. The FDA advises that CDAD be considered in all patients who present with diarrhea after antibiotic use. Careful examination of medical history is required because of the potential for late-onset disease; cases of CDAD have been reported more than 2 months after completion of an antimicrobial course of therapy.
The FDA notes that current antibiotic therapy for the primary infection may need to be discontinued in patients with known or suspected CDAD. Appropriate fluid and electrolyte management, protein supplementation, antibiotic therapy for C difficile, and surgical evaluation also may be required.
Patients should be advised that diarrhea is a common problem caused by antibiotics and usually ceases after completion of therapy; watery and bloody stools (with or without stomach cramps and fever) can occur after initiation of therapy, sometimes as late as 2 or more months after the last dose has been taken. Patients should be instructed to contact their healthcare clinician as soon as possible if symptoms occur.
Minocycline is a tetracycline-derived antibiotic indicated for the treatment of gram-positive and gram-negative infections resulting from susceptible strains of designated microorganisms. It also may be used as adjunctive therapy for acute intestinal amebiasis and severe acne. Linezolid is indicated for the treatment of infections caused by susceptible strains of designated microorganisms. Indications include vancomycin-resistant Enterococcus faecium infections, nosocomial pneumonia, complicated infections of the skin or skin structure (including diabetic foot infections, without concomitant osteomyelitis), uncomplicated infections of the skin or skin structure, and community-acquired pneumonia.
http://www.fda.gov/medwatch/SAFETY/2007/Apr_PI/Levitra_PI.pdf
http://www.fda.gov/medwatch/SAFETY/2007/Apr_PI/Minocin_PI.pdf
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