FDA Safety Changes: Zantac, Zithromax, Noxafil

Yael Waknine

April 23, 2009

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April 23, 2009 — The US Food and Drug Administration (FDA) has approved safety labeling revisions to advise of drug interactions with ranitidine HCl that increase exposure to orally administered midazolam, drug interactions with azithromycin that potentiate the effects of oral anticoagulants, and drug interactions with metoclopramide and esomeprazole magnesium that decrease posaconazole therapeutic efficacy.

Ranitidine HCl (Zantac) Increases Potency of Orally Coadministered Midazolam

On February 17, the FDA approved safety labeling revisions for ranitidine HCl tablets, effervescent tablets, syrup, and injection (Zantac; GlaxoSmithKline) to warn of drug interactions with midazolam.

Ranitidine has been reported to affect the bioavailability of other drugs through several different mechanisms such as competition for renal tubular secretion, alteration of gastric pH, and inhibition of cytochrome P450 hepatic enzymes.

Data from a pharmacokinetic study (n = 5) have demonstrated that oral ranitidine (150 mg twice daily) significantly increases oral midazolam exposure by up to 65%. As a result, patients receiving ranitidine and oral midazolam should be monitored for excessive or prolonged sedation.

However, this effect may be reduced by parenteral administration of midazolam. In a study of 8 volunteers receiving intravenous midazolam, a 300-mg oral dose of ranitidine only increased midazolam exposure by approximately 9%.

Ranitidine is a histamine H2 receptor antagonist indicated for the treatment and maintenance treatment of duodenal and gastric ulcers and erosive esophagitis. It is also used to treat gastroesophageal reflux disease and pathologic hypersecretory conditions such as Zollinger-Ellison syndrome and systemic mastocytosis.

Midazolam is a short-acting benzodiazepine derivative with anxiolytic, hypnotic, anticonvulsant, skeletal muscle relaxant, and sedative properties.

Azithromycin (Zithromax) May Potentiate the Effects of Oral Anticoagulants

On March 6, the FDA approved safety labeling revisions for azithromycin tablets and injection (Zithromax; Pfizer, Inc) to warn of a drug interaction with warfarin.

Although a study of 22 healthy men demonstrated that a 5-day course of azithromycin had no effect on prothrombin time from a subsequently administered dose of warfarin, spontaneous postmarketing reports suggest that concomitant administration of azithromycin may potentiate the effects of oral anticoagulants. The FDA advises that prothrombin times be carefully monitored in patients receiving azithromycin with oral anticoagulants.

Azithromycin is a macrolide antibiotic indicated for the treatment of mild to moderate infections caused by susceptible strains of designated microorganisms. Specific indications include nongonococcal urethritis and cervicitis from Chlamydia trachomatis; and the prophylaxis and treatment of disseminated mycobacterium avium complex disease.

Warfarin is an anticoagulant indicated for the prophylaxis and/or treatment of venous thrombosis, pulmonary embolism, and thromboembolic complications associated with atrial fibrillation and/or cardiac valve replacement. It is also indicated to reduce the risk for death, recurrent myocardial infarction, and thromboembolic events after myocardial infarction.

Efficacy of Posaconazole (Noxafil) Decreased by Coadministered Metoclopramide and Esomeprazole

On February 19, the FDA approved safety labeling revisions for posaconazole oral suspension (Noxafil; Schering Corp) to add information regarding drug interactions with metoclopramide and esomeprazole magnesium that decrease therapeutic efficacy.

Patients receiving metoclopramide or esomeprazole during posaconazole therapy should be monitored for breakthrough fungal infections, the FDA warned.

In a pharmacokinetic study, administration of 10-mg metoclopramide three times daily for 2 days increased gastric motility and yielded significant decreases in single-dose (400-mg) posaconazole plasma concentration (mean Cmax, ↓ 21%; AUC, ↓ 19%).

Similarly, use of 40-mg esomeprazole daily for 3 days increased gastric pH levels and led to even greater decreases in single-dose posaconazole plasma concentrations (mean Cmax, ↓ 46%; AUC, ↓ 32%).

Posaconazole is a triazole antifungal agent indicated for prophylaxis of invasive Aspergillus and Candida infections in patients 13 years and older who are at high risk for the development of these infections because of being severely immunocompromised, such as hematopoietic stem cell transplant recipients with graft-versus-host disease or those with hematologic malignant neoplasms with prolonged neutropenia from chemotherapy. Posaconazole is also indicated for the treatment of oropharyngeal candidiasis, including cases refractory to itraconazole and/or fluconazole.

The FDA notes that each dose of posaconazole should be taken with or immediately (within 20 minutes) after a full meal or liquid nutritional supplement to increase absorption. Alternatively, posaconazole may be taken with an acidic carbonated beverage such as ginger ale.

Metoclopramide is a prokinetic agent indicated for the treatment of symptomatic gastroesophageal reflux disease and diabetic gastroparesis.

Esomeprazole is a proton pump inhibitor indicated for the treatment of symptomatic gastroesophageal reflux disease, for the healing of erosive esophagitis, to reduce the risk for nonsteroidal anti-inflammatory drug–associated gastric cancer, and for the treatment of pathologic hypersecretory conditions such as Zollinger-Ellison syndrome. It is also indicated for use in triple therapy for Helicobacter pylori eradication to reduce the risk for duodenal ulcer recurrence.

Zantac Tablets Prescribing Information

Zantac Injection and Injection Premixed Prescribing Information

Zithromax Prescribing Information

Noxafil Prescribing Information


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