FDA Safety Changes: Boniva, Emend, Clozaril

Yael Waknine

February 26, 2009

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February 25, 2009 — The US Food and Drug Administration (FDA) has approved safety labeling revisions to warn of the risk for upper gastrointestinal tract effects and hypocalcemia in patients receiving ibandronate sodium, the need for back-up oral contraceptive measures during and after aprepitant therapy, and drug interactions with clozapine that can decrease therapeutic efficacy and increase the risk for adverse events.

Ibandronate ( Boniva) Linked to Risk for Upper GI Tract Effects and Hypocalcemia

On November 28, 2008, the FDA approved safety labeling revisions for ibandronate sodium tablets (Boniva; Roche) to warn of the risk for upper gastrointestinal tract effects and hypocalcemia.

As with other oral bisphosphonates, ibandronate may cause upper gastrointestinal tract disorders such as dysphagia, esophagitis, and esophageal or gastric ulcer. To minimize the risk for these adverse events, patients should be advised to swallow the tablets with a full glass of water while standing or sitting in an upright position, and to remain in an upright position for 60 minutes thereafter. Chewing or sucking on tablets should be avoided because of the potential for oropharyngeal ulceration. Ibandronate should be discontinued if new or worsening gastrointestinal tract symptoms develop.

The FDA also warned of the potential for hypocalcemia after dosing with ibandronate. Preexisting hypocalcemia and other disturbances of bone and mineral metabolism should be treated before initiating ibandronate therapy, and adequate intake of calcium and vitamin D should be maintained during treatment.

Because products containing calcium and other multivalent cations (eg, aluminum, magnesium, and iron) are likely to interfere with ibandronate absorption, patients should wait at least 60 minutes before taking any other oral medications, including antacids, supplements, or vitamins.

Ibandronate is indicated for the treatment and prevention of postmenopausal osteoporosis.

Aprepitant ( Emend) May Decrease Efficacy of Hormonal Contraceptives

On November 18, 2008, the FDA approved safety labeling revisions for aprepitant capsules (Emend; Merck & Co, Inc) to warn of drug interactions with hormonal contraceptives.

According to the agency, coadministration of 40-mg aprepitant may reduce the efficacy of hormonal contraceptives during and for 28 days after the end of therapy. Alternative or back-up methods of contraception should therefore be used during this period.

The recommendation was based on data from a pharmacokinetic study in which a daily dose of an oral contraceptive containing ethinyl estradiol and norgestimate (which is converted to norelgestromin) was administered on days 1 through 21, and aprepitant 40 mg was given on day 8.

In the study, exposure (area under the receiver operating characteristic curve) to ethinyl estradiol decreased by 4% and 29% on days 8 and 12, respectively; norelgestromin area under the receiver operating characteristic curve increased by 18% on day 8 and decreased by 10% on day 12. Coadministration of aprepitant also yielded decreased trough concentrations for both hormonal products vs that associated with their use alone.

Previous studies of oral contraceptives and aprepitant (100 mg given once daily for 14 days, and 125 mg given as a 3-day regimen) support these findings.

Aprepitant, in combination with other antiemetic agents, is indicated for the prevention of acute and delayed nausea and vomiting associated with initial and repeated courses of moderately and highly emetogenic cancer chemotherapy; it also may be used for the prevention of postoperative nausea and vomiting.

Clozapine ( Clozaril) Drug Interactions Linked to Decreased Efficacy, Adverse Events

On November 6, 2008, the FDA approved safety labeling revisions for clozapine tablets (Clozaril; Novartis Pharmaceuticals Corp) to warn of drug interactions.

Because clozapine is a substrate for many hepatic cytochrome P 450 isoenzymes (CYP1A2, CYP2D6, and CYP3A4), the risk for metabolic interactions caused by an effect on an individual isoform is minimized. However, caution is advised with concomitant use of other drugs that are either inhibitors or inducers of these enzymes.

Coadministration of drugs known to induce CYP450 isoenzymes may decrease clozapine plasma levels and treatment efficacy. Agents known to have this effect include phenytoin, nicotine, and rifampin.

In contrast, concomitant use of drugs known to inhibit the activity of CYP450 isoenzymes may increase the plasma levels of clozapine and the potential for adverse events. Drugs in this category include citalopram, cimetidine, caffeine, ciprofloxacin, and erythromycin.

Clozapine is an atypical antipsychotic agent indicated for the management of treatment-resistant schizophrenia and for reducing the risk for recurrent suicidal behavior in at-risk patients with schizophrenia or schizoaffective disorder.

Boniva Prescribing Information

Emend Prescribing Information

FDA Safety Information


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