[U.S. Food and Drug Administration]

FDA Medical Bulletin * March 1997 * Volume 27 Number 1

First Nonprescription Nasal Spray to Prevent, Treat Allergic Rhinitis

FDA has approved cromolyn sodium for over-the-counter marketing. It is the first nonprescription nasal spray that specifically helps prevent and treat symptoms related to nasal allergies. Cromolyn sodium, available by prescription since 1983, can be used regularly by adults and by children age 6 and older.

When used prior to allergen exposure, such as before the start of the hay fever season, cromolyn sodium is effective in diminishing allergic nasal symptoms (rhinitis). Although it is also effective for treating established allergic nasal symptoms, the full benefit may not become apparent for up to 2 weeks of treatment, so antihistamines and/or nasal decongestants may be necessary during the initial phase of treatment with cromolyn sodium nasal spray. The nasal spray is generally well tolerated, although some patients may experience local reactions that include sneezing and nasal stinging, burning, and irritation.

McNeil Consumer Products will market cromolyn sodium under the trade name Nasalcrom (Nasal Allergy Symptom Controller).

[Table of Contents]

First Prescription Treatment for Oral Ulcers

FDA has approved amlexanox oral paste, 5 percent, the first prescription treatment for aphthous ulcers in people with normal immune systems. Aphthous ulcers are painful, severe canker sores in the mouth. FDA based its approval on placebo-controlled clinical trials demonstrating that amlexanox reduced the time for ulcers to heal. In general, patients improved 1 to 1-1/2 days sooner with amlexanox; pain relief was also faster. While people with AIDS do develop especially virulent forms of aphthous ulcers, the safety and effectiveness of this drug in immunocompromised individuals has not been assessed at this time.

The drug is contained in a paste that is applied directly to the ulcers four times a day, following oral hygiene after meals and before bedtime. Health care providers should advise their patients to make a return visit if the ulcers have not healed in 10 days. Some clinical trial participants reported stinging or burning where the medicine was applied and, less frequently, nausea and diarrhea.

Block Drug Company Inc. of Jersey City, New Jersey, manufactures amlexanox under the trade name Aphthasol.

[Table of Contents]

Significant Devices Approved Faster

FDA approved 43 premarket approval applications (PMAs) in fiscal year 1996, 16 more than in fiscal year 1995. Half these devices are new technologies for diagnosis and treatment. Eight PMAs were reviewed in 1 year or less. Key 1996 PMA approvals in fiscal year 1996 include the following:

For more information, contact Center for Devices and Radiological Health, CDRH, Program Operations Staff, phone (301) 594-2186, Fax (301) 443-8299.

[Table of Contents]

FDA Proposes to Withdraw Seldane Approval

FDA has announced its intention to withdraw the approval of Seldane (terfenadine), Seldane-D (terfenadine and pseudoephedrine), and generic versions of the prescription antihistamine. The Agency has determined that drugs containing terfenadine are no longer shown to be safe because Allegra (fexofenadine) is now available. Terfenadine is a pro-drug. Fexofenadine is the active metabolite of terfenadine produced in the body, and it provides nearly all of terfenadine's therapeutic effect. It does not, however, block cardiac potassium channels or cause QT prolongation or ventricular arrhythmias, notably torsades de pointes type ventricular tachycardia, as terfenadine can at greater than usual blood levels.

Introduced in 1985, terfenadine is marketed by Hoechst Marion Roussel of Kansas City, Missouri, and was the first prescription antihistamine to relieve the symptoms of allergic rhinitis without causing drowsiness. Following its approval, FDA received reports of serious and sometimes fatal cardiac arrhythmias associated with terfenadine when it was taken with some other medications that interfere with its metabolism to fexofenadine by cytochrome P450 3A4 or when taken by patients with liver disease. These other drugs, such as erythromycin (an antibiotic) and ketoconazole (an antifungal drug), can lead to terfenadine buildup in the blood and the resulting potential for serious, sometimes fatal, cardiac arrhythmias.

Since the serious cardiac risks of terfenadine were identified, several educational campaigns have been launched by the drug's sponsor and FDA to inform health care providers and patients about the dangers of these drug interactions. These have included FDA warning statements, labeling changes, and "Dear Doctor" letters. Although these efforts have reduced inappropriate prescribing and dispensing of terfenadine with other drugs and reports of arrhythmias, such events have not been, and almost certainly cannot be, eliminated.

Prior to the approval of fexofenadine, FDA considered the benefits of terfenadine to outweigh its risks despite the serious arrhythmias that could result from its inappropriate use. Now that fexofenadine is available (approved July 1996) and provides the therapeutic benefits of terfenadine without the associated serious cardiac risks, FDA has determined that terfenadine-containing products should be removed from the market. The Agency has provided the manufacturers of these products an opportunity to request a hearing to show that the products should not be withdrawn. In the meantime, FDA is advising health care professionals to switch patients currently taking Seldane, Seldane-D, and generic terfenadine products to alternative medications.

[Table of Contents]

Medication Errors

FDA is asking the help of the medical community in reporting medication errors that result, or could result, in adverse drug events. Medication errors can be a source of significant morbidity and mortality in the health care setting. Therefore, it is important that medication errors be monitored so that similar incidents can be prevented in the future. Problems associated with devices that lead to medication errors should also be reported. FDA reviews each medication error report and, if warranted, takes appropriate action on labeling and packaging problems. In some cases, changing the design, name, or packaging of a product can help prevent medication errors.

Medication errors or potential errors may be reported in confidence to FDA's MEDWATCH program (call 1-800-FDA-1088 or fax the MEDWATCH form to 1-800-FDA-0178). When reporting a medication error to MEDWATCH, the "Product Problem" portion of the form should be completed with a description of the packaging, labeling, or device problem. We know that confidentiality is extremely important, especially in the area of reporting errors. Current federal regulations protect the identities of reporting individuals and institutions from disclosure.

The FDA Medical Bulletin will be routinely providing feedback to the medical community on some of the more significant medication errors. Here are some of the more important medication errors reported recently:

CAMPTOSAR INJECTION
(Irinotecan HCl Injection; Pharmacia and Upjohn)
FDA has received several reports, including fatalities, of accidental overdoses when the total drug content of the 5 mL vial was inadvertently given instead of 1 mL. A label change for this product has been made that includes the total drug content (100 mg/5 mL) and the concentration per milliliter (20 mg/mL).

CEREBYX INJECTION
(Fosphenytoin Sodium Injection; Parke-Davis)
FDA has received numerous reports of confusion and error resulting in overdoses and underdoses. Practitioners should be aware that this product has a unique way of expressing the dosage. The drug dosage should be prescribed in terms of its "phenytoin equivalent" (PE). Although 150 mg of fosphenytoin sodium will be administered, a prescription should be written as "fosphenytoin 100 mg PE." FDA is monitoring these reports. Certain labeling changes have recently been approved to clarify these dosing relationships.

CISPLATIN INJECTION
Several reports have been received of overdoses with cisplatin injection (Platinol-AQ; Bristol-Myers Squibb) when carboplatin was the intended agent. The flip-off seal and aluminum caps have now been imprinted "CALL DR IF DOSE > 100 MG/M2/CYCLE." In addition, a boxed warning now appears stating that doses greater than 100 mg/m2 once every 3 to 4 weeks are rarely used. Other labeling enhancements include highlighting the "cis" in "cisplatin," so that it is less likely to be confused with "carboplatin," and a red stop sign to encourage verifying the dose and drug.

NAME CONFUSION

The following represent some of the name confusion reports that the Agency has received. Confusion could be due to similarities in the sound or written form of the names: