FDA Safety Changes: Promethazine HCl and Codeine Oral Solution, Ranexa, Ethyol

Yael Waknine

February 11, 2009

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April 23, 2009 — Editor's Note: The information for ranolazine (Ranexa) has been revised to reflect that the 2008 safety labeling changes differ from the original labeling issued in 2006.

February 11, 2009 (UPDATED April 23, 2009)— The US Food and Drug Administration (FDA) has approved safety labeling revisions to warn against the use of promethazine HCl plus codeine oral solution in children younger than 6 years, advise of drug interactions with ranolazine extended-release tablets, and inform clinicians regarding the risk for severe cutaneous reactions in patients receiving treatment with amifostine injection.

Promethazine/Codeine Combination Contraindicated in Young Children

In November 2008, the FDA approved safety labeling revisions for promethazine HCl and codeine phosphate oral solution (ANI Pharmaceuticals, Inc) to include strengthened warnings against its use in children younger than 6 years. The warning was also included in the prescribing information for promethazine, codeine, and phenylephrine HCl oral solution (ANI Pharmaceuticals, Inc).

A new boxed warning advises that concomitant use of promethazine products with other respiratory depressants has been linked to postmarketing cases of pediatric respiratory depression, some of which have resulted in death.

Such cases have also been reported in connection with a wide range of weight-based promethazine doses in children younger than 2 years.

The FDA notes that both therapeutic and overdoses of promethazine may cause hallucinations and convulsions in pediatric patients, and excessively large doses of this or other antihistamines may result in sudden death.

Caregivers and patients who can use the drug should be advised to measure medicated oral solutions with an accurate dosing device vs household teaspoons that vary in size and can lead to inadvertent overdose, particularly when a half-teaspoon dose is required.

Promethazine plus codeine oral solution is indicated for the temporary relief of coughs and upper respiratory tract symptoms associated with allergy or the common cold. The drug combination is also available with phenylephrine to address nasal congestion.

Ranolazine (Ranexa) Linked to Metabolism-Based Drug Interactions

On November 5, 2008, the FDA approved safety labeling revisions for ranolazine extended-release tablets (Ranexa; CV Therapeutics, Inc).

The 2008 safety labeling revisions differ from the original labeling issued in 2006.

In the 2008 label, the FDA has removed the restriction that limited the use of ranolazine for the treatment of chronic angina to second-line therapy because of the dose-related risk for QT interval prolongation. The drug can now be used alone or in combination with beta-blockers, nitrates, calcium channel blockers, antiplatelet therapy, lipid-lowering therapy, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers.

The agency notes that although QT interval prolongation is still possible, the effect of high doses, use with QT interval-prolonging drugs, or potassium channel variants causing prolonged QT interval remain unclear.

Because ranolazine is primarily metabolized by cytochrome P-450 hepatic isoenzyme 3A (CYP3A), concomitant use of strong enzyme inhibitors increases average steady-state plasma concentrations and the potential for dose-related adverse events such as QT interval prolongation. Use of ranolazine should be avoided in patients taking strong CYP3A inhibitors such as ketoconazole, itraconazole, clarithromycin, nefazodone, nelfinavir, ritonavir, indinavir, and saquinavir.

For patients taking moderate CYP3A inhibitors, ranolazine dosing should be limited to 500 mg twice daily. Drugs classified as moderate inhibitors include diltiazem, verapamil, aprepitant, erythromycin, fluconazole, and grapefruit juice/products.

Because of the potential for decreased steady-state concentrations and efficacy, use of ranolazine should be avoided in patients taking CYP3A inducers such as rifampin, rifabutin, rifapentin, phenobarbital, phenytoin, carbamazepine, and St. John's Wort.

Amifostine ( Ethyol) Linked to Risk for Severe Cutaneous Reactions

On November 7, 2008, the FDA approved safety labeling revisions for amifostine injection (Ethyol; MedImmune, Inc) to provide strengthened warnings regarding the risk for cutaneous reactions.

Severe reactions associated with amifostine administration have included erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, toxoderma, and exfoliative dermatitis. These events, some of which have resulted in death or required hospitalization and/or discontinuation of therapy, have been reported more frequently when amifostine is used as a radioprotectant.

The FDA advises that patients be carefully monitored before, during, and after amifostine administration and warns that the development of serious cutaneous reactions may be delayed by several weeks after initiation of therapy.

Amifostine should be permanently discontinued in patients who experience serious or severe cutaneous reactions or cutaneous reactions associated with fever or other constitutional symptoms of unknown cause.

Treatment with amifostine should be withheld and dermatologic consultation and biopsy considered for cutaneous reactions or mucosal lesions of unknown cause that appear outside of the injection site or radiation port, and for erythematous, edematous, or bullous lesions on the palms of the hand or soles of the feet. Resumption of therapy should be at the clinician's discretion based on clinical judgment and appropriate dermatologic evaluation.

Amifostine injection is indicated to reduce the incidence of moderate to severe xerostomia in patients undergoing postoperative radiation treatment for head and neck cancer, where the radiation port includes a substantial portion of the parotid glands. It also may be used to reduce the cumulative renal toxicity associated with repeated administration of cisplatin in patients with advanced ovarian cancer.

Promethazine HCl and Codeine Phosphate Oral Solution Prescribing Information

Promethazine HCl, Phenylephrine, and Codeine Phosphate Oral Solution Prescribing Information

Ranexa Prescribing Information

Ethyol Prescribing Information


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