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FDA Safety Labeling Changes: Ellence, Abilify, Kaletra

Yael Waknine;

June 1, 2005 The U.S. Food and Drug Administration (FDA) approved in March revisions to safety labeling to advise that use of epirubicin HCl is associated with a cumulative risk of developing leukemia; use of aripiprazole HCl in elderly patients with dementia-related psychosis is associated with an increased risk of cerebrovascular adverse events; and coadministration of fluticasone propionate and ritonavir plus lopinavir is not recommended because of a drug interaction with the ritonavir component of the combination drug.

Epirubicin HCl (Ellence) Linked to Cumulative Risk of Leukemia

On March 2, the FDA approved revisions to the safety labeling for epirubicin HCl injection (Ellence, made by Pfizer, Inc.) to warn of the cumulative dose-related increase in risk of acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS) secondary to its use.

Secondary AML with or without a preleukemic phase has been reported in patients treated with anthracyclines and is more common after dose escalations, heavy pretreatment with cytotoxic agents, or when they are used in combination with DNA-damaging antineoplastic agents. The leukemias can have a short one- to three-year latency period.

An analysis of data from controlled clinical trials involving 7,110 patients who received epirubicin as a component of adjuvant polychemotherapy regimens for early breast cancer revealed a cumulative risk of secondary AML/MDS of about 0.27% (approximate 95% confidence interval [CI], 0.14 - 0.40) at three years, 0.46% (approximate 95% CI, 0.28 - 0.65) at five years, and 0.55% (approximate 95% CI, 0.33 - 0.78) at eight years.

Increasing cumulative doses of epirubicin was associated with an increasing risk of developing AML/MDS, particularly in patients who had received more than the maximum recommended cumulative dose of epirubicin (720 mg/m2) or cyclophosphamide (6,300 mg/m2).

The FDA notes that results of animal studies have shown epirubicin to be mutagenic, clastogenic, and carcinogenic.

Epirubicin HCl injection is indicated as a component of adjuvant therapy in patients with evidence of axillary node tumor involvement following resection of primary breast cancer.

Aripiprazole (Abilify) Increases Risk of Stroke in Elderly Patients With Dementia

On March 1, the FDA approved revisions to the safety labeling for aripiprazole tablets and oral solution (Abilify, made by Otsuka Maryland Research Institute) to warn of the risk of cerebrovascular adverse events, including stroke, associated with its use in elderly patients with dementia-related psychosis.

Results of three placebo-controlled clinical studies (one fixed-dose and two flexible-dose studies) showed that aripiprazole was associated with an increased incidence of cerebrovascular adverse events (eg, stroke, transient ischemic attack), including fatalities, in elderly patients (mean age, 84 years; range, 78 - 88 years) with dementia-related psychosis.

Results of the fixed-dose study further revealed a statistically significant dose-response relationship for cerebrovascular adverse events in patients treated with aripiprazole.

Aripiprazole is indicated for the treatment of schizophrenia. It is also indicated for the treatment of acute manic and mixed episodes associated with bipolar disorder and the maintenance of stability for up to six weeks. Aripiprazole is not approved for the treatment of dementia-related psychosis.

Ritonavir/Lopinavir (Kaletra) Not Recommended for Use With Fluticasone Propionate

On March 28, the FDA approved revisions to the safety labeling for lopinavir plus ritonavir capsules and oral solution (Kaletra, made by Abbot Laboratories) to warn against their coadministration with fluticasone propionate.

Results of a drug interaction study in healthy adults have shown that the ritonavir component of the combination drug significantly increases plasma fluticasone propionate exposures, resulting in significantly decreased serum cortisol concentrations.

In addition, the FDA has received postmarketing reports of systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression, in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate.

Coadministration of fluticasone propionate and the combination drug therefore is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid adverse effects.

Lopinavir plus ritonavir capsules and oral solution are indicated for use in combination with other antiretroviral agents for the treatment of HIV-1 infection.

Reviewed by Gary D. Vogin, MD

Johnson & Johnson Pharmaceutical Research & Development, L.L.C. Receives Not Approvable Letter From FDA for Tipifarnib Based on Phase II Data

RARITAN, N.J., June 30, 2005 /PRNewswire-FirstCall/ -- Johnson & Johnson Pharmaceutical Research & Development, L.L.C. (J&JPRD) announced it has received a not approvable letter from the U.S. Food and Drug Administration (FDA) for the tipifarnib new drug application (NDA), which was based on data from a single Phase II study. Tipifarnib is an oral medication studied to treat acute myeloid leukemia (AML) in elderly patients who are not candidates for standard chemotherapy. The not approvable letter explains why the NDA cannot be approved based on currently submitted data.

The company remains committed to the development of tipifarnib. Recognizing the unmet medical need in this area, the company is reviewing the FDA's letter and will determine appropriate next steps.

J&JPRD completed the submission of the tipifarnib NDA to the FDA under the Continuous Marketing Application Pilot-1 Program in December 2004, and the application was discussed at a May 5, 2005 Oncology Drugs Advisory Committee meeting. As a drug intended to treat a life-threatening disease for which there is an unmet medical need, tipifarnib was granted "Fast Track" status by the FDA in June 2004. Tipifarnib also was granted Orphan Drug status, a designation given to medications used to treat a rare disease or condition.

AML is a rare but often fatal cancer that will impact nearly 12,000 Americans in 2005.

About Johnson & Johnson Pharmaceutical Research & Development, L.L.C.

Johnson & Johnson Pharmaceutical Research & Development, L.L.C. (J&JPRD) is part of the Johnson & Johnson Family of Companies, the world's most broadly-based producer of healthcare products. J&JPRD, with its headquarters in Raritan, N.J., has eleven sites throughout Europe and the United States. J&JPRD is leveraging drug discovery and drug development in a variety of therapeutic areas to address unmet medical needs worldwide. Combining innovation and experience, the company's major therapeutic areas of focus include hematology, oncology, infectious disease, neurology and psychiatry, pain and women's health.

This press release contains "forward-looking statements" as defined in the Private Securities Litigation Reform Act of 1995. These statements are based on current expectations of future events. If underlying assumptions prove inaccurate or unknown risks or uncertainties materialize, actual results could vary materially from the Company's expectations and projections. Risks and uncertainties include general industry conditions and competition; economic conditions, such as interest rate and currency exchange rate fluctuations; technological advances and patents attained by competitors; challenges inherent in new product development, including obtaining regulatory approvals; domestic and foreign health care reforms and governmental laws and regulations; and trends toward health care cost containment. A further list and description of these risks, uncertainties and other factors can be found in Exhibit 99(b) of the Company's Annual Report on Form 10-K for the fiscal year ended January 2, 2005. Copies of this Form 10-K are available online at http://www.sec.gov or on request from the Company. The Company assumes no obligation to update any forward-looking statements as a result of new information or future events or developments.

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Source: Johnson & Johnson Pharmaceutical Research & Development, L.L.C.

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