Novartis promotes imatinib (Gleevec) for unapproved dosages to treat gastrointestinal tumours (GIST), myelogenous leukemia (CML): Warns US FDA

US FDA has warned Novartis against promoting the use of imatinib (Gleevec) in gastrointestinal stromal tumours (GIST) and chronic myelogenous leukemia (CML) in unapproved dosage strengths.

The U.S. Food and Drug Administration  has reviewed two websites (www.gistalliance.com and www.cmlalliance.com) sponsored by Novartis.These websites are false and misleading because they promote the drug for an unapproved use, fail to disclose the risks associated with the use of Gleevec and make unsubstantiated dosing claims about this medication that can put patients at higher risk of experiencing serious adverse events, US FDA said.

Gleevec is not approved for neoadjuvant use in GIST patients (nor is any other drug), and the approved product insert (PI) for Gleevec does not include any information on the safety and efficacy of this drug when used before surgical resection of GIST tumours.

Therefore, the webpages suggest a use for Gleevec for which safety and effectiveness has not been established, thereby creating a new intended use for the drug for which the approved PI lacks adequate directions.

The recommended dose of Gleevec is 400 mg/day for adult patients in chronic phase CML and 600 mg/day for adult patients in accelerated phase or blast crisis.

In CML, a dose increase from 400 mg to 600 mg in adult patients with chronic phase disease, or from 600 mg to 800 mg (given as 400 mg twice daily) in adult patients in accelerated phase or blast crisis may be considered in the absence of severe adverse drug reaction and severe non-leukemia related neutropenia or thrombocytopenia in the following circumstances: disease progression (at any time), failure to achieve a satisfactory hematologic response after at least 3 months of treatment, failure to achieve a cytogenetic response after 6-12 months of treatment, or loss of a previously achieved hematologic or cytogenetic response.

The recommended dose of Gleevec is 400 mg/day for adult patients with unresectable and/or metastatic, malignant GIST. A dose increase up to 800 mg daily (given as 400 mg twice daily) may be considered, as clinically indicated, in patients showing clear signs or symptoms of disease progression at a lower dose and in the absence of severe adverse drug reactions.

The recommended dose of Gleevec is 400 mg/day for the adjuvant treatment of adult patients following complete gross resection of GIST. In the clinical study, Gleevec was administered for one year. The optimal treatment duration with Gleevec is not known.

The likelihood of developing an adverse reaction to Gleevec increases with higher doses. In the event of certain severe adverse reactions, such as hepatotoxicity, cytopenias, or severe fluid retention.

Promotional materials are misleading if they omit material facts about the consequences that may result from the use of the drug as recommended or suggested by the materials. The websites make prominent claims of effectiveness for Gleevec in GIST and CML, but omit material facts about the considerable risks associated with this drug.

The totality of these presentations suggests that a lack of response in patients may be due to low plasma levels of Gleevec, and that the dose of Gleevec should be modified (i.e., increased) in the event that plasma concentrations of the drug are found to be “suboptimal.”

US FDA is not aware of substantial evidence or substantial clinical experience to support a correlation between patient outcome and plasma levels of imatinib.

Also, the referenced publications cited on the GIST Alliance webpage do not provide substantial evidence or substantial clinical experience to support these claims. Specifically, only one of the publications referenced to support such an implication is relevant to GIST patients.

Furthermore, the suggestion that the dose of Gleevec should be modified in the event that plasma concentrations of the drug are found to be “suboptimal” may put patients at considerable risk of adverse events, many of which are dose-related.

The fact that these misleading dosing claims are presented without any discussion of serious or potentially dose-related side effects, such as neutropenia or thrombocytopenia, is grossly misleading and greatly minimizes the potential risk to patients of increasing the dose.

US FDA further noted that these websites heavily promote the “CML & GIST Alliance™ Blood Level Testing Program,” which encourages physicians to test their patients for “suboptimal” plasma levels of imatinib.

Novartis explicitly recommends a laboratory (Avantix Laboratories) to provide the corresponding testing services and provides hyperlinks that physicians can use to access these recommended services, US FDA said.