Wyeth Pharmaceuticals affirms the safety and efficacy of
EFFEXOR (venlafaxine HCl) and EFFEXOR XL? (venlafaxine HCl sustained release), (collectively EFEXOR), and disagrees with the United Kingdom's (UK) Medicine and Healthcare Products Regulatory Agency's (MHRA) decision to require interim measures that would restrict access to these treatments.
"Wyeth's most recent review of preclinical and clinical data, and 10 years of post-marketing experience with more than 10 million patients, confirm the safety and efficacy of
EFFEXOR for the treatment of depression and anxiety," says Gary L. Stiles, M.D., Executive Vice President, Chief Medical Officer for Wyeth Pharmaceuticals. "Importantly, these data do not establish a relationship between therapeutic doses of EFEXOR and cardiac arrhythmias (disruptions of the heart rhythm) beyond what is currently described in our labeling."
The MHRA has required provisional labeling for EFEXOR in the UK that will state that: initiation of treatment should be restricted to specialist care with starting doses limited to 75mg; the products are indicated for moderate to severe patients; a baseline ECG is recommended for new patients; and, the products are contraindicated in patients with preexisting cardiovascular disease. Additional information regarding the MHRA's action is available on its Internet web site at www.mhra.gov.uk.
The MHRA's provisional action stems from, among other factors, its view that EFEXOR could be associated with disruption of the heart rhythm, and could be associated with severe reactions following abrupt discontinuation. Additionally, the Agency reviewed publications relying on data from the Office of National Statistics (ONS). The ONS data suggest that EFEXOR is associated with a rate of fatal overdose significantly higher than selective serotonin reuptake inhibitors (SSRIs), but significantly lower than the rate associated with tricyclic antidepressants (TCAs).
Wyeth's analyses of the ONS report using the UK's General Practice Research Database (GPRD) found that physicians prescribed EFEXOR to patients who on average had more risk factors for suicide than patients who were prescribed certain SSRIs. This is not unexpected since in clinical practice EFEXOR is frequently used when other agents (SSRIs, TCAs) have been ineffective. Specifically, prior to receiving EFEXOR, these patients had a higher incidence of prior hospitalizations for depression, schizophrenia along with depression, failure to respond to other antidepressants, and suicidal behavior in the preceding year. The magnitude of these risk factors is strikingly similar to the different rates of fatal overdose that were seen.
Moreover, in data from clinical trials in which there were controls to assure that patients were similar, EFEXOR was superior to placebo in reducing suicidal thoughts and performed at least as well as comparator SSRIs. Thus it appears most likely that the increased rate of fatal overdose observed with EFEXOR actually reflects a differential risk of suicide attempt inherent to the patients' conditions rather than a direct effect of EFEXOR itself.
Allison Jeynes-Ellis, M.D., Wyeth Medical Director, United Kingdom and Republic of Ireland, adds, "The MHRA's conclusions fail to account for these critical data. Restricting access to medication is not in the best interest of patients, and is a backward step in the treatment of depression in this country. In the UK, many of the nearly 300,000 EFEXOR patients have failed on one or more other antidepressants. The MHRA's action may lead to the increased use of less appropriate medications such as TCAs that have a long history of safety concerns - including a higher risk of fatal overdose, suicide, and disruptions of cardiac rhythm at therapeutic doses."
The MHRA has asked for new class labeling addressing suicide risk, dosing and discontinuation. Wyeth finds these changes consistent with the Company's recent labeling proposals made in the UK and is evaluating the appropriateness of these changes in other parts of the world.
While the MHRA has reaffirmed EFEXOR as an "important drug in treating many patients with depressive illness," Wyeth finds that the provisional labeling required by the MHRA will needlessly place restrictions on the future use of EFEXOR by inappropriately defining broad cardiovascular contraindications and by limiting initiation of EFEXOR therapy to specialist care.
Wyeth will challenge the MHRA's action and has urged the agency to accept the Company's previous recommendations for enhanced labeling, educational initiatives, and new packaging aimed to help physicians and patients reduce the risk of suicide and overdose. During the process, Wyeth will comply with the MHRA interim measures in accordance with regulation 6A of the Medicines for Human Use Regulations 1994. In addition, the Company intends to communicate with regulatory bodies worldwide regarding this information.