New antidepressant warnings in US and Britain

pharmafile | March 25, 2004 | News story | |   

New warnings about the prescribing of the Selective Serotonin Reuptake Inhibitor (SSRI) class of antidepressants have been issued in the US and UK, raising further doubts about the safety of the drugs.

The FDA has instructed the manufacturers of ten drugs in the class to include new warnings on their labels recommending close observation of adults and children for worsening depression or emergence of suicidal thoughts or behaviour.

The review has been in progress since June last year after reports that GlaxoSmithKline's Paxil (Seroxat in the UK) increased suicidal thoughts and actions in children given the drug off-label.

US media scrutiny of the drugs has intensified in recent weeks in the wake of the FDA inquiry and the suicide of a 19 year-old woman taking part in a trial of Eli Lilly's Cymbalta, a drug from the closely related selective norepinephrine reuptake inhibitor (SNRI) class. Four people diagnosed with depression committed suicide during the trial but Lilly say there is no evidence its drug caused the suicide.

Similarly, the FDA has indicated that a link has not been firmly established between the drugs and increased suicidal tendencies, with the pre-existing depression of patients being a significant confounding factor. The FDA says it will issue more definitive guidance on suicidal tendencies in the summer.

Meanwhile, a long-running investigation into SSRIs by the UK's MHRA has also recently released newly updated advice to doctors about prescribing Seroxat.

The expert working group of the Committee on Safety of Medicines has reminded health professionals that the licensed starting dose for Seroxat (paroxetine) for adults is 20mg in patients with depression, after finding that as many as 17,000 patients were started on higher doses last year. It said high doses and rapid increases in doses could result in serious adverse events, but said there was no evidence to suggest these included suicidality.

The CSM also advised that there is no clinical trial evidence that Seroxat has increased efficacy in treating depression in doses above 20mg, but GSK strongly dispute this conclusion.

Dr Alastair Benbow, European medical director at GlaxoSmithKline said the new guidance was "surprising and disappointing" and not supported by all the available evidence.

He added: "We believe that doctors should continue to have the flexibility to prescribe this medicine according to the needs of their patients – as they have done successfully for many years.

"We remain fully confident in the effectiveness of Seroxat, an important medicine with a well understood safety profile that has helped many millions of people around the world lead fuller and more productive lives."

The new advice recommends that for people with obsessive compulsive disorder (OCD) and panic disorder the recommended daily dose should be 40mg.

The CSM working group has been dogged by controversy since it was first launched towards the end of 2002, having to be re-launched in early 2003 because of conflicts of interest in two of its original members and continuing disagreements over scientific evidence.

Richard Brook, chief executive of mental health charity MIND was appointed in 2003 to the second expert group to represent the patient perspective, but has now resigned in protest at what he claims is the MHRA negligence.

"The Agency at last published information advising that many thousands of men and women in this country may have been taking Seroxat at a dose that was unsafe. What they failed to mention – and what I am now making public is the fact that the regulator had the data on which the basis of this decision was made for well over a decade as part of the original license application," Mr Brook said.

"Either they didn't understand the full implications of the available medical data at the time or, worse, that data was fully understood and they failed to act. Either way it amounts to extreme negligence and a clear dereliction of the MHRA duty to safeguard the well-being of the British public.

Drugs regulation simply has to put patients' interests first. We will continue to press the MHRA to release any information that is in the direct interests of consumers promptly and fully and we are restating our previous calls for a full and independen review of UK drugs regulation."

Mr Brook renewed his calls for a full and independent review of the MHRA, and has the backing of a number of campaigners in the field such as consumer activist Charles Medawar.

Meanwhile SANE, another UK mental health charity which takes a less adversorial approach to the MHRA and industry warned that the row could be bad news for patients.

Marjorie Wallace, chief executive of SANE said 70% of people with depression respond well to antidepressants but that inevitably some patients suffer serious side-effects.

"It's a pity that there should have been this unpleasant exchange between MIND and the Medicines and Healthcare Products Regulatory Agency," she said.  

"Our concern is not so much whether information on studies which apparently showed increased side effects, but which did not involve aggression or suicidality, was overlooked deliberately or accidentally which can only emerge in a further inquiry but that if the public loses faith in the safety of the newer medications prescribed for people with severe and crippling depression, many thousands will go untreated and others will be afraid to seek help. The alternative, older medications such as the tri-cyclic antidepressants not only have their own debilitating side effects but can be fatal even in a small overdose."

The Department of Health say a new lay person will be appointed to the expert group to replace Mr Brook and that it is expected to complete its inquiry by the summer.



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