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Another safety scare for Roche

By Anna Lewcock , 30-Oct-2007

In another safety concern over a long-approved drug, Roche has been forced to add new warnings to its anti-transplant rejection drug CellCept (mycophenolate mofetil (MMF)) amid the news that it is associated with increased risk of miscarriage and congenital birth defects.

Roche sent out a warning letter to healthcare professionals informing them of the change to US labelling for the drug, which upped the pregnancy warnings from Category C - 'risk of foetal harm cannot be ruled out' - to Category D - 'positive evidence of foetal risk.' The change has come following postmarketing data collected by the United States National Transplantation Pregnancy Registry (NTPR) and Roche's adverse event reporting system, looking at women exposed to systemic MMF during pregnancy. The NTPR's December 2006 figures showed that from a total of 24 female patients there were 33 pregnancies exposed to the drug. 45 per cent of these (15 cases) were spontaneously aborted, leaving 18 live births. Of these 18, 4 children were reported to have 'structural malformations.' Additional postmarketing data collected from 1995 (when the drug was first approved) through to 2007 on 77 women exposed to systemic MMF during pregnancy, revealed 25 spontaneous abortions and 14 malformed infants or foetuses, six of which had ear abnormalities.


Roche has now informed healthcare professionals that the use of CellCept is "associated with an increased risk of first trimester pregnancy loss and increased risk of congenital malformations, especially external ear and other facial abnormalities including cleft lip and palate, and abnormalities of the distal limbs, heart, oesophagus and kidney." While the drug had always carried a warning recommending that it not be used in pregnancy unless no alternatives could be found, the changes to the labelling reflect the evidence of the post-marketing data and the distinct risk to unborn children that has been identified. A Roche spokesperson told in-PharmaTechnologist.com that despite the fact that the majority of women experiencing miscarriages or malformed infants were taking CellCept in combination with other drugs, the company changed the product labelling in the interest of patient safety. At present the change has only been implemented in the US, but discussions have been taking place over in Europe in parallel with the FDA, and a European Medicines Agency (EMEA) approved letter is due to be sent out to doctors shortly.


According to a spokesperson from the EMEA, updates were made to the CellCept's paperwork in September, referring to evidence of congenital malformations (particularly of the ear) in children whose mothers had been treated with the drug whilst pregnant. CellCept, however, is not the only drug having its pregnancy warnings updated. Fellow anti-rejection drugs, based on the immunosuppressant mycophenolic acid (MPA), are also being amended to reflect the more concrete findings regarding the risks to unborn children. MPA is the basis of Novartis anti-rejection drug Myfortic. Both drugs exhibited reproductive toxicity in animal studies, but human data regarding potential harm to foetuses was lacking until now. CellCept is currently one of the key products in Roche's portfolio, having brought in CHF1.5bn (€0.9bn) over the year to date (8 per cent up on last year). Despite the change to the drug's black box warning, however, revenues are unlikely to be damaged too much considering the stringent instructions regarding female patients that were included in the drug's original warnings.


The change to the labelling serves to reinforce these requirements, including the condition that women should have a negative pregnancy test within one week of starting therapy, and use two forms of contraception from four weeks prior to starting CellCept treatment through to six weeks after treatment is completed. Though this update does not represent a major change for prescribers, the negative publicity regarding the safety of another Roche drug comes relatively hot on the heels of the safety concerns over another long-standing product, Viracept (nelfinavir).


Despite the fact that the marketing authorisation for the drug was reinstated two weeks ago following its suspension after contamination with a carcinogenic compound over the summer, any safety concerns over Roche drugs are now perhaps likely to garner a little more attention and potential negative publicity for the company.

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