There are currently two types of mycophenolate preparations available in Singapore - mycophenolate mofetil (MMF) (Cellcept®, Roche) and mycophenolic acid (MPA) as sodium salt (Myfortic®, Novartis). MMF is approved for use in combination with ciclosporin and corticosteroids for the prophylaxis of acute transplant rejection in adults receiving allogenic renal, cardiac or hepatic transplants while MPA is approved for use in combination with ciclosporin microemulsion and corticosteroids for the prophylaxis of acute transplant rejection in patients receiving allogenic renal transplants.
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A) Teratogenic risks associated with mycophenolate group of drugs
Based on the publication by Sifontis et al1,post-marketing data from the US National Transplant Pregnancy Registry (NTPR), and MMF worldwide adverse event reporting, use of MMF during pregnancy is associated with an increased risk of first trimester pregnancy loss and an increased risk of congenital malformations. External ear and other facial abnormalities including cleft lip and palate, and anomalies of the distal limbs, heart, oesophagus, and kidney were the main congenital malformations observed.
In December 2006, the NTPR published data about the pregnancy outcomes of 24 female transplant patients exposed to MMF-containing regimens. A total of 33 pregnancies were reported by these patients to the registry, of which there were 15 spontaneous abortions (45%). Of the 18 live-born infants, four had structural malformations (22%). Three of the four of these structural malformations include microtia.2
In post-marketing data collected worldwide from 1995 to 2007, of the 77 women exposed to systemic MMF during pregnancy, 25 had spontaneous abortions and 14 had a malformed infant or foetus. Six of these 14 malformed offsprings had ear abnormalities. As these post-marketing data were reported voluntarily, it was not always possible to reliably estimate the frequency of any particular adverse outcomes.
Similar structural malformations have been observed in preclinical animal reproductive toxicology studies.
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B) Post-marketing reports of progressive multifocal leukoencephalopathy
The US Food and Drug Administration recently issued a class-label request to all US manufacturers of marketed mycophenolate group of drugs with respect to the risk of progressive multifocal leukoencephalopathy (PML).
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Background information on PML
PML is a rare, progressive, demyelinating disease of the central nervous system (CNS) that usually leads to death or severe disability.3 PML is caused by the reactivation of the JC virus, a polyomavirus that resides in latent form in 70%–90% of the adult population worldwide. JC virus usually remains latent, typically only causing PML in immunocompromised patients. The factors leading to activation of the latent infection are not fully understood although abnormalities in T-cells have been described as important for reactivation of JC virus and PML. Patients usually present with focal CNS abnormalities and radiographic evidence of white matter disease without mass effect.
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PML cases reported with mycophenolate group of drugs
PML has been described in transplant patients involving different immunosuppressant medicines. Seventy-five percent of all the PML cases reported in transplant recipients presented subacutely: haemiparesis, apathy, confusion, cognitive deficiencies, and ataxia were the most frequently presented features. Roche has confirmed that in the Roche worldwide adverse event reporting system, there are currently 17 cases of PML that are potentially associated with MMF. To date, Novartis' global safety database for MPA has no cases of PML.
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Conclusion
In view that MMF is converted to MPA following oral or intravenous administration, both drugs would be deemed to carry the same potential risks for teratogenicity and PML.
The local package inserts of Cellcept® and Myfortic® have been amended to include the updated safety information on teratogenic risks and PML associated with the use of these products. Roche and Norvartis have separately issued Dear Healthcare Professional Letters to alert healthcare professionals about the labelling update regarding the teratogenic risks with Cellcept®. The letters also reiterated that these drugs are not recommended in pregnancy unless the benefit outweighs the potential risk to the foetus.
Roche has updated the local Cellcept® package inserts with information on PML and issued a Dear Healthcare Professional Letter to provide more information about this matter. The product insert of Myfortic® is in the process of being updated with safety information on PML. Healthcare professionals are advised to consider PML in the differential diagnosis of any transplant recipient who develops neurological symptoms. Consideration should also be given to reducing the amount of immunosuppression if a patient develops PML whilst balancing against the possible risk of graft rejection.
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References
1. Transplantation Dec 2006;82:1698-1702
2. FDA Information for Healthcare Professionals. http://www.fda.gov/cder/drug/InfoSheets/HCP/mycophelolateHCP.htm
3. Communication About an Ongoing Safety Review of CellCept and Myfortic. http://www.fda.gov/cder/drug/early_comm/mycophenolate.htm
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