Atajec Special Precautions

Neoplasms: Patients receiving immunosuppressive regimens involving combinations of medicinal products, including mycophenolate mofetil, are at increased risk of developing lymphomas and other malignancies, particularly of the skin. The risk appears to be related to the intensity and duration of immunosuppression rather than to the use of any specific agent. As general advice to minimize the risk for skin cancer, exposure to sunlight and UV light should be limited by wearing protective clothing and using a sunscreen with a high protection factor.
Infections: Patients treated with immunosuppressants, including mycophenolate mofetil, are at increased risk for opportunistic infections (bacterial, fungal, viral and protozoal), fatal infections and sepsis. Such infections include latent viral reactivation, such as hepatitis B or hepatitis C reactivation and infections caused by polyomaviruses (BK virus-associated nephropathy, JC virus-associated progressive multifocal leucoencephalopathy PML). Cases of hepatitis due to reactivation of hepatitis B or hepatitis C have been reported in carrier patients treated with immunosuppressants. These infections are often related to a high total immunosuppressive burden and may lead to serious or fatal conditions that physicians should consider in the differential diagnosis in immunosuppressed patients with deteriorating renal function or neurological symptoms.
There have been reports of hypogammaglobulinaemia in association with recurrent infections in patients receiving mycophenolate mofetil in combination with other immunosuppressants. In some of these cases, switching mycophenolate mofetil to an alternative immunosuppressant resulted in serum IgG levels returning to normal. Patients on mycophenolate mofetil who develop recurrent infections should have their serum immunoglobulins measured. In cases of sustained, clinically relevant hypogammaglobulinaemia, appropriate clinical action should be considered taking into account the potent cytostatic effects that mycophenolic acid has on T- and B-lymphocytes.
There have been published reports of bronchiectasis in adults and children who received mycophenolate mofetil in combination with other immunosuppressants. In some of these cases, switching mycophenolate mofetil to another immunosuppressant resulted in improvement in respiratory symptoms. The risk of bronchiectasis may be linked to hypogammaglobulinaemia or to a direct effect on the lung. There have also been isolated reports of interstitial lung disease and pulmonary fibrosis, some of which were fatal. It is recommended that patients who develop persistent pulmonary symptoms, such as cough and dyspnoea, are investigated.
Blood and immune system: Patients receiving mycophenolate mofetil should be monitored for neutropenia, which may be related to mycophenolate mofetil itself, concomitant medications, viral infections, or some combination of these causes. Patients taking mycophenolate mofetil should have complete blood counts weekly during the first month, twice monthly for the second and third months of treatment, then monthly through the first year. If neutropenia develops (absolute neutrophil count <1.3 x 10³/μL), it may be appropriate to interrupt or discontinue mycophenolate mofetil.
Cases of pure red cell aplasia (PRCA) have been reported in patients treated with mycophenolate mofetil in combination with other immunosuppressants. The mechanism for mycophenolate mofetil induced PRCA is unknown. PRCA may resolve with dose reduction or cessation of mycophenolate mofetil therapy. Changes to mycophenolate mofetil therapy should only be undertaken under appropriate supervision in transplant recipients in order to minimize the risk of graft rejection.
Patients receiving mycophenolate mofetil should be instructed to report immediately any evidence of infection, unexpected bruising, bleeding or any other manifestation of bone marrow depression.
Patients should be advised that during treatment with mycophenolate mofetil, vaccinations may be less effective and the use of live attenuated vaccines should be avoided. Influenza vaccination may be of value. Prescribers should refer to national guidelines for influenza vaccination.
Gastrointestinal: Mycophenolate mofetil has been associated with an increased incidence of digestive system adverse events, including infrequent cases of gastrointestinal tract ulceration, haemorrhage and perforation. Mycophenolate mofetil should be administered with caution in patients with active serious digestive system disease.
Mycophenolate mofetil is on IMPDH (inosine monophosphate dehydrogenase) inhibitor. Therefore, it should be avoided in patients with rare hereditary deficiency of hypoxanthine-guanine phosphoribosyl-transferase (HGPRT) such as Lesch-Nyhan and Kelley-Seegmiller syndrome.
Interactions: Caution should be exercised when switching combination therapy from regimens containing immunosuppressants, which interfere with MPA enterohepatic recirculation e.g. ciclosporin to others devoid of this effect e.g. sirolimus, belatacept, or vice versa, as this might result in changes of MPA exposure. Medicinal products of other classes which interfere with MPA's enterohepatic cycle e.g. cholestyramine should be used with caution due to their potential to reduce the plasma levels and efficacy of mycophenolate mofetil.
It is recommended that mycophenolate mofetil should not be administered concomitantly with azathioprine because such concomitant administration has not been studied.
The ask/benefit ratio of mycophenolate mofetil in combination with tacrolimus or sirolimus has not been established.
Special populations: Elderly patients may be at an increased risk of adverse events such as certain infections (including cytomegalovirus tissue invasive disease) and possibly gastrointestinal haemorrhage and pulmonary oedema, compared with younger individuals.
Teratogenic effects: Mycophenolate is a powerful human teratogen. Spontaneous abortion (rare of 45-49%) and congenital malformations (estimated rats of 23-27%) have been reported following MMF exposure during pregnancy. Therefore, mycophenolate mofetil is contraindicated in pregnancy unless there are no suitable alternative treatments to prevent transplant rejection. Female and male patients of reproductive potential should be made aware of the risks and follow the recommendations provided in Pregnancy and lactation (e.g. contraceptive methods, pregnancy testing) prior no, during, and after therapy with mycophenolate mofetil. Physicians should ensure that women and men taking mycophenolate understand the risk of harm to the baby, the need for effective contraception, and the need to immediately consult their physician if there is a possibility of pregnancy.
Contraception: Because of the genotoxic and teratogenic potential of mycophenolate mofetil, women with childbearing potential should use two reliable forms of contraception simultaneously before starling mycophenolate mofetil therapy, during therapy, and for six weeks after stopping the therapy; unless abstinence is the chosen method of contraception.
Sexually active men are recommended to use condoms during treatment and for at least 90 days after cessation of treatment. Condom use applies for both reproductively competent and vasectomized men, because the risks associated with the transfer of seminal fluid also apply to men who have had a vasectomy. In addition, female partners of male patients treated with mycophenolate mofetil are recommended to use highly effective contraception during treatment and for a total of 90 days after the last dose of mycophenolate mofetil.
Educational materials: In order to assist patients in avoiding foetal exposure to mycophenolate and to provide additional important safety information, the Marketing Authorization holder will provide educational materials to healthcare professionals. The educational materials will reinforce the warnings about the teratogenicity of mycophenolate, provide advice on contraception before therapy is started and guidance on the need for pregnancy testing. Full patient information about the teratogenic risk and the pregnancy prevention measures should be given by the physician to women of childbearing potential and, as appropriate, to male patients.
Additional precautions: Patients should not donate blood during therapy or for at least 6 weeks following discontinuation of mycophenolate. Man should not donate semen during therapy or for 90 days following discontinuation of mycophenolate.
Effects On Ability to Drive and Use Machines: No studies on the effects on the ability to drive and use machines have been performed. The pharmacodynamic profile and the reported adverse reactions indicate that an effect is unlikely.