ne and etoposide. If unexplained reductions in serum bicarbonate (< 20 mmol/l) or elevations of serum creatinine or BUN occur, the dose should be reduced or administration delayed (see section 4.2).
The patients should be advised to report oliguria and anuria to the health care provider immediately.
Patients with renal impairment should be closely monitored for toxicity since azacitidine and/or its metabolites are primarily excreted by the kidney (see section 4.2).
Cardiac and pulmonary disease
Patients with a history of severe congestive heart failure, clinically unstable cardiac disease or pulmonary disease were excluded from the pivotal clinical study and therefore the safety and efficacy of Vidaza in these patients has not been established.
4.5 Interaction with other medicinal products and other forms of interaction
Based on in vitro data, azacitidine metabolism does not appear to be mediated by cytochrome P450 isoenzymes (CYPs), UDP-glucuronosyltransferases (UGTs), sulfotransferases (SULTs), and glutathione transferases (GSTs); interactions related to these metabolizing enzymes in vivo are therefore considered unlikely.
Clinically significant inhibitory or inductive effects of azacitidine on cytochrome P450 enzymes are unlikely (see section 5.2).
No formal clinical drug interaction studies with azacitidine have been conducted.
4.6 Pregnancy and lactation
Women of childbearing potential / Contraception in males and females
Men and women of childbearing potential must use effective contraception during and up to 3 months after treatment.
Pregnancy
There are no adequate data on the use of azacitidine in pregnant women. Studies in mice have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Based on results from animal studies and its mechanism of action, azacitidine should not be used during pregnancy, especially during the first trimester, unless clearly necessary. The advantages of treatment should be weighed against the possible risk for the foetus in every individual case.
Breastfeeding
It is not known whether azacitidine or its metabolites are excreted in human milk. Due to the potential serious adverse reactions in the nursing child, breastfeeding is contraindicated during azacitidine therapy.
Fertility
There are no human data on the effect of azacitidine on fertility. In animals, adverse effects of azacitidine on male fertility have been documented (see section 5.3). Men should be advised not to father a child while receiving treatment and must use effective contraception during and up to 3 months after treatment. Before starting treatment, male patients should be advised to seek counselling on sperm storage.
4.7 Effects on ability to drive and use machines
No studies of the effects on the ability to drive and use machines have been performed. Patients should be advised that they may experience undesirable effects such as fatigue, during treatment. Therefore, caution should be recommended when driving a car or operating machines.
4.8 Undesirable effects
Adverse reactions considered to be possibly or probably related to the administration of Vidaza have occurred in 97 % of patients.
The most commonly reported adverse reactions with azacitidine treatment were haematological reactions (71.4 %) including thrombocytopenia, neutropenia and leukopenia (usually Grade 3-4), gastrointestinal events (60.6 % |
