Certican Adverse Reactions

The frequencies of adverse reactions listed as follows are derived from analysis of the 12-month incidences of events reported in multicenter, randomized, controlled trials investigating Certican in combination with calcineurin inhibitors (CNI) and corticosteroids in transplant recipients. All but two of the trials (in renal transplant) included non-Certican, CNI-based standard-therapy arms. Certican combined with ciclosporin, was studied in five trials in renal transplant recipients totalising 2497 patients, and three trials in heart transplant recipients totalising 1531 patients (ITT populations, see Pharmacology: Pharmacodynamics under Actions).
Certican combined with tacrolimus, was studied in one trial, which included 719 liver transplant recipients (ITT population, see Pharmacology: Pharmacodynamics under Actions).
Table 17 contains adverse drug reactions possibly or probably related to Certican seen in phase III clinical trials. Unless noted otherwise, these disorders have been identified by an increased incidence in the phase III studies comparing Certican-treated patients with patients on a non-Certican, standard therapy regimens (see Pharmacology: Pharmacodynamics under Actions). Except where noted otherwise, the adverse reaction profile is relatively consistent across all transplant indications. It is compiled according to MedDRA standard organ classes: Adverse reactions are listed according to their frequencies which are defined as: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000). (See Table 19.)

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Preclinical toxicology studies having shown that everolimus can reduce spermatogenesis, male infertility must be considered a potential risk of prolonged Certican therapy. There are literature reports of reversible azospermia and oligospermia in patients treated with mTOR inhibitors.
In controlled clinical trials in which a total of 3256 patients receiving Certican in combination with other immunosuppressants were monitored for at least 1 year, a total of 3.1% developed malignancies, with 1.0% developing skin malignancies and 0.60% developing lymphoma or lymphoproliferative disorder.
The occurrence of the adverse events may depend on the immunosuppressive regimen (i.e. degree and duration). In the studies combining Certican with ciclosporin elevated serum creatinine was observed more frequently in patients dosed with Certican in combination with full dose ciclosporin for microemulsion than in control patients. The overall incidence of adverse events was lower with reduced dose ciclosporin for microemulsion (see Pharmacology: Pharmacodynamics under Actions).
The safety profile of Certican administered with reduced-dose ciclosporin was similar to that described in the 3 pivotal studies in which full dose of ciclosporin was administered, except that elevation of serum creatinine was less frequent, and mean and median serum creatinine values were lower, than in the phase III studies.
Cases of interstitial lung disease, implying lung intraparenchymal inflammation (pneumonitis) and/or fibrosis of non-infectious etiology, some fatal, have occurred in patients receiving rapamycin and derivatives, including Certican. Mostly, the condition resolves after discontinuation of Certican and/or addition of glucocorticoids. However, fatal cases have also occurred.