Sandimmun/Sandimmun Neoral Adverse Reactions

Summary of the safety profile: The principal adverse reactions observed in clinical trials and associated with the administration of ciclosporin include renal dysfunction, tremor, hirsutism, hypertension, diarrhea, anorexia, nausea and vomiting.
Many side effects associated with ciclosporin therapy are dose-dependent and responsive to dose reduction. In the various indications the overall spectrum of side effects is essentially the same; there are, however, differences in incidence and severity. As a consequence of the higher initial doses and longer maintenance therapy required after transplantation, side effects are more frequent and usually more severe in transplant patients than in patients treated for other indications.
Anaphylactoid reactions have been observed following i.v. administration (see Precautions).
Patients receiving immunosuppressive therapies, including ciclosporin and ciclosporin-containing regimens, are at increased risk of infections (viral, bacterial, fungal, parasitic) (see Precautions). Both generalized and localized infections can occur. Pre-existing infections may also be aggravated and reactivation of Polyomavirus infections may lead to Polyomavirus associated nephropathy (PVAN) or to JC virus-associated progressive multifocal leukoencephalopathy (PML). Serious and/or fatal outcomes have been reported.
Patients receiving immunosuppressive therapies, including ciclosporin and ciclosporin-containing regimens, are at increased risk of developing lymphomas or lymphoproliferative disorders and other malignancies, particularly of the skin. The frequency of malignancies increases with the intensity and duration of therapy (see Precautions). Some malignancies may be fatal.
Tabulated summary of adverse drug reactions from clinical trials: Adverse drug reactions from clinical trials (Table 6) are listed by MedDRA system organ class. Within each system organ class, the adverse drug reactions are ranked by frequency, with the most frequent reactions first. Within each frequency grouping, adverse drug reactions are presented in order of decreasing seriousness. In addition the corresponding frequency category for each adverse drug reaction is based, on the following convention (CIOMS III): very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1,000, <1/100); rare (≥1/10,000, <1/1,000), very rare (<1/10,000), including isolated reports. (See Table 6.)

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Adverse drug reactions from post-marketing experience (frequency not known): The following adverse drug reactions have been derived from post-marketing experience with Sandimmun Neoral or Sandimmun via spontaneous case reports and literature cases. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency which is therefore categorized as not known. Adverse drug reactions are listed according to system organ classes in MedDRA. Within each organ class, ADRs are presented as follows in Table 7 in order of decreasing seriousness. (See Table 7.)

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Description of selected adverse drug reactions: Hepatotoxicity and liver injury: There have been solicited and spontaneous postmarketing reports of hepatotoxicity and liver injury including cholestasis, jaundice, hepatitis and liver failure in patients treated with ciclosporin. Most reports included patients with significant co-morbidities, underlying conditions and other confounding factors including infectious complications and co-medications with hepatotoxic potential. In some cases, mainly in transplant patients, fatal outcomes have been reported (see Precautions).
Acute and chronic nephrotoxicity: Patients receiving calcineurin inhibitors (CNIs) therapies, including ciclosporin and ciclosporin-containing regimens, are at increased risk of acute or chronic nephrotoxicity. There have been reports from clinical trials and from the post-marketing setting associated with the use of ciclosporin. Cases of acute nephrotoxicity reported disorders of ion homeostasis, such as hyperkalemia, hypomagnesemia, hyperuricemia which developed in the majority of the cases within the first month of treatment. Cases reporting chronic morphological changes included arteriolar hyalinosis, tubular atrophy and interstitial fibrosis, (see Precautions).
Pain of lower extremities: Isolated cases of pain of lower extremities have been reported in association with ciclosporin. Pain of lower extremities has also been noted as part of Calcineurin-Inhibitor Induced Pain Syndrome (CIPS) as described in the literature.