Adverse reactions : תופעות לוואי

4.8   Undesirable effects
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, diarrhoea, 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 intravenous administration (see section 4.4).

Infections and infestations
Patients receiving immunosuppressive therapies, including ciclosporin and ciclosporin-containing regimens, are at increased risk of infections (viral, bacterial, fungal, parasitic) (see section 4.4). Both generalised and localised 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 leukopathy (PML). Serious and/or fatal outcomes have been reported.

Neoplasms benign, malignant and unspecified (including cysts and polyps) 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 section 4.4). Some malignancies may be fatal.

Tabulated summary of adverse drug reactions from clinical trials
Adverse drug reactions from clinical trials (Table 2) 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), not known (cannot be estimated from the available data).

Table 2: Adverse drug reactions from clinical trials
Blood and lymphatic system disorders
Common                Leucopenia
Uncommon              Thrombocytopenia, anaemia
Rare                  Haemolytic uraemic syndrome, microangiopathic haemolytic anaemia Not known*            Thrombotic microangiopathy, thrombotic thrombocytopenic purpura Metabolism and nutrition disorders
Very common           Hyperlipidaemia
Common                Hyperglycaemia, anorexia, hyperuricaemia, hyperkalaemia, hypomagnesaemia Nervous system disorders
Very common           Tremor, headache
Common                Convulsions, paraesthesia
Uncommon              Encephalopathy including Posterior Reversible Encephalopathy Syndrome (PRES), signs and symptoms such as convulsions, confusion, disorientation, decreased responsiveness, agitation, insomnia, visual disturbances, cortical blindness, coma, paresis and cerebellar ataxia
Rare                  Motor polyneuropathy
Very rare             Optic disc oedema, including papilloedema, with possible visual impairment secondary to benign intracranial hypertension
Not known*            Migraine
Ear and labyrinth disorders
Not known*            Hearing impairment#
Vascular disorders
Very common           Hypertension (see section 4.4)
Common                Flushing
Gastrointestinal disorders
Common                Nausea, vomiting, abdominal discomfort/pain, diarrhoea, gingival hyperplasia, peptic ulcer
Rare                  Pancreatitis
Hepatobiliary disorders
Common                Hepatic function abnormal (see section 4.4)
Not known*            Hepatotoxicity and liver injury including cholestasis, jaundice, hepatitis and liver failure with some fatal outcome (see section 4.4)
Skin and subcutaneous tissue disorders
Very common           Hirsutism
Common                Acne, hypertrichosis
Uncommon              Allergic rashes

Musculoskeletal and connective tissue disorders
Common                  Myalgia, muscle cramps
Rare                    Muscle weakness, myopathy
Not known*              Pain of lower extremities
Renal and urinary disorders
Very common             Renal dysfunction (see section 4.4)
Reproductive system and breast disorders
Rare                    Menstrual disturbances, gynaecomastia
General disorders and administration site conditions
Common                  Pyrexia, fatigue
Uncommon                Oedema, weight increase
* Adverse events reported from post marketing experience where the ADR frequency is not known due to the lack of a real denominator.
#
Hearing impairment has been reported in the post-marketing phase in patients with high levels of ciclosporin.

Other adverse drug reactions from post-marketing experience
There have been solicited and spontaneous 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 section 4.4).

Acute and chronic nephrotoxicity
Patients receiving calcineurin inhibitor (CNI) 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 Sandimmun. Cases of acute nephrotoxicity reported disorders of ion homeostasis, such as hyperkalaemia, hypomagnesaemia, and hyperuricaemia. Cases reporting chronic morphological changes included arteriolar hyalinosis, tubular atrophy and interstitial fibrosis (see section 4.4).

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).

Paediatric population
Clinical studies have included children from 1 year of age using standard ciclosporin dosage with a comparable safety profile to adults.

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.
Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form https://sideeffects.health.gov.il