Adverse reactions : תופעות לוואי

4.8 Undesirable effects
Undesirable effects observed with prophylaxis of organ rejection in renal transplantation 
The most commonly reported adverse reactions (occurring in >10% of patients) are thrombocytopaenia, anaemia, pyrexia, hypertension, hypokalaemia, hypophosphataemia, urinary tract infection, hypercholesterolaemia, hyperglycaemia, hypertriglyceridaemia, abdominal pain, lymphocoele, peripheral oedema, arthralgia, acne, diarrhoea, pain, constipation, nausea, headache, increased blood creatinine, and increased blood lactate dehydrogenase (LDH).

The incidence of any adverse reaction(s) may increase as the trough sirolimus level increases.

The following list of adverse reactions is based on experience from clinical studies and on postmarketing experience.

Within the system organ classes, adverse reactions are listed under headings of frequency (number of patients expected to experience the reaction), using the following categories: 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); not known (cannot be estimated from the available data).

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Most patients were on immunosuppressive regimens, which included Rapamune in combination with other immunosuppressive agents.

System organ       Very common        Common             Uncommon         Rare              Frequency class              (≥1/10)            (≥1/100 to         (≥1/1,000 to     (≥1/10,000 to     not known <1/10)             <1/100)          <1/1,000)         (cannot be estimated from available data)
System organ       Very common          Common              Uncommon             Rare            Frequency class              (≥1/10)              (≥1/100 to          (≥1/1,000 to         (≥1/10,000 to   not known <1/10)              <1/100)              <1/1,000)       (cannot be estimated from available data)
Infections and     Pneumonia,           Sepsis,             Clostridium infestations       Fungal infection,    Pyelonephritis,     difficile colitis, Viral infection,     Cytomegalo-         Mycobacterial
Bacterial            virus infection,    infection infection,           Herpes zoster       (including
Herpes simplex       caused by the       tuberculosis),
infection, Urinary   varicella zoster    Epstein-Barr tract infection      virus               virus infection

Neoplasms                               Non-                Lymphoma*,                           Neuroendocr benign,                                 melanoma            Malignant                            ine malignant and                           skin cancer*        melanoma*;                           carcinoma of unspecified                                                 post-                                the skin* (including cysts                                            transplant and polyps)                                                 lymphoproli- ferative disorder

Blood and          Thrombocyto-         Haemolytic          Pancyto- lymphatic          paenia,              uraemic             paenia,
system             Anaemia,             syndrome,           Thrombotic disorders          Leucopenia           Neutropaenia        thrombo- cytopaenic purpura
Immune system                           Hyper- disorders                               sensitivity
(including angioedema,
anaphylactic reaction, and anaphylactoid reaction)
Metabolism and     Hypokalaemia,
nutrition          Hypophospha- disorders          taemia,
Hyperlipidaemia
(including hypercholeste- rolaemia),
Hyperglycaemia,
Hypertriglyceri- daemia, Diabetes mellitus
Nervous system     Headache                                                                      Posterior disorders                                                                                        reversible encephalo-
System organ         Very common           Common             Uncommon         Rare            Frequency class                (≥1/10)               (≥1/100 to         (≥1/1,000 to     (≥1/10,000 to   not known <1/10)             <1/100)          <1/1,000)       (cannot be estimated from available data) pathy syndrome
Cardiac              Tachycardia           Pericardial disorders                                  effusion
Vascular             Hypertension,         Venous             Lymphoedema disorders            Lymphocele            thrombosis
(including deep vein thrombosis)
Respiratory,                               Pulmonary          Pulmonary         Alveolar thoracic, and                              embolism,          haemorrhage      proteinosis mediastinal                                Pneumonitis* ,
disorders                                   Pleural effusion,
Epistaxis
Gastrointestinal     Abdominal pain,       Pancreatitis,
disorders            Constipation,         Stomatitis,
Diarrhoea,            Ascites
Nausea
Hepatobiliary        Liver function test                       Hepatic disorders            abnormal                                 failure* (including alanine aminotransferase increased and aspartate amino- transferase increased)
Skin and             Rash, Acne                               Dermatitis       Hypersen- subcutaneous                                                  exfoliative      sitivity tissue disorders                                                               vasculitis Musculoskeletal      Arthralgia            Osteonecrosis and connective tissue disorders
Renal and            Proteinuria                              Nephrotic urinary                                                       syndrome (see disorders                                                     section 4.4) , Focal segmental glomerulo- sclerosis*
Reproductive         Menstrual             Ovarian cyst system and           disorder breast disorders     (including amenorrhoea and menorrhagia)

System organ      Very common           Common             Uncommon         Rare              Frequency class             (≥1/10)               (≥1/100 to         (≥1/1,000 to     (≥1/10,000 to     not known <1/10)             <1/100)          <1/1,000)         (cannot be estimated from available data)
General            Oedema ,
disorders and      Oedema administration     peripheral,
site conditions    Pyrexia,
Pain, Impaired healing*
Investigations     Blood lactate dehydrogenase increased,
Blood creatinine increased
*See section below.

Description of selected adverse reactions

Immunosuppression increases the susceptibility to the development of lymphoma and other malignancies, particularly of the skin (see section 4.4).

Cases of BK virus-associated nephropathy, as well as cases of JC virus-associated progressive multifocal leukoencephalopathy (PML), have been reported in patients treated with immunosuppressants, including Rapamune.

Hepatoxicity has been reported. The risk may increase as the trough sirolimus level increases. Rare reports of fatal hepatic necrosis have been reported with elevated trough sirolimus levels.

Cases of interstitial lung disease (including pneumonitis and infrequently bronchiolitis obliterans organising pneumonia (BOOP) and pulmonary fibrosis), some fatal, with no identified infectious aetiology have occurred in patients receiving immunosuppressive regimens including Rapamune. In some cases, the interstitial lung disease has resolved upon discontinuation or dose reduction of Rapamune. The risk may be increased as the trough sirolimus level increases.

Impaired healing following transplant surgery has been reported, including fascial dehiscence, incisional hernia, and anastomotic disruption (e.g., wound, vascular, airway, ureteral, biliary).

Impairments of sperm parameters have been observed among some patients treated with Rapamune. These effects have been reversible upon discontinuation of Rapamune in most cases (see section 5.3).

In patients with delayed graft function, sirolimus may delay recovery of renal function.

The concomitant use of sirolimus with a calcineurin inhibitor may increase the risk of calcineurin inhibitor-induced HUS/TTP/TMA.

Focal segmental glomerulosclerosis has been reported.

There have also been reports of fluid accumulation, including peripheral oedema, lymphoedema, pleural effusion and pericardial effusions (including haemodynamically significant effusions in children and adults) in patients receiving Rapamune.

In a study evaluating the safety and efficacy of conversion from calcineurin inhibitors to sirolimus (target levels of 12-20 ng/mL in maintenance renal transplant patients, enrollment was stopped in the subset of patients (n=90) with a baseline glomerular filtration rate of less than 40 mL/min (see section 5.1). There was a higher rate of serious adverse events, including pneumonia, acute rejection, graft loss and death, in this sirolimus treatment arm (n=60, median time post-transplant 36 months).
Ovarian cysts and menstrual disorders (including amenorrhoea and menorrhagia) have been reported. Patients with symptomatic ovarian cysts should be referred for further evaluation.
The incidence of ovarian cysts may be higher in premenopausal females compared to postmenopausal females. In some cases, ovarian cysts and these menstrual disorders have resolved upon discontinuation of Rapamune.

Paediatric population

Controlled clinical studies with posology comparable to that currently indicated for the use of Rapamune in adults have not been conducted in children or adolescents below 18 years of age).

Safety was assessed in a controlled clinical study enrolling renal transplant patients below 18 years of age considered of high immunologic risk, defined as a history of one or more acute allograft rejection episodes and/or the presence of chronic allograft nephropathy on a renal biopsy (see section 5.1). The use of Rapamune in combination with calcineurin inhibitors and corticosteroids was associated with an increased risk of deterioration of renal function, serum lipid abnormalities (including, but not limited to, increased serum triglycerides and cholesterol), and urinary tract infections. The treatment regimen studied (continuous use of Rapamune in combination with calcineurin inhibitor) is not indicated for adult or paediatric patients (see section 4.1).

In another study enrolling renal transplant patients 20 years of age and below that was intended to assess the safety of progressive corticosteroid withdrawal (beginning at six months post-transplantation) from an immunosuppressive regimen initiated at transplantation that included full-dose immunosuppression with both Rapamune and a calcineurin inhibitor in combination with basiliximab induction, of the 274 patients enrolled, 19 (6.9%) were reported to have developed post-transplant lymphoproliferative disorder (PTLD). Among 89 patients known to be Epstein-Barr virus (EBV) seronegative prior to transplantation, 13 (15.6%) were reported to have developed PTLD. All patients who developed PTLD were aged below 18 years.

There is insufficient experience to recommend the use of Rapamune in children and adolescents (see section 4.2).

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
http://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=AdversEffec tMedic@moh.gov.il