Adverse reactions : תופעות לוואי

4.8   Undesirable effects
 a) Summary of the safety profile
The frequencies of adverse reactions listed below are derived from analysis of the 12-month incidences of events reported in multicentre, randomised, controlled trials investigating Certican in combination with calcineurin inhibitors (CNI) and corticosteroids in adult transplant recipients. All but two of the trials (in renal transplantation) included non-Certican, CNI-based standard-therapy arms.
Certican combined with ciclosporin was studied in five trials in renal transplant recipients totalling 2,497 patients (including two studies without a non-Certican control group), and three trials in heart transplant recipients totalling 1,531 patients (ITT populations, see section 5.1).

Certican combined with tacrolimus was studied in one trial, which included 719 liver transplant recipients (ITT population, see section 5.1).

The most common events are: infections, anaemia, hyperlipidaemia, new onset of diabetes mellitus, insomnia, headache, hypertension, cough, constipation, nausea, peripheral oedema, impaired healing (including pleural and pericardial effusion).

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 administered 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 section 5.1).

The safety profile of Certican administered with reduced-dose ciclosporin was similar to that described in the 3 pivotal studies in which full-dose 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.
 b) Tabulated summary of adverse reactions
Table 4 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 regimen, or the same incidence in case the event is a known ADR of the comparator MPA in renal and heart transplant studies (see section 5.1). 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).

Table 4      Adverse drug reactions possibly or probably related to Certican 

Body system               Incidence              Adverse reaction
Infections and            Very common            Infections (viral, bacterial, fungal), upper respiratory infestations                                     tract infection, lower respiratory tract and lung infections (including pneumonia)1, urinary tract infections2

Common                 Sepsis, wound infection


Neoplasms benign,         Common           Malignant or unspecified tumours, malignant and malignant and                              unspecified skin neoplasms unspecified

Uncommon         Lymphomas/post-transplant lymphoproliferative disorders ( PTLD)

Blood and lymphatic       Very common      Leukopaenia, anaemia/erythropenia, system disorders                           thrombocytopenia1

Common           Pancytopenia, thrombotic microangiopathies
(including thrombotic thrombocytopenic purpura/haemolytic uraemic syndrome)


Endocrine disorders       Uncommon         Hypogonadism male (testosterone decreased, FSH and LH increased)

Metabolism and            Very common      Hyperlipidaemia (cholesterol and triglycerides), new nutrition disorders                        onset diabetes mellitus, hypokalaemia 
Psychiatric disorders     Very common      Insomnia, anxiety

Nervous system            Very common      Headache disorders
Cardiac disorders         Very common      Pericardial effusion3

Common           Tachycardia

Vascular disorders        Very common      Hypertension, venous thromboembolic events 
Common           Lymphocoele 4, epistaxis, renal graft thrombosis

Respiratory, thoracic     Very common      Pleural effusion1, cough1, dyspnoea1 and mediastinal disorders

Uncommon         Interstitial lung disease5

Gastrointestinal          Very common      Abdominal pain, diarrhoea ,nausea, vomiting disorders

Common           Pancreatitis, stomatitis/mouth ulceration,
oropharyngeal pain

Hepatobiliary disorders   Uncommon         Non infectious hepatitis, jaundice 
Skin and subcutaneous     Common           Angiooedema6, acne, rash tissue disorders

Musculoskeletal and       Common           Myalgia, arthralgia connective tissue disorders


Renal and urinary          Common                 Proteinuria2, renal tubular necrosis7 disorders


Reproductive system        Common                 Erectile dysfunction, menstrual disorder (including and breast disorders                              amenorrhoea and menorrhagia) 

Uncommon               Ovarian cyst

General disorders and      Very common            Peripheral oedema, pain, healing impaired, pyrexia administration site conditions

Common                 Incisional hernia

Investigations             Common                 Hepatic enzyme abnormal8 1 common in renal and liver transplantation
2 common in cardiac and liver transplantation
3 in cardiac transplantation
4 in renal and cardiac transplantation
5 the SMQ-based search for ILD showed the frequency of ILD in the clinical trials. This broad search also included cases caused by related events, e.g. by infections. The frequency category given here is derived from the medical review of the known cases.
6 predominantly in patients receiving concomitant ACE inhibitors
7 in renal transplantation
8
γ-GT, AST, ALT elevated
 c) Description of selected adverse reactions
As preclinical toxicology studies have shown that everolimus can reduce spermatogenesis, male infertility must be considered a potential risk of prolonged Certican therapy. There are literature reports of reversible azoospermia and oligospermia in patients treated with mTOR inhibitors.

In controlled clinical trials in which a total of 3,256 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 lymphomas or lymphoproliferative disorders.

Cases of interstitial lung disease, implying lung intraparenchymal inflammation (pneumonitis) and/or fibrosis of non-infectious aetiology, 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.
 d) Adverse drug reactions from post-marketing spontaneous reports
The following adverse drug reactions have been derived from post-marketing experience with Certican 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 categorised as not known. Adverse drug reactions are listed according to system organ classes in MedDRA. Within each system organ class, ADRs are presented in order of decreasing seriousness.


Table 5 Adverse drug reactions from spontaneous reports and literature (frequency not known) 
Body system                       Incidence                  Adverse reaction 
Metabolism and nutrition          Not known                  Iron deficiency disorders

Vascular disorders                Not known                  Leukocytoclastic vasculitis, lymphoedema

Respiratory, thoracic and         Not known                  Pulmonary alveolar proteinosis mediastinal disorders

Skin and subcutaneous tissue      Not known                  Erythroderma disorders


Paediatric population
The safety information in children and adolescents is based on the data of 12-months in renal and 24- months in hepatic paediatric transplant patients (see section 5.1).

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation 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 and to Novartis using the following email address: safetydesk.israel@novartis.com