Adverse reactions : תופעות לוואי

4.8     Undesirable effects

Summary of the safety profile
Based on clinical trial experience, overall 32.2% of the patients experienced adverse drug reactions.
The most frequently reported adverse reactions were nausea (2.8%), blood alkaline phosphatase increased (2.7%), phlebitis (2.5%, primarily in HIV infected patients with peripheral lines), vomiting (2.5%), and aspartate aminotransferase increased (2.3%).

Tabulated list of adverse reactions
In the following table adverse reactions are listed by system organ class and MedDRA preferred term.
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

System Organ                Common                  Uncommon                Rare           Not known Class                   ≥ 1/100 to < 1/10       ≥ 1/1,000 to < 1/100    ≥ 1/10,000 to      (frequency < 1/1,000         cannot be estimated from available data)
Blood and            leukopenia,               pancytopenia,            haemolytic       disseminated lymphatic system     neutropenia, anaemia      thrombocytopenia,        anaemia,         intravascular disorders                                      eosinophilia,            haemolysis       coagulation hypoalbuminaemia         (see section
4.4)
Immune system                                  anaphylactic /                            anaphylactic disorders                                      anaphylactoid                             and reaction (see section                     anaphylactoid
4.4), hypersensitivity                    shock (see section 4.4)
Endocrine                                      hyperhidrosis disorders
Metabolism and       hypokalaemia,             hyponatraemia,
nutritional          hypomagnesaemia,          hyperkalaemia,
disorders            hypocalcaemia             hypophosphataemia,
anorexia
Psychiatric                                    insomnia, anxiety,
disorders                                      confusion
Nervous system       headache                  somnolence, tremor,
disorders                                      dizziness, dysgeusia
Cardiac disorders                              tachycardia,
palpitations,
bradycardia

System Organ               Common                  Uncommon                Rare          Not known Class                  ≥ 1/100 to < 1/10       ≥ 1/1,000 to < 1/100    ≥ 1/10,000 to     (frequency < 1/1,000        cannot be estimated from available data)
Vascular            phlebitis                 hypotension,                             shock disorders                                     hypertension,
flushing
Respiratory,                                  dyspnoea thoracic and mediastinal disorders
Gastrointestinal    nausea, vomiting,         dyspepsia,
disorders           diarrhoea, abdominal      constipation pain
Hepatobiliary       blood alkaline            hepatic failure (see                     hepatocellular disorders           phosphatase increased,    section 4.4), gamma-                     damage aspartate                 glutamyltransferase                      including fatal aminotransferase          increased, jaundice,                     cases (see increased, alanine        cholestasis,                             section 4.4) aminotransferase          hepatomegaly,
increased, blood          hepatitis bilirubin increased
(including hyperbilirubinaemia),
liver function test abnormal
Skin and            rash                      urticaria, pruritus,                     toxic skin subcutaneous                                  erythema                                 eruption, tissue disorders                                                                       erythema multiforme,
Stevens-
Johnson syndrome,
toxic epidermal necrolysis (see section 4.4)
Renal and urinary                             blood creatinine                         renal disorders                                     increased, blood urea                    impairment increased, renal                         (see section failure aggravated                       4.4), acute renal failure
General disorders   pyrexia, rigors           injection site and                                           thrombosis, infusion administration                                site inflammation,
site conditions                               injection site pain,
peripheral oedema
Investigations                                blood lactate dehydrogenase increased

Description of selected adverse reactions
Possible allergic-like symptoms
Symptoms such as rash and rigors have been reported in clinical studies. The majority were of mild to moderate intensity and not treatment limiting. Serious reactions (e.g. anaphylactoid reaction 0.2%, 
6/3028) were uncommonly reported during therapy with micafungin and only in patients with serious underlying conditions (e.g. advanced AIDS, malignancies) requiring multiple co-medications.

Hepatic adverse reactions
The overall incidence of hepatic adverse reactions in the patients treated with micafungin in clinical studies was 8.6% (260/3028). The majority of hepatic adverse reactions were mild and moderate. Most frequent reactions were increase in AP (2.7%), AST (2.3%), ALT (2.0%), blood bilirubin (1.6%) and liver function test abnormal (1.5%). Few patients (1.1%; 0.4% serious) discontinued treatment due to a hepatic event. Cases of serious hepatic dysfunction occurred uncommonly (see section 4.4).

Injection-site reactions
None of the injection-site adverse reactions were treatment limiting.

Paediatric population
The incidence of some adverse reactions (listed in the table below) was higher in paediatric patients than in adult patients. Additionally, paediatric patients < 1 year of age experienced about two times more often an increase in ALT, AST and AP than older paediatric patients (see section 4.4). The most likely reason for these differences were different underlying conditions compared with adults or older paediatric patients observed in clinical studies. At the time of entering the study, the proportion of paediatric patients with neutropenia was several-fold higher than in adult patients (40.2% and 7.3% of children and adults, respectively), as well as allogeneic HSCT (29.4% and 13.4%, respectively) and haematological malignancy (29.1% and 8.7%, respectively).

Blood and lymphatic system disorders common                       thrombocytopenia

Cardiac disorders common                          tachycardia
Vascular disorders common                          hypertension, hypotension

Hepatobiliary disorders common                          hyperbilirubinaemia, hepatomegaly

Renal and urinary disorders common                          acute renal failure, blood urea increased 
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 http://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=AdversEffectMedic@moh.go v.il