Adverse reactions : תופעות לוואי

4.8    Undesirable effects

Summary of the safety profile

The most common adverse reactions are nausea (23.5%), headache (20.5%), white blood cell count decreased (18.7%), upper respiratory tract infection (14.5%), diarrhoea (15.1%), vomiting (15.1%), and nasopharyngitis (15.1%).
The most common serious adverse reactions are liver function abnormalities (5.4%) and pneumonia (4.8%).

Tabulated list of adverse reactions

The adverse reactions observed in the ANCA-associated vasculitis pivotal phase 3 study in patients treated with avacopan are listed in Table 1 by system organ class (SOC) and by frequency.
Frequencies are defined as: very common (≥ 1/10), common (≥ 1/100 to < 1/10) and uncommon (≥ 1/1,000 to < 1/100). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.


Table 1:      Adverse reactions
System Organ Class       Very Common                      Common                     Uncommon (≥ 1/10)                         (≥ 1/100 to < 1/10)        (≥ 1/1,000 to < 1/100) Infections and           Upper respiratory tract          Pneumonia,
infestations             infection,                       Rhinitis,
Nasopharyngitis                  Urinary tract infection,
Sinusitis,
Bronchitis,
Gastroenteritis,
Lower respiratory tract infection,
Cellulitis,
Herpes zoster,
Influenza,
Oral candidiasis,
Oral herpes,
Otitis media
Blood and lymphatic                                        Neutropenia system disorders
Nervous system              Headache disorders
Gastrointestinal            Nausea,                        Abdominal pain upper disorders                   Diarrhoea,
Vomiting
Hepatobiliary disorders Liver function test increased*
Skin and subcutaneous                                                                 Angioedema tissue disorders
Investigations          White blood cell count             Blood creatine decreased**                        phosphokinase increased
* Alanine aminotransferase increased, total blood bilirubin increased, hepatic function abnormal, gamma glutamyl transferase increased, hepatic enzyme increased, transaminases increased.
** Includes leukopenia.

Description of selected adverse reactions

Liver function test increased
In the pivotal phase 3 study in which 330 patients were dosed, 13.3% of patients in the avacopan group and 11.6% of patients in the prednisone group had an adverse reaction of elevated liver function test (LFT).
In the avacopan group, LFT increased was reported in the phase 3 study and included hepatitis (1.2%), hepatitis cholestatic (0.6%) of which one patient reported both hepatitis and hepatitis cholestatic as a diagnosis, hepatocellular injury (0.6%) in one patient diagnosed with asymptomatic hepatitis, cytolysis and anicteric cholestasis without hepatocellular insufficiency.

In the pivotal phase 3 study, adverse events of hepatobiliary disorders were more frequent in patients treated with a regimen based on a combination with cyclophosphamide followed by azathioprine (10.2%) as compared to those treated with a regimen based on a combination with rituximab (3.7%).

Study medicinal product was paused or discontinued permanently due to LFT increased in 5.4% of patients in the avacopan group and 3.0% of patients in the prednisone group. Serious adverse reactions of LFT increased were reported in 5.4% of patients in the avacopan group and 3.7% of patients in the prednisone group. All serious hepatic events resolved with either the withdrawal of avacopan and/or other potentially hepatotoxic medicinal products, including trimethoprim and sulfamethoxazole.
Neutropenia

In the pivotal phase 3 study, neutropenia was reported in 4 patients (2.4%) in each treatment group.
A single case of agranulocytosis was reported each in the prednisone group and in the avacopan group.

The patient in the avacopan group was noted to have central neutropenia on a bone marrow biopsy which resolved spontaneously without additional treatment.

Creatine phosphokinase increased

In the pivotal phase 3 study, 6 patients (3.6%) in the avacopan group and 1 patient (0.6%) in the prednisone group had adverse reactions of increased creatine phosphokinase (CPK).

Hypersensitivity including angioedema

In the pivotal phase 3 study, 2 patients (1.2%) in the avacopan group had an adverse reaction of angioedema. One patient was hospitalised for the event. Avacopan was paused and both events resolved without sequelae. Avacopan was restarted in one patient and angioedema did not reoccur.

Gastrointestinal disorders

In the pivotal phase 3 study, adverse reactions of gastrointestinal disorders were observed in 74.6% of patients treated with avacopan and a regimen based on a combination with cyclophosphamide followed by azathioprine as compared to those treated with a regimen based on a combination with rituximab (53.3%).

Special populations

Paediatric population
A total of 3 adolescents were studied in the phase 3 study, one in the prednisone group and two in the avacopan group. There are no data in children below 12 years of age (see section 5.1).

Elderly patients

The safety profile was similar between patients ≥ 65 years of age and adult patients < 65 years of age in the clinical studies.

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/