Special Warning : אזהרת שימוש

4.4   Special warnings and precautions for use

Hepatotoxicity
Serious adverse reactions of elevated hepatic transaminases with elevated total bilirubin have been observed in patients receiving avacopan in combination with cyclophosphamide (followed by azathioprine or mycophenolate) or rituximab, and trimethoprim and sulfamethoxazole.
In the post-marketing setting, drug-induced liver injury and vanishing bile duct syndrome (VBDS), including cases with fatal outcome, have been reported (see section 4.8).

Avacopan must be avoided in patients with signs of liver disease, such as elevated AST, ALT, alkaline phosphatase (ALP), or total bilirubin > 3 times ULN.

Hepatic transaminases and total bilirubin must be obtained prior to initiation of therapy.

Patients must be monitored for hepatic transaminases and total bilirubin as clinically indicated and as part of the routine follow-up of patient’s underlying condition (see section 4.2).

Blood and immune system

White blood cell (WBC) count must be obtained prior to initiation of therapy and patients must be monitored as clinically indicated and as part of the routine follow-up of patient’s underlying condition (see section 4.2).

Treatment with avacopan must not be initiated if WBC count is < 3.5 × 109/L, or neutrophil count < 1.5 × 109/L, or lymphocyte count < 0.5 × 109/L.

Patients receiving avacopan must be instructed to report immediately any evidence of infection, unexpected bruising, bleeding, or any other manifestations of bone marrow failure.

Serious infections

Serious infections have been reported in patients receiving combination agents for treatment of GPA or MPA, including avacopan in combination with rituximab or cyclophosphamide (see section 4.8).

Patients must be assessed for any serious infections.

Avacopan has not been studied in patients with hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) infections. Before and during treatment, patients must notify their physician if they have been diagnosed with tuberculosis, hepatitis B, hepatitis C, or HIV infection.
Be cautious when treating patients with a history of tuberculosis, hepatitis B, hepatitis C, or HIV infection.

Avacopan does not decrease the formation of the membrane attack complex (C5b-9) or terminal complement complex (TCC). No cases of Neisseria meningitidis have been identified in the avacopan clinical programme. Monitor patients treated for ANCA-associated vasculitis according to standard practice for clinical signs and symptoms of Neisseria infections.

Pneumocystis jirovecii pneumonia prophylaxis

Pneumocystis jirovecii pneumonia prophylaxis is recommended for adult patients with GPA or MPA during avacopan treatment, as appropriate according to local clinical practice guidelines.

Immunisation

The safety of immunisation with live vaccines, following avacopan therapy has not been studied.
Administer vaccinations preferably prior to initiation of treatment with avacopan or during quiescent phase of the disease.

Angioedema

Angioedema has been reported in patients receiving avacopan (see section 4.8).
Patients must notify their physician if they develop any symptoms such as swelling of the face, lips, or tongue, throat tightness, or difficulty breathing.

Avacopan must be withheld in cases of angioedema.

Interaction with strong CYP3A4 inducers
The use of strong CYP3A4 enzyme inducers (e.g., carbamazepine, enzalutamide, mitotane, phenobarbital, phenytoin, rifampicin, and St. John’s Wort) with avacopan is to be avoided (see section 4.5).
Patients anticipated to require long-term administration of these medicinal products are not to be treated with avacopan.
If short-term co-administration cannot be avoided in a patient already using avacopan, the patient must be closely monitored in case of any reoccurrence of disease activity.

Cardiac disorders

Patients with GPA or MPA are at risk of cardiac disorders such as myocardial infarction, cardiac failure, and cardiac vasculitis.

Serious adverse events (SAEs) of cardiac disorder have been reported in patients treated with avacopan. A treatment regimen based on the combination with cyclophosphamide followed by azathioprine may carry an increased risk for cardiac disorders as compared to a regimen based on the combination with rituximab.

Malignancy

Immunomodulatory medicinal products may increase the risk for malignancies. The clinical data are currently limited (see section 5.1).


Macrogolglycerol hydroxystearate content
This medicinal product contains macrogolglycerol hydroxystearate, which may cause stomach upset and diarrhoea.

Effects on Driving

4.7    Effects on ability to drive and use machines

Tavneos has no or negligible influence on the ability to drive and use machines.