TAVNEOS Hard capsule Ref.[28343] Active ingredients: Avacopan

Liver function test increased

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. Liver function test (LFT) increased is considered as an adverse reaction (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 less than 3500/μL, or neutrophil count less than 1500/μL, or lymphocyte count less than 500/μL.

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 viral 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.

Avacopan is a substrate of CYP3A4. Co-administration of inducers or inhibitors of this enzyme may affect the pharmacokinetics of avacopan.

Effect of strong CYP3A4 inducers on avacopan

Co-administration of avacopan with rifampicin, a strong CYP3A4 enzyme inducer, resulted in a decrease in area-under-the-concentration time curve (AUC) and maximum plasma concentration (C_max) of avacopan by approximately 93% and 79%, respectively. Since this interaction may result in loss of efficacy of avacopan, 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 4.4). 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 for any reoccurrence of disease activity.

Effect of moderate CYP3A4 inducers on avacopan

Exercise caution when using moderate CYP3A4 inducers (e.g., bosentan, efavirenz, etravirine, and modafinil) prescribed as concomitant medicinal product with avacopan and carefully evaluate the benefit/risk of avacopan.

Effect of strong CYP3A4 inhibitors on avacopan

Co-administration of avacopan with itraconazole, a strong CYP3A4 enzyme inhibitor, resulted in an increase in AUC and C_max of avacopan by approximately 2.2-fold and 1.9-fold, respectively. Therefore, strong CYP3A4 enzyme inhibitors (e.g., boceprevir, clarithromycin, conivaptan, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, mibefradil, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, and voriconazole) should be used with caution in patients who are being treated with avacopan. Patients must be monitored for potential increase of side effects due to the increased exposure of avacopan.

Grapefruit and grapefruit juice can increase the concentration of avacopan; therefore, grapefruit and grapefruit juice are to be avoided in patients treated with avacopan.

Effect of avacopan on other medicinal products

Avacopan is a weak inhibitor of CYP3A4 in vivo and may increase the plasma exposures of concomitant medicinal products that are CYP3A4 substrates with a narrow therapeutic index (e.g., alfentanil, ciclosporin, dihydroergotamine, ergotamine, fentanyl, sirolimus and tacrolimus). Be cautious when these medicinal products are used with avacopan. Patients must be managed according to the summary of product characteristics of the respective medicinal products with a narrow therapeutic index.

Effect of macrogolglycerol hydroxystearate on sensitive P-glycoprotein (P-gp) substrates

A clinically relevant effect of the excipient macrogolglycerol hydroxystearate on sensitive P-gp substrates with relatively low bioavailability (e.g., dabigatran etexilate) cannot be excluded. Exercise caution when using low-bioavailability P-gp substrates in patients who are being treated with avacopan.

Women of childbearing potential / Pregnancy

There are no data from the use of avacopan in pregnant women.

Studies in animals have shown reproductive toxicity (see section 5.3).

Avacopan is not recommended during pregnancy and in women of childbearing potential not using contraception.

Breast-feeding

Avacopan has not been measured in milk of lactating animals; however, avacopan has been detected in the plasma of nursing animal offspring without apparent offspring effects (see section 5.3).

A risk to newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from therapy with avacopan, taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

There are no data on the effects of avacopan on human fertility. Animal data did not indicate any impairment of male or female fertility (see section 5.3).

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

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:

^* 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. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Not applicable.