4.1. Therapeutic indications

Avacopan Vifor, in combination with a rituximab or cyclophosphamide regimen, is indicated for the treatment of adult patients with severe, active granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) (see section 4.2).

4.2. Posology and method of administration

Treatment should be initiated and monitored by healthcare professionals experienced in the diagnosis and treatment of GPA or MPA (see section 4.4).

Posology

The recommended dose is 30 mg Avacopan Vifor (3 hard capsules of 10 mg each) taken orally twice daily, morning and evening, with food.

Avacopan Vifor should be administered in combination with a rituximab or cyclophosphamide regimen as follows:

• rituximab for 4 weekly intravenous doses or,

• intravenous or oral cyclophosphamide for 13 or 14 weeks, followed by oral azathioprine or mycophenolate mofetil and,

• glucocorticoids as clinically indicated.

For details on doses, concomitant glucocorticoids and data on efficacy and safety for the combinations, please see sections 4.8 and 5.1.

Clinical study data are limited to 52 weeks of exposure followed by 8 weeks of observation.

Missed doses

If a patient misses a dose, the missed dose is to be taken as soon as possible, unless within three hours of the next scheduled dose. If within three hours, then the missed dose is not to be taken.

Dose management

Treatment must be re-assessed clinically and temporarily stopped if:

• alanine aminotransferase (ALT) or aspartate aminotransferase (AST) is more than 3 times the upper limit of normal (ULN).

Treatment must be temporarily stopped if:

• ALT or AST > 5 × ULN,

• a patient develops leukopenia (white blood cell count < 2 × 109/L) or neutropenia (neutrophils < 1 × 109/L), or lymphopenia (lymphocytes < 0.2 × 109/L),

• a patient has an active, serious infection (i.e. requiring hospitalisation or prolonged hospitalisation).

Treatment may be resumed:

• upon normalisation of values and based on an individual benefit/risk assessment.

If treatment is resumed, hepatic transaminases and total bilirubin are to be monitored closely.

Permanent discontinuation of treatment must be considered if:

• ALT or AST > 8 × ULN,

• ALT or AST > 5 × ULN for more than 2 weeks,

• ALT or AST > 3 × ULN and total bilirubin > 2 × ULN or international normalised ratio (INR) > 1.5,

• ALT or AST > 3 × ULN with the appearance of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (> 5%),

• an association between avacopan and hepatic dysfunction has been established.

Special populations

Elderly

No dose adjustment is required in elderly patients (see section 5.2).

Hepatic impairment

No dose adjustment is required for patients with mild or moderate hepatic impairment (see section 5.2).

Avacopan has not been studied in patients with severe hepatic impairment (Child-Pugh Class C) and it is therefore not recommended for use in these patient populations.

Renal impairment

No dose adjustment is needed based on renal function (see section 5.2).

Avacopan has not been studied in patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis with an estimated glomerular filtration rate (eGFR) below 15 mL/min/1.73 m2, who are on dialysis, in need of dialysis or plasma exchange.

Severe disease manifested as alveolar haemorrhage

Avacopan has not been studied in patients with severe disease manifested as alveolar haemorrhage.

Paediatric population

The safety and efficacy of avacopan in adolescents (12 to 17 years of age) have not yet been established. Currently available data are described in sections 4.8 and 5.1 but no recommendation on a posology can be made. The safety and efficacy of avacopan in children below 12 years of age have not yet been established. No data are available.

Method of administration

This medicinal product is for oral use.

The hard capsules are to be taken with food and swallowed whole with water and must not be crushed, chewed, or opened.

Grapefruit and grapefruit juice are to be avoided in patients treated with avacopan (see section 4.5).

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

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).

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

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.

Patients must be monitored for hepatic transaminases and total bilirubin at least every 4 weeks after start of therapy for the first 6 months of treatment, and as clinically indicated thereafter (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.

4.5. Interaction with other medicinal products and other forms of interaction

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 (Cmax) 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 Cmax 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 moderate inhibitor of CYP3A4 in vivo and may increase the plasma exposures of concomitant medicinal products that are CYP3A4 substrates (e.g., alfentanil, ciclosporin, dihydroergotamine, ergotamine, fentanyl, sirolimus and tacrolimus). Patients must be managed according to the Summary of Product Characteristics of the concomitant medicinal products. Dose reductions or monitoring of adverse events may be necessary.

In a clinical study, the co-administration of avacopan with simvastatin, a sensitive CYP3A4 substrate, increased the total systemic exposure (AUC) of simvastatin by 3.5-fold and Cmax by 3.2-fold. Please consult the Summary of Product Characteristics for simvastatin for appropriate dose adjustments.

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.

4.6. Fertility, pregnancy and lactation

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).

4.7. Effects on ability to drive and use machines

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

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 and in the post-marketing setting 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), uncommon (≥ 1/1,000 to < 1/100) and not known (frequency cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.

Table 1: Adverse reactions

System Organ Class

Very Common

(≥ 1/10)

Common

(≥ 1/100 to < 1/10)

Uncommon

(≥ 1/1,000 to < 1/100)

Not known

Infections and infestations

Upper respiratory tract infection,

Nasopharyngitis

Pneumonia,

Rhinitis,

Urinary tract infection,

Sinusitis,

Bronchitis,

Gastroenteritis,

Lower respiratory tract infection,

Cellulitis,

Herpes zoster,

Influenza,

Oral candidiasis,

Oral herpes,

Otitis media

Blood and lymphatic system disorders

Neutropenia1

Nervous system disorders

Headache

Gastrointestinal disorders1

Nausea,

Diarrhoea,

Vomiting

Abdominal pain upper

Hepatobiliary disorders

Liver function test increased1,2

Drug-induced liver injury1,

Vanishing bile duct syndrome1

Skin and subcutaneous tissue disorders

Angioedema1

Investigations

White blood cell count decreased3

Blood creatine phosphokinase increased1

1 See section “Description of selected adverse reactions”.

2 Alanine aminotransferase increased, total blood bilirubin increased, hepatic function abnormal, gamma glutamyl transferase increased, hepatic enzyme increased, transaminases increased.

3 Includes leukopenia.

Description of selected adverse reactions

Hepatotoxicity

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.

Drug-induced liver injury and vanishing bile duct syndrome (VBDS) have been reported in the post-marketing setting (see section 4.4).

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 Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for 'MHRA Yellow Card' in the Google Play or Apple App Store.

4.9. Overdose

Avacopan was studied in healthy subjects at a maximum total daily dose of 200 mg (given as 100 mg twice daily) for 7 days without evidence of dose limiting toxicities. In case of an overdose, it is recommended that the patient is monitored for any signs or symptoms of adverse effects, and appropriate symptomatic treatment and supportive care are provided.