TAVNEOS 10mg hard capsules medication leaflet

Tavneos 10 mg hard capsules

Each hard capsule contains 10 mg of avacopan.

Each hard capsule contains 245 mg of macrogolglycerol hydroxystearate.

For the full list of excipients, see section 6.1.

Hard capsule

Capsules with yellow body and light orange cap with “CCX168” in black ink.

One capsule has a length of 22 mm and a diameter of 8 mm (size 0).

Tavneos, in combination with a rituximab or cyclophosphamide regimen, is indicated for the treatmentof adult patients with severe, active granulomatosis with polyangiitis (GPA) or microscopicpolyangiitis (MPA) (see section 4.2).

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

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

Tavneos should be administered in combination with a rituximab or cyclophosphamide regimen asfollows:

* rituximab for 4 weekly intravenous doses or,

* intravenous or oral cyclophosphamide for 13 or 14 weeks, followed by oral azathioprine ormycophenolate mofetil and,

* glucocorticoids as clinically indicated.

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

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

If a patient misses a dose, the missed dose is to be taken as soon as possible, unless within three hoursof 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 theupper 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 prolongedhospitalisation).

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 quadrantpain or tenderness, fever, rash, and/or eosinophilia (> 5%),

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

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

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

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

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.

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

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).

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

Serious adverse reactions of elevated hepatic transaminases with elevated total bilirubin have beenobserved in patients receiving avacopan in combination with cyclophosphamide (followed byazathioprine or mycophenolate) or rituximab, and trimethoprim and sulfamethoxazole. In the post-marketing setting, drug-induced liver injury and vanishing bile duct syndrome (VBDS), includingcases 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, alkalinephosphatase (ALP), or total bilirubin > 3 times ULN.

Patients must be monitored for hepatic transaminases and total bilirubin at least every 4 weeks afterstart of therapy for the first 6 months of treatment, and as clinically indicated thereafter (seesection 4.2).

Blood and immune system

White blood cell (WBC) count must be obtained prior to initiation of therapy and patients must bemonitored 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 have been reported in patients receiving combination agents for treatment of GPAor 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 immunodeficiencyvirus (HIV) infections. Before and during treatment, patients must notify their physician if they havebeen 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 HIVinfection.

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

Pneumocystis jirovecii pneumonia prophylaxis

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

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 quiescentphase of the disease.

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, ortongue, 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 (seesection 4.5).

Patients anticipated to require long-term administration of these medicinal products are not to betreated with avacopan.

If short-term co-administration cannot be avoided in a patient already using avacopan, the patient mustbe closely monitored in case of any reoccurrence of disease activity.

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

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

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

Macrogolglycerol hydroxystearate content

This medicinal product contains macrogolglycerol hydroxystearate, which may cause stomach upsetand diarrhoea.

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

Effect of strong CYP3A4 inducers on avacopan

Co-administration of avacopan with rifampicin, a strong CYP3A4 enzyme inducer, resulted in adecrease 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 inloss 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 isto be avoided (see section 4.4). Patients anticipated to require long-term administration of thesemedicinal products are not to be treated with avacopan. If short-term co-administration cannot beavoided in a patient already using avacopan, the patient must be closely monitored for anyreoccurrence of disease activity.

Effect of moderate CYP3A4 inducers on avacopan

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

Effect of strong CYP3A4 inhibitors on avacopan

Co-administration of avacopan with itraconazole, a strong CYP3A4 enzyme inhibitor, resulted in anincrease 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 inpatients who are being treated with avacopan. Patients must be monitored for potential increase of sideeffects due to the increased exposure of avacopan.

Grapefruit and grapefruit juice can increase the concentration of avacopan; therefore, grapefruit andgrapefruit 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 ofconcomitant medicinal products that are CYP3A4 substrates (e.g., alfentanil, ciclosporin,dihydroergotamine, ergotamine, fentanyl, sirolimus and tacrolimus). Patients must be managedaccording to the Summary of Product Characteristics of the concomitant medicinal products. Dosereductions 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. Pleaseconsult 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-gpsubstrates with relatively low bioavailability (e.g., dabigatran etexilate) cannot be excluded. Exercisecaution when using low-bioavailability P-gp substrates in patients who are being treated withavacopan.

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 usingcontraception.

Avacopan has not been measured in milk of lactating animals; however, avacopan has been detected inthe 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 discontinuebreast-feeding or to discontinue/abstain from therapy with avacopan, taking into account the benefit ofbreast-feeding for the child and the benefit of therapy for the woman.

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

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

The most common adverse reactions are nausea (23.5%), headache (20.5%), white blood cell countdecreased (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%).

The adverse reactions observed in the ANCA-associated vasculitis pivotal phase 3 study and in thepost-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). Withineach frequency grouping, adverse reactions are presented in the order of decreasing seriousness.

Table 1: Adverse reactions

System Organ Very Common Common Uncommon Not Known

Class (≥ 1/10) (≥ 1/100 to (≥ 1/1,000 to< 1/10) < 1/100)

Infections and Upper respiratory Pneumonia,infestations tract infection, Rhinitis,

Nasopharyngitis Urinary tractinfection,

Sinusitis,

Bronchitis,

Gastroenteritis,

Lower respiratorytract infection,

Cellulitis,

Herpes zoster,

Influenza,

Oral candidiasis,

Oral herpes,

Otitis media

Blood and Neutropenia1lymphatic systemdisorders

Nervous system Headachedisorders

Gastrointestinal Nausea, Abdominal paindisorders1 Diarrhoea, upper

Hepatobiliary Liver function test Drug-induceddisorders increased1,2 liver injury1,

Vanishing bileduct syndrome1

Skin and Angioedema1subcutaneoustissue disorders

Investigations White blood cell Blood creatinecount decreased3 phosphokinaseincreased11 See section “Description of selected adverse reactions”.2 Alanine aminotransferase increased, total blood bilirubin increased, hepatic function abnormal, gammaglutamyl transferase increased, hepatic enzyme increased, transaminases increased.3 Includes leukopenia.

In the pivotal phase 3 study in which 330 patients were dosed, 13.3% of patients in the avacopangroup and 11.6% of patients in the prednisone group had an adverse reaction of elevated liver functiontest (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 adiagnosis, hepatocellular injury (0.6%) in one patient diagnosed with asymptomatic hepatitis, cytolysisand anicteric cholestasis without hepatocellular insufficiency.

In the pivotal phase 3 study, adverse events of hepatobiliary disorders were more frequent in patientstreated 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% ofpatients in the avacopan group and 3.0% of patients in the prednisone group. Serious adverse reactionsof LFT increased were reported in 5.4% of patients in the avacopan group and 3.7% of patients in theprednisone group. All serious hepatic events resolved with either the withdrawal of avacopan and/orother 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).

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 biopsywhich 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 theprednisone 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 ofangioedema. One patient was hospitalised for the event. Avacopan was paused and both eventsresolved without sequelae. Avacopan was restarted in one patient and angioedema did not reoccur.

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

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

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

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

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

Pharmacotherapeutic group: Complement inhibitors, ATC code: L04AJ05

Avacopan is a selective antagonist of the human complement 5a receptor (C5aR1 or CD88) andcompetitively inhibits the interaction between C5aR1 and the anaphylatoxin C5a.

The specific and selective blockade of C5aR1 by avacopan reduces the pro-inflammatory effects of

C5a, which include neutrophil activation, migration, and adherence to sites of small blood vesselinflammation, vascular endothelial cell retraction and permeability.

Avacopan blocks the C5a-induced upregulation of CD11b (integrin alpha M) on neutrophils takenfrom humans dosed with avacopan. CD11b facilitates neutrophil adherence to vascular endothelialsurfaces, one of the steps in the vasculitis disease process.

A total of 330 patients aged 13 years or older with granulomatosis with polyangiitis (GPA) (54.8%) ormicroscopic polyangiitis (MPA) (45.2%) were treated in the active-comparator, randomised, double-blind, double-dummy, multicentre, pivotal phase 3 ADVOCATE study for 52 weeks.

The ADVOCATE study design is depicted in Figure 1.

Figure 1 ADVOCATE study design

AZA = azathioprine; CYC = cyclophosphamide; IV = intravenous; MMF = mycophenolate mofetil;

RTX =rituximab

Patients were randomised in a 1:1 ratio to one of the two groups:

* Avacopan group (N = 166): Patients received 30 mg avacopan twice daily for 52 weeks plusprednisone-matching placebo tapering regimen over 20 weeks,

* Comparator group (N = 164): Patients received avacopan-matching placebo twice daily for52 weeks plus prednisone (tapered from 60 mg/day to 0 over 20 weeks).

All patients in both groups received standard immunosuppressive regimens of either:

* Rituximab at the dose of 375 mg/m² for 4 weekly intravenous doses, or

* Intravenous cyclophosphamide for 13 weeks (15 mg/kg up to 1.2 g every 2 to 3 weeks), andthen starting on week 15 oral azathioprine 1 mg/kg daily with titration up to 2 mg/kg daily(Mycophenolate mofetil 2 g daily was allowed in place of azathioprine. If mycophenolatemofetil was not tolerated or not available, enteric coated mycophenolate sodium could be givenat a target dose of 1,440 mg/day), or

* Oral cyclophosphamide for 14 weeks (2 mg/kg daily) followed by oral azathioprine ormycophenolate mofetil/sodium starting at week 15 (same dosing regimen as intravenouscyclophosphamide).

For the first rituximab infusion, 100 mg methylprednisolone, or equivalent was given before startingthe infusion with rituximab. Glucocorticoid pre-medication for the second, third, and fourth rituximabinfusions was allowed.

Dose reductions or adjustments in cyclophosphamide, azathioprine, and mycophenolate were allowedto conform to standard approaches to maximize safety of these medicinal products.

The following study-supplied glucocorticoid tapering schedule was used (Table 2).

Table 2: Glucocorticoid tapering schedule - Prednisone dose (mg per day)

Study Day Avacopan Comparator

All ≥ 55 kg < 55 kg1 to 7 0 60 458 to 14 0 45 4515 to 21 0 30 3022 to 42 0 25 2543 to 56 0 20 2057 to 70 0 15 1571 to 98 0 10 1099 to 140 0 5 5≥ 141 0 0 0

Non-study supplied glucocorticoids, unless strictly necessary due to a condition requiring the use ofglucocorticoids (such as adrenal insufficiency), had to be avoided as much as possible during thestudy. However, patients who experienced worsening or a relapse of their ANCA-associated vasculitisduring the study could be treated with a limited course of glucocorticoids.

Patients were stratified at time of randomisation to obtain balance across treatment groups based on3 factors:

* Newly-diagnosed or relapsed ANCA-associated vasculitis,

* Proteinase-3 (PR3) positive or myeloperoxidase (MPO) positive ANCA-associated vasculitis,

* Receiving either intravenous rituximab, intravenous cyclophosphamide, or oralcyclophosphamide.

The two treatment groups were well balanced regarding baseline demographics and diseasecharacteristics of patients (Table 3).

Table 3: Selected baseline characteristics in the pivotal phase 3 ADVOCATE study (Intent-to-Treat Population)

Demographic characteristic Avacopan Comparator(N = 166) (N = 164)

Age at screening

Mean (SD), years 61 (14.6) 61 (14.5)

Range, years 13-83 15-88

ANCA-associated vasculitis status, n (%)

Newly diagnosed 115 (69.3) 114 (69.5)

Relapsed 51 (30.7) 50 (30.5)

ANCA positivity, n (%)

PR3 72 (43.4) 70 (42.7)

MPO 94 (56.6) 94 (57.3)

Type of ANCA-associated vasculitis, n (%)

Granulomatosis with polyangiitis (GPA) 91 (54.8) 90 (54.9)

Microscopic polyangiitis (MPA) 75 (45.2) 74 (45.1)

BVAS score

Mean (SD) 16.3 (5.87) 16.2 (5.69)eGFR

Mean (SD), mL/min/1.73 m2 50.7 (30.96) 52.9 (32.67)

Prior Glucocorticoid Use (during Screening)n (%) 125 (75.3) 135 (82.3)

Mean (SD), prednisone-equivalent dose (mg) 907 (1145.9) 978 (1157.5)

ANCA = antineutrophil cytoplasmic autoantibody; BVAS = Birmingham Vasculitis Activity Score;

MPO = myeloperoxidase; PR3 = proteinase-3, SD = standard deviation

The aim of the study was to determine if avacopan could provide an effective treatment for patientswith ANCA-associated vasculitis, while also allowing for the reduction of glucocorticoids use withoutcompromising safety or efficacy.

The primary objective was to evaluate the efficacy of the above described treatment regimens toinduce and sustain remission in patients with ANCA-associated vasculitis based on the following twoprimary endpoints:

* the proportion of patients in disease remission defined as achieving a Birmingham Vasculitis

Activity Score (BVAS) of 0 and not taking glucocorticoids for treatment of ANCA-associatedvasculitis within 4 weeks prior to week 26,

* the proportion of patients in sustained remission defined as remission at week 26 withoutrelapse to week 52, and BVAS of 0 and not taking glucocorticoids for treatment of ANCA-associated vasculitis within 4 weeks prior to week 52.

The two primary endpoints were tested sequentially for non-inferiority and superiority using agatekeeping procedure to preserve the Type I error rate at 0.05.

Results from this study are showed in Table 4.

Table 4: Remission at week 26 and sustained remission at week 52 in the pivotal phase 3

ADVOCATE study (Intent-to-Treat Population)

Avacopan Comparator Estimate of

N = 166 N = 164 Treatmentn (%) n (%) Difference in %a

Remission at week 26 120 (72.3) 115 (70.1) 3.495% CI 64.8, 78.9 62.5, 77.0 −6.0, 12.8

Sustained remission at week 52 109 (65.7) 90 (54.9) 12.5 b95% CI 57.9, 72.8 46.9, 62.6 2.6, 22.3

CI = confidence intervala Two-sided 95% CIs are calculated by adjusting for randomisation stratification factors.b superiority p value = 0.013 (2-sided)

The efficacy observed was consistent across pertinent subgroups, i.e., those with newly-diagnosed andrelapsed disease, PR3 and MPO ANCA positive, GPA and MPA, and men and women. Efficacyresults by background treatment are presented in Table 5.

Table 5: Remission at week 26 and sustained remission at week 52 in the pivotal phase 3

ADVOCATE study by background treatment (Intent-to-Treat Population)

Avacopan Comparator Difference in %,n/N (%) n/N (%) 95% CIa

Remission at week 26

Patients receiving intravenous 83/107 (77.6) 81/107 (75.7) 1.9 (−9.5, 13.2)rituximab

Patients receiving intravenous or 37/59 (62.7) 34/57 (59.6) 3.1 (−14.7, 20.8)oral cyclophosphamide

Sustained remission at week 52

Patients receiving intravenous 76/107 (71.0) 60/107 (56.1) 15.0 (2.2, 27.7)rituximab

Patients receiving intravenous or 33/59 (55.9) 30/57 (52.6) 3.3 (−14.8, 21.4)oral cyclophosphamidea Two-sided 95% confidence intervals (CI) are calculated for the difference in proportions (avacopan minuscomparator) using the Wald method.

Glucocorticoid toxicity

In the pivotal phase 3 ADVOCATE study, the mean total cumulative prednisone-equivalent dose fromday 1 to end-of-treatment was approximately 2.3-fold higher in the comparator group versus theavacopan group (3846.9 mg vs 1675.5 mg, respectively).

From baseline to week 26, 86.1 % of patients using avacopan received non-study suppliedglucocorticoids. In the comparator group, the majority of glucocorticoids use was due to the protocol-defined prednisone course.

Figure 2: Total mean daily prednisone-equivalent glucocorticoid dose (in mg) per patient bystudy week by treatment group in the ADVOCATE study (Intent-to-Treat

Population)40 Prednisone

Avacopan0 4 8 12 16 20 24 28 32 36 40 44 48 52

Study Week

The Glucocorticoid Toxicity Index (GTI) assesses glucocorticoid-related morbidity, includingmeasures of body mass index, glucose tolerance, lipids, steroid myopathy, skin toxicity,neuropsychiatric toxicity, and infection. A higher GTI indicates greater glucocorticoid toxicity. The

GTI contains the Cumulative Worsening Score (CWS) that captures cumulative toxicity over thecourse of time, and the Aggregate Improvement Score (AIS) that captures both improvement andworsening of toxicity over time.

The two GTI scores (CWS and AIS) of the avacopan group versus the comparator group aresummarised in Table 6. The GTI measures were secondary endpoints in the study and not controlledfor multiplicity

Table 6: Glucocorticoid Toxicity Index results in the pivotal phase 3 ADVOCATE study(Intent-to-Treat Population)

Avacopan Comparator Difference

N = 166 N = 164 between Groups,95% CI

Cumulative Worsening Score (CWS)

Week 13 (least squares mean) 25.7 36.6 −11.0 (−19.7, −2.2)

Week 26 (least squares mean) 39.7 56.6 −16.8 (−25.6, −8.0)

Aggregate Improvement Score (AIS)

Week 13 (least squares mean) 9.9 23.2 −13.3 (−22.2, −4.4)

Week 26 (least squares mean) 11.2 23.4 −12.1 (−21.1, −3.2)

A total of 3 adolescents were studied in the pivotal phase 3 ADVOCATE study, two in the avacopangroup and one in the comparator group. One adolescent in the avacopan group discontinued treatment

Mean Daily Total Prednisone-Equivalent Dose (mg)due to worsening renal vasculitis. The second adolescent patient who received avacopan completedtreatment, achieved both remission at week 26 and sustained remission at week 52.

The adolescent in the comparator group discontinued treatment due to non-adherence to contraception.

The European Medicines Agency has deferred the obligation to submit the results of studies withavacopan in one or more subsets of the paediatric population in treatment of ANCA-associatedvasculitis (see section 4.2 for information on paediatric use).

When administered without food, avacopan peak plasma concentration (Cmax) occurs at a median time(tmax) of approximately 2 hours. Avacopan has shown an approximate dose-proportional increase insystemic exposure in the dose range of 10 to 30 mg.

Co-administration of 30 mg in capsule formulation with a high-fat, high-calorie meal increases theplasma exposure (AUC) of avacopan by approximately 72% and delays tmax by approximately 3 hours;however, the Cmax is not affected.

The reversible plasma protein binding (e.g., to albumin and α1-acid glycoprotein) of avacopan andmetabolite M1 is greater than 99.9%. The apparent volume of distribution is high(Vz/F 3,000 - 11,000 L), indicating broad tissue distribution of the active substance.

Avacopan is eliminated mainly through phase I metabolism. Following oral administration ofradiolabelled avacopan, the bulk of the active substance-related materials was recovered in faeces inthe form of phase I metabolites. One major circulating metabolite (M1), a mono-hydroxylated productof avacopan, was present at ~ 12% of the total active substance-related materials in plasma. Thismetabolite constitutes 30 to 50% of the parent exposure and has approximately the same activity asavacopan on C5aR1. Cytochrome P450 (CYP) 3A4 is the major enzyme responsible for the clearanceof avacopan and for the formation and clearance of metabolite M1.

Clinical interaction of avacopan with the sensitive CYP3A4 substrate simvastatin is described insection 4.5. Avacopan is a weak inhibitor of CYP2C9 as indicated by a modest increase in the AUC ofthe probe active substance celecoxib (1.15-fold).

In vitro, avacopan is not an inhibitor of other CYP enzymes and is not an inducer of CYP enzymes.

Avacopan showed negligible to weak inhibition of common transporters in vitro. Therefore, clinicallyrelevant interactions are unlikely when avacopan is co-administered with substances that are substratesor inhibitors of these transporters.

Based on population pharmacokinetic analysis, the total apparent body clearance (CL/F) of avacopanis 16.3 L/h (95% CI: 13.1 - 21.1 L/h). The median terminal elimination half-life is 510 hours (21 days)based on population pharmacokinetic analysis. When avacopan is stopped after steady state has beenreached, the residual plasma concentration of avacopan is projected to decrease to ~ 20%, < 10%, and< 5% of the steady state maximum concentration approximately 4 weeks, 7 weeks, and 10 weeks,respectively, after the last dose.

Following oral administration of radiolabelled avacopan, about 77% and 10% of the radioactivity wasrecovered in faeces and urine, respectively, and 7% and < 0.1% of the radioactive dose was recoveredas unchanged avacopan in faeces and urine, respectively. These results suggest that the main route ofclearance of avacopan is metabolism followed by biliary excretion of the metabolites into faeces, andthat direct excretion of avacopan into urine or faeces via bile is negligible.

Population pharmacokinetic analysis found no significant effect of age (among adults) on the plasmaexposure of avacopan; however, there were limited pharmacokinetic data in patients over 75 years ofage in clinical studies. No dose adjustment is necessary for elderly patients (see section 4.2).

The pharmacokinetic properties of avacopan have been examined in 16 patients with mild (Child-Pughclass A) or moderate (Child-Pugh class B) hepatic impairment. When compared to normal controls, nopharmacologically relevant differences in exposure (mean ratios of Cmax and AUC ≤ 1.3) of avacopanor its major metabolite M1 was observed; therefore, no dose adjustment is necessary (see section 4.2).

Avacopan has not been studied in patients with severe hepatic impairment (Child-Pugh class C) (seesection 4.2).

Based on population pharmacokinetic analysis, the plasma exposure of avacopan is similar betweenpatients with renal impairment and healthy subjects. Therefore, no dose adjustment is necessary basedon renal function (see section 4.2).

Avacopan has not been studied in patients with ANCA-associated vasculitis with an eGFRbelow 15 mL/min/1.73 m², who are on dialysis, in need of dialysis or plasma exchange.

Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, repeated dose toxicity, genotoxicity and carcinogenicity.

Fertility and early embryonic development

Avacopan produced no effects on male or female reproductive performance (fertility) or earlydevelopment in hamsters at oral doses equivalent up to 6.8-fold the clinical AUC.

Embryo-foetal development

Avacopan was not teratogenic when dosed orally to hamsters and rabbits. In hamsters, an increasedincidence of skeletal variations (short thoracolumbar supernumerary rib) was observed at exposureequivalent to 5.3-fold the clinical AUC. In rabbits, avacopan caused maternal toxicity (adverse clinicalsigns and abortions), but no foetal toxicity at 0.6-fold the clinical AUC.

Pre- and post-natal development

Avacopan did not result in adverse effects in female offspring when administered in hamsters atexposures up to 6.3-fold the clinical AUC during gestation and through lactation until weaning. Inmales, there was a slight delay in preputial separation at 3.7-fold the clinical AUC. This isolatedfinding was considered to be of low toxicological significance and was not associated with anyimpairment of reproductive performance.

Analysis of avacopan plasma levels in the lactating dams and the plasma levels in nursing offspringshowed the presence of avacopan, suggesting that avacopan is likely secreted into the milk of lactatinghamsters.

The carcinogenic potential of avacopan was evaluated in a 2-year study in both rats and hamsters.

In male rats, a slightly increased incidence of C-cell thyroid adenoma was noted in avacopan-treatedrats; this increase was not statistically significant, and the incidence was within the historical controlrange. Avacopan was not carcinogenic in hamsters, the pharmacologically relevant species.

Macrogolglycerol hydroxystearate

Macrogol (4000)

Gelatin

Red iron oxide (E172)

Yellow iron oxide (E172)

Titanium dioxide (E171)

Polysorbate 80

Imprinting ink

Black iron oxide (E172)

Shellac

Potassium hydroxide

Not applicable.

4 years

This medicinal product does not require any special temperature storage conditions.

Store in the original bottle in order to protect from light.

High density polyethylene (HDPE) bottle with child-resistant closure and induction seal.

Pack sizes of 30 or 180 hard capsules or multipack of 540 hard capsules (3 packs of 180).

Not all pack sizes may be marketed.

No special requirements.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Vifor Fresenius Medical Care Renal Pharma France100-101 Terrasse Boieldieu

Tour Franklin La Défense 892042 Paris la Défense Cedex

France

EU/1/21/1605/001

EU/1/21/1605/002

EU/1/21/1605/003

Date of first authorisation: 11 January 2022

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.