Tavneos - summary of medicine characteristics

1. NAME OF THE MEDICINAL PRODUCT

Tavneos 10 mg hard capsules

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each hard capsule contains 10 mg of avacopan.

Excipient with known effect

Each hard capsule contains 245 mg of macrogolglycerol hydroxystearate.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

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).

4. CLINICAL PARTICULARS4.1 Therapeutic indications

Tavneos, 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.

Posology

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 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 x 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 x ULN,
• • ALT or AST > 5 x ULN for more than 2 weeks,
• • ALT or AST > 3 x ULN and total bilirubin > 2 x ULN or international normalised ratio

(INR) > 1.5,

• • ALT or AST > 3 x 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 subjects 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

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/^L, or neutrophil count less than 1500/p.L, or lymphocyte count less than 500/p.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 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.

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 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.

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

Tavneos 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 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 (> 1/10)	Common (> 1/100 to < 1/10)	Uncommon (> 1/1,000 to < 1/100)
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		Neutropenia
Nervous system disorders	Headache
Gastrointestinal disorders	Nausea, Diarrhoea, Vomiting	Abdominal pain upper
Hepatobiliary disorders	Liver function test increased*
Skin and subcutaneous tissue disorders			Angioedema
Investigations	White blood cell count decreased	Blood creatine 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. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in

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.

5. PHARMACOLOGICAL PROPERTIES5.1 Pharmacodynamic properties

Pharmacotherapeutic group: not yet assigned, ATC code: not yet assigned

Mechanism of action

Avacopan is a selective antagonist of the human complement 5a receptor (C5aR1 or CD88) and competitively 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 vessel inflammation, vascular endothelial cell retraction and permeability.

Pharmacodynamic effects

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

Clinical efficacy and safety

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

The ADVOCATE study design is depicted in

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 plus prednisone-matching placebo tapering regimen over 20 weeks,
• • Comparator group (N=164): Patients received avacopan-matching placebo twice daily for

52 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), and then 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 mycophenolate mofetil was not tolerated or not available, enteric coated mycophenolate sodium could be given at a target dose of 1,440 mg/day), or
• • Oral cyclophosphamide for 14 weeks (2 mg/kg daily) followed by oral azathioprine or mycophenolate mofetil/sodium starting at week 15 (same dosing regimen as intravenous cyclophosphamide).

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

Dose reductions or adjustments in cyclophosphamide, azathioprine, and mycophenolate were allowed to 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 kg
1 to 7	0	60	45
8 to 14	0	45	45
15 to 21	0	30	30
22 to 42	0	25	25
43 to 56	0	20	20
57 to 70	0	15	15
71 to 98	0	10	10
99 to 140	0	5	5
> 141	0	0	0

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

3 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 oral cyclophosphamide.

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

Table 3: Selected baseline characteristics in the pivotal phase 3 ADVOCATE study (Intent-

to-Treat Population)

Demographic characteristic	Avacopan (N = 166)	Comparator (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)	654 (744.4)	728 (787.8)

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 patients with ANCA-associated vasculitis, while also allowing for the reduction of glucocorticoids use without compromising safety or efficacy.

The primary objective was to evaluate the efficacy of the above described treatment regimens to induce and sustain remission in patients with ANCA-associated vasculitis based on the following two primary 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-associated vasculitis within 4 weeks prior to week 26,
• • the proportion of patients in sustained remission defined as remission at week 26 without relapse to week 52, and BVAS of 0 and not taking glucocorticoids for treatment of ANCA-associated vasculitis within 4 weeks prior to week 52.

5.2 Pharmacokinetic properties

Absorption

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 in systemic 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 the plasma exposure (AUC) of avacopan by approximately 72% and delays tmax by approximately 3 hours; however, the Cmax is not affected.

Distribution

The reversible plasma protein binding (e.g., to albumin and a1-acid glycoprotein) of avacopan and metabolite Ml 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.

Biotransformation

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

Avacopan is a weak inhibitor of CYP3A4 and CYP2C9 as indicated by a modest increase in the AUC of the probe active substances midazolam (1.81-fold) and celecoxib (1.15-fold), respectively.

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

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

Elimination

Based on population pharmacokinetic analysis, the total apparent body clearance (CL/F) of avacopan is 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 been reached, 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 was recovered in faeces and urine, respectively, and 7% and < 0.1% of the radioactive dose was recovered as unchanged avacopan in faeces and urine, respectively. These results suggest that the main route of clearance of avacopan is metabolism followed by biliary excretion of the metabolites into faeces, and that direct excretion of avacopan into urine or faeces via bile is negligible.

Special populations

Elderly

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

Hepatic impairment

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

Avacopan has not been studied in subjects with severe hepatic impairment (Child-Pugh class C) (see section 4.2).

Renal impairment

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

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

5.3 Preclinical safety data

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

Fertility and early embryonic development

Avacopan produced no effects on male or female reproductive performance (fertility) or early development 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 increased incidence of skeletal variations (short thoracolumbar supernumerary rib) was observed at exposure equivalent to 5.3-fold the clinical AUC. In rabbits, avacopan caused maternal toxicity (adverse clinical signs 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 at exposures up to 6.3-fold the clinical AUC during gestation and through lactation until weaning. In males, there was a slight delay in preputial separation at 3.7-fold the clinical AUC. This isolated finding was considered to be of low toxicological significance and was not associated with any impairment of reproductive performance.

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

Carcinogenicity

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-treated rats; this increase was not statistically significant, and the incidence was within the historical control range. Avacopan was not carcinogenic in hamsters, the pharmacologically relevant species.

6. PHARMACEUTICAL PARTICULARS6.1 List of excipients

Capsule content

Macrogolglycerol hydroxystearate

Macrogol (4000)

Capsule shell

Gelatin

Red iron oxide (E172)

Yellow iron oxide (E172)

Titanium dioxide (E171)

Polysorbate 80

Imprinting ink

Black iron oxide (E172)

Shellac

Potassium hydroxide

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years

6.4 Special precautions for storage

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

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

6.5 Nature and contents of container

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

Pack sizes of 30 or 180 hard capsules.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements.

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

7. MARKETING AUTHORISATION HOLDER

Vifor Fresenius Medical Care Renal Pharma France

100–101 Terrasse Boieldieu

Tour Franklin La Défense 8

92042 Paris la Défense Cedex

France

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/21/1605/001

EU/1/21/1605/002

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: