Avacopan

TAVNEOS (avacopan capsules) is indicated for: • the adjunctive treatment of adult patients with severe active anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (granulomatosis with polyangiitis [GPA] and microscopic polyangiitis [MPA]) in combination with standard background therapy including glucocorticoids.

TAVNEOS does not eliminate glucocorticoid use. 1 Pediatrics Pediatrics (<18 years of age): No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use. 2 Geriatrics Geriatrics (≥ 65 years of age): Evidence from clinical trials suggest that use in geriatric population is not associated with a difference in effectiveness.

1 Dosing Considerations Treatment with TAVNEOS should be initiated and monitored by healthcare professionals experienced in the diagnosis and treatment of ANCA-associated vasculitis (GPA and MPA). Serum alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase and total bilirubin and Hepatitis B virus (HBV) serology should be obtained prior to initiating treatment with TAVNEOS to establish baseline liver function.

For patients with evidence of prior or current HBV infection, consult with a physician with expertise in managing hepatitis B regarding monitoring and consideration for HBV treatment before or during treatment with TAVNEOS. TAVNEOS is not recommended for use in patients with cirrhosis, especially with severe hepatic impairment (Child-Pugh Class C) (see 7 WARNINGS AND PRECAUTIONS, Hepatic ).

Treatment with TAVNEOS should be re-assessed clinically if alanine aminotransferase (ALT) or aspartate aminotransferase (AST) is more than 3 times the upper limit of normal. Obtain liver function tests (ALT, AST, alkaline phosphatase and total bilirubin) before initiating treatment with TAVNEOS, and monitor every 4 weeks after start of therapy for the first 6 months of treatment and as clinically indicated thereafter.

2 Recommended Dose and Dosage Adjustment The recommended dose of TAVNEOS is 30 mg (3 capsules of 10 mg each) taken orally twice daily with food. 2 × 109/L), • a patient has an active, serious infection. Treatment may be resumed once drug-induced liver injury has been ruled out and upon normalization of values and based on an individual benefit/risk assessment.

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

Pediatric patients. Health Canada has not authorized an indication for pediatric use. Patients with renal impairment. No dosage adjustment is required in patients with mild, moderate, or severe renal impairment. Avacopan has not been studied in patients with ANCA-associated vasculitis who are on dialysis.

Patients with hepatic impairment. Avacopan should be used with caution in patients with mild or moderate hepatic impairment. If a positive benefit-risk assessment is made, no dose adjustment is required in these patients. 3 Pharmacokinetics: Special Populations and Conditions ; Hepatic Insufficiency).

Geriatric patients. No dose adjustment is required in geriatric patients. Patients taking strong CYP3A4 inhibitors. 4 Drug-Drug Interactions). Patients taking CYP3A4 substrates. 4 Drug-Drug Interactions). 4 Administration TAVNEOS is for oral use.

The capsules should be taken with food in the morning and the evening. The capsules should be swallowed whole with water and must not be crushed, chewed, or opened. 5 Missed Dose If a patient misses a dose, the missed dose should be taken as soon as possible, unless within three hours of the next scheduled dose.

If within three hours, then the missed dose should not be taken.

). 2 Recommended Dose and Dosage Adjustment). , chronic active hepatitis B, untreated hepatitis C, uncontrolled autoimmune hepatitis) and cirrhosis. Consider the risks and benefits before administrating TAVNEOS to a patient with a liver disease.

1 Special Populations). Immune Angioedema TAVNEOS may cause angioedema (see 8 ADVERSE REACTIONS). In clinical trials, two cases of angioedema occurred, including one serious event requiring hospitalization. If angioedema occurs, discontinue TAVNEOS immediately, provide appropriate therapy, and monitor for airway compromise.

TAVNEOS must not be re-administered unless another cause has been established. Educate patients on recognizing the signs and symptoms of a hypersensitivity reaction and to seek immediate medical care should they develop. Immunization The safety of immunization with live vaccines, following avacopan has not been studied.

Administer vaccination preferably prior to initiation of treatment with avacopan. Infection Serious infections, including fatal infections, have been reported in patients receiving TAVNEOS. 8%). Avoid use of TAVNEOS in patients with an active serious infection, including localized infections.

Consider the risks and benefits of treatment prior to initiating TAVNEOS in patients: - With chronic or recurrent infections - Who have been exposed to tuberculosis - With a history of a serious or an opportunistic infection TAVNEOS avacopan Page 8 of 29 Unclassified / Non classifié - Who have resided or traveled in areas of endemic tuberculosis or endemic mycoses; or - With underlying conditions that may predispose them to infection.

Closely monitor patients for the development of signs and symptoms of infection during and after treatment with TAVNEOS. Interrupt TAVNEOS if a patient develops a serious or opportunistic infection and treat accordingly. TAVNEOS may be resumed once the infection is controlled.

Pneumocystis jirovecii pneumonia prophylaxis:

Pneumocystis jirovecii pneumonia prophylaxis is recommended for adult patients with GPA or MPA during TAVNEOS treatment, as appropriate according to local clinical practice guidelines. 1 Dosing Considerations and 7 WARNINGS AND PRECAUTIONS, Hepatic ).

1 Dosing Considerations and 7 WARNINGS AND PRECAUTIONS).

Reproductive Health:

Female and Male Potential • Fertility There are no data on the effects of avacopan on human fertility. Fertility/early embryo development, embryo/foetal development, and pre- and post-natal development studies conducted with avacopan in hamsters or rabbits generally showed no evidence of reproductive toxicity or teratogenicity, at doses up to 1,000 mg/kg/day in hamsters and 200 mg/kg/day in rabbits; the only exceptions were an increased incidence of skeletal variations at 1,000 mg/kg/day avacopan in hamster and of abortion at 200 mg/kg/day avacopan in rabbits (see 16 NON-CLINICAL TOXICOLOGY, Reproductive and Developmental Toxicology ).

1 Pregnant Women Avacopan is not recommended during pregnancy and in women of childbearing potential not using contraception. There are no data from the use of avacopan in pregnant women. In animal studies designed to assess effects of avacopan upon embryo-fetal development with pregnant hamsters (dosed by the oral route during the period of organogenesis from gestation day 6 to 12), there was an increased incidence of skeletal variations (short thoracolumbar supernumerary rib) at the highest dose tested (500 mg/kg BID, which is equivalent to an exposure of 5 times the maximum recommended human dose calculated on an AUC basis with 1000 mg/kg/day).

In a prenatal and postnatal development study with pregnant hamsters (orally dosed from gestation day 6 to lactation day 20), avacopan had no effects on the growth and development of offspring with exposures up to approximately 5 times the maximum recommended human dose (based on maternal doses of up to 1000 mg/kg/day).

An embryo-fetal development study with pregnant rabbits dosed by the oral route during the period of organogenesis from gestation day 6 to 18 was conducted. 6 times the maximum recommended human dose (based on AUCs with the maternal oral doses of 30 mg/kg/day and higher) (see 16 NON-CLINICAL TOXICOLOGY, Reproductive and Developmental Toxicology ).

2 Breast-feeding The safety of avacopan when used during pregnancy or breastfeeding has not been evaluated in humans. There are no data on the use of avacopan in lactating women and it is unknown whether avacopan is excreted in human milk.

37. The no-observed-adverse-effect-level (NOAEL) for viability, growth, and reproduction in F1 offspring was 1,000 mg/kg/day (500 mg/kg twice daily) (see 16 NON-CLINICAL TOXICOLOGY, Reproductive and […]

TAVNEOS is contraindicated in: • Patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. For a complete listing, see 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING.

2).

4). 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.

1. Clinical study data are limited to 52 weeks of exposure followed by 8 weeks of observation. 3 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).

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.

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.

2). 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. 2). 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. 4 Paediatric population The safety and efficacy of avacopan in adolescents (12 to 17 years of age) have not yet been established.

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. 5).

1%). 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.

8 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. 6% of patients in the prednisone group had an adverse reaction of elevated liver function test (LFT).

6%) in one patient diagnosed with asymptomatic hepatitis, cytolysis and anicteric cholestasis without hepatocellular insufficiency. 7%). 0% of patients in the prednisone group. 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.

4). 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.

6%) in the prednisone group had adverse reactions of increased creatine phosphokinase (CPK). 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. 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.

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. 10

1.