4.1. Therapeutic indications

ASPAVELI is indicated as monotherapy in the treatment of adult patients with paroxysmal nocturnal haemoglobinuria (PNH) who have haemolytic anaemia.

ASPAVELI is indicated for the treatment of adult and adolescent patients aged 12 to 17 years with C3 glomerulopathy (C3G) or primary immune-complex membranoproliferative glomerulonephritis (IC-MPGN) in combination with a renin-angiotensin system (RAS) inhibitor, unless RAS inhibitor treatment is not tolerated or contraindicated.

4.2. Posology and method of administration

Therapy should be initiated under the supervision of a healthcare professional experienced in the management of patients with haematological or renal disorders. Self‑administration and home infusion should be considered for patients who have tolerated treatment well in experienced treatment centres. The decision of a possibility of self‑administration and home infusions should be made after evaluation and recommendation from the treating physician.

Posology

Pegcetacoplan can be given by a healthcare professional or administered by the patient or caregiver following proper instruction.

PNH

Adult patients with PNH

Pegcetacoplan is administered twice weekly as a 1 080 mg subcutaneous infusion with a commercially available syringe system infusion pump or on-body delivery system, that can deliver doses up to 20 mL. The twice weekly dose should be administered on Day 1 and Day 4 of each treatment week.

PNH is a chronic disease and treatment with ASPAVELI is recommended to continue for the patient's lifetime, unless the discontinuation of this medicinal product is clinically indicated (see section 4.4).

Patients with PNH switching to ASPAVELI from a C5 inhibitor

For the first 4 weeks, pegcetacoplan is administered as twice weekly subcutaneous doses of 1 080 mg in addition to the patient's current dose of C5 inhibitor treatment to minimise the risk of haemolysis with abrupt treatment discontinuation. After 4 weeks, the patient should discontinue C5 inhibitor before continuing on monotherapy with ASPAVELI.

Switches from complement inhibitors other than eculizumab have not been studied. Discontinuing other complement inhibitors before reaching steady state of pegcetacoplan should be done with caution (see section 5.2).

Dose adjustment in PNH

The dosing regimen may be changed to 1 080 mg every third day (e.g., Day 1, Day 4, Day 7, Day 10, Day 13, and so forth) if a patient has a lactate dehydrogenase (LDH) level greater than 2 x upper limit of normal (ULN). In the event of a dose increase, LDH should be monitored twice weekly for at least 4 weeks (see section 4.4).

C3G and primary IC-MPGN

Pegcetacoplan is administered twice weekly as a subcutaneous infusion with a commercially available syringe system infusion pump or on-body delivery system, that can deliver doses up to 20 mL. The twice weekly dose should be administered on Day 1 and Day 4 of each treatment week.

C3G and primary IC-MPGN are chronic diseases. Discontinuation of this medicinal product is not recommended unless clinically indicated.

Adult patients with C3G or primary IC-MPGN

Pegcetacoplan is administered twice weekly as a 1 080 mg subcutaneous infusion.

Adolescent patients with C3G or primary IC-MPGN

For adolescent patients, the dosing regimen is based on the patient´s body weight and consists of the following:

Body weight

First dose

(infusion volume)

Second dose

(infusion volume)

Maintenance dose

(infusion volume)

≥ 50 kg

1 080 mg twice weekly (20 mL)

35 to < 50 kg

648 mg (12 mL)

810 mg (15 mL)

810 mg twice weekly (15 mL)

30 to < 35 kg

540 mg (10 mL)

540 mg (10 mL)

648 mg twice weekly (12 mL)

Missed dose

If a dose of pegcetacoplan for treatment of PNH, C3G or primary IC-MPGN is missed, it should be administered as soon as possible, then the regular schedule should be resumed even if this results in an interval of less than 3 days between the replacement dose and the subsequent dose.

Patients with post-transplant recurrent C3G or primary IC-MPGN

Diagnosis of post-transplant recurrent C3G or primary IC-MPGN should be made based on a renal allograft biopsy. C3G or primary IC-MPGN recurrence may be detected in a routine post-transplant biopsy; otherwise, a biopsy should be performed when clinical signs indicate recurrent disease. As done in study APL2-C3G-204 (see section 5.1), treatment with pegcetacoplan can be started before the onset of clinical signs such as estimated glomerular filtration rate (eGFR) decrease or urine to protein-to-creatinine ratio (uPCR) increase. There is limited experience with the use of pegcetacoplan in patients with recurrent C3G or primary IC-MPGN after transplantation in clinical studies (see section 5.1).

Special populations

Elderly

Although there were no apparent age‑related differences observed in clinical studies, the number of patients aged 65 and over is not sufficient to determine whether they respond differently from younger patients. There is no evidence indicating any special precautions are required for treating an elderly population.

Renal impairment

Severe renal impairment (creatinine clearance <30 mL/min) had no effect on the pharmacokinetics (PK) of pegcetacoplan; therefore, pegcetacoplan dose adjustment in patients with renal impairment is not necessary. There are no data available for the use of pegcetacoplan in patients with end‑stage renal disease (ESRD) requiring dialysis (see section 5.2).

Hepatic impairment

The safety and efficacy of pegcetacoplan have not been studied in patients with hepatic impairment; however, no dose adjustment is recommended, as hepatic impairment is not expected to impact clearance of pegcetacoplan.

Paediatric population

The safety and efficacy of ASPAVELI in children with PNH aged 0 to <18 years have not yet been established. No data are available.

The safety and efficacy of ASPAVELI in children with C3G or primary IC-MPGN aged below 12 years have not been established. No data are available.

This medicinal product should not be used in children <12 years of age, as non‑clinical safety data are not available for this age group.

Method of administration

ASPAVELI should only be administered via subcutaneous administration using a commercially available syringe system infusion pump or on-body delivery system. This medicinal product can be self‑administered. When self‑administration is initiated, the patient will be instructed by a qualified healthcare professional in infusion techniques, the use of a syringe system infusion pump or on-body delivery system, the keeping of a treatment record, the recognition of possible adverse reactions, and measures to be taken in case these occur.

• When using a syringe system infusion pump, ASPAVELI should be infused in the abdomen, thighs, hips, or upper arms. Infusion sites should be at least 7.5 cm apart from each other. The infusion sites should be rotated between administrations. The infusion time is approximately 30 minutes (if using two sites) or approximately 60 minutes (if using one site).

• When using an on-body delivery system, ASPAVELI should be infused at a site on the abdomen. The infusion site should be rotated between administrations following the device manufacturer´s instructions. The infusion time varies by patient and typically ranges from 30 to 60 minutes.

Infusion into areas where the skin is tender, bruised, red, or hard should be avoided. Infusion into tattoos, scars, or stretch marks should be avoided. The infusion should be started promptly after drawing this medicinal product into the syringe. Administration should be completed within 2 hours after preparing the syringe. For instructions on the preparation and infusion of the medicinal product, see section 6.6.

4.3. Contraindications

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

Pegcetacoplan therapy must not be initiated in patients:

• with unresolved infection caused by encapsulated bacteria including Neisseria meningitidis, Streptococcus pneumoniae, and Haemophilus influenzae (see section 4.4).

• who are not currently vaccinated against Neisseria meningitidis, Streptococcus pneumoniae, and Haemophilus influenzae unless they receive prophylactic treatment with appropriate antibiotics until 2 weeks after vaccination (see section 4.4).

4.4. Special warnings and precautions for use

Serious infections caused by encapsulated bacteria

The use of pegcetacoplan may predispose individuals to serious infections caused by encapsulated bacteria including Neisseria meningitidis, Streptococcus pneumoniae, and Haemophilus influenzae. To reduce the risk of infection, all patients must be vaccinated against these bacteria according to applicable local guidelines at least 2 weeks prior to receiving pegcetacoplan, unless the risk of delaying therapy outweighs the risk of developing an infection.

Patients with known history of vaccination

Before receiving treatment with pegcetacoplan in patients with a known history of vaccination, it should be ensured that patients have received vaccines against encapsulated bacteria including Streptococcus pneumoniae, Neisseria meningitidis types A, C, W, Y, and B, and Haemophilus influenzae Type B within 2 years prior to starting pegcetacoplan.

Patients without known history of vaccination

For patients without known history of vaccination, the required vaccines should be administered at least 2 weeks prior to receiving the first dose of pegcetacoplan. If immediate therapy is indicated, the required vaccines should be administered as soon as possible and the patient treated with appropriate antibiotics until 2 weeks after vaccination.

Monitoring patients for serious infections

Vaccination may not be sufficient to prevent serious infection. Consideration should be given to official guidance on the appropriate use of antibacterial agents. All patients should be monitored for early signs of infections caused by encapsulated bacteria including Neisseria meningitidis, Streptococcus pneumoniae, and Haemophilus influenzae, evaluated immediately if infection is suspected, and treated with appropriate antibiotics if necessary. Patients should be informed of these signs and symptoms, and steps taken to seek medical care immediately. Physicians must discuss the benefits and risks of pegcetacoplan therapy with patients.

Hypersensitivity

Hypersensitivity reactions have been reported. If a severe hypersensitivity reaction (including anaphylaxis) occurs, infusion with pegcetacoplan must be discontinued immediately, and appropriate treatment instituted.

Injection site reactions

Injection site reactions have been reported with the use of subcutaneous pegcetacoplan (see section 4.8). Patients should be trained appropriately in proper injection technique.

PNH laboratory monitoring

Patients with PNH receiving pegcetacoplan should be monitored regularly for signs and symptoms of haemolysis, including measuring LDH levels, and may require dose adjustment within the recommended dosing schedule (see section 4.2).

Effects on laboratory tests

There may be interference between silica reagents in coagulation panels and pegcetacoplan that results in artificially prolonged activated partial thromboplastin time (aPTT); therefore, the use of silica reagents in coagulation panels should be avoided.

Treatment discontinuation for PNH

If patients with PNH discontinue treatment with pegcetacoplan, they should be closely monitored for signs and symptoms of serious intravascular haemolysis. Serious intravascular haemolysis is identified by elevated LDH levels along with sudden decrease in PNH clone size or haemoglobin (Hb), or reappearance of symptoms such as fatigue, haemoglobinuria, abdominal pain, dyspnoea, major adverse vascular event (including thrombosis), dysphagia, or erectile dysfunction. If discontinuation of this medicinal product is necessary, alternate therapy should be considered. If serious haemolysis occurs after discontinuation, consider the following procedures/treatments: blood transfusion (packed RBCs), exchange transfusion, anticoagulation, and corticosteroids. Patients should be closely monitored for at least 8 weeks from the last dose, representing more than 5 half‑lives of this medicinal product, to allow for medicinal product washout (see section 5.2) to detect serious haemolysis and other reactions. In addition, slow weaning should be considered.

Contraception in women of childbearing potential

It is recommended that women of childbearing potential use effective contraception methods to prevent pregnancy during treatment with pegcetacoplan and for at least 8 weeks after the last dose of pegcetacoplan (see section 4.6).

Polyethylene glycol (PEG) accumulation

ASPAVELI is a PEGylated medicinal product. The potential long-term effects of PEG accumulation in the kidneys, the choroid plexus of the brain, and other organs are unknown (see section 5.3). Regular laboratory testing of renal function is recommended.

Educational materials

All physicians who intend to prescribe ASPAVELI must ensure they have received and are familiar with the physician educational material. Physicians must explain and discuss the benefits and risks of ASPAVELI therapy with the patient and provide them with the patient information pack and the patient card. The patient should be instructed to seek prompt medical care if they experience any sign or symptom of serious infection or hypersensitivity during therapy with ASPAVELI, especially if indicative of infection with encapsulated bacteria.

Excipients with known effect

Sorbitol content

ASPAVELI 1 080 mg contains 820 mg sorbitol in each vial.

Patients with hereditary fructose intolerance (HFI) should not take/be given this medicinal product.

Sodium content

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say, essentially 'sodium‑free'.

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

No interaction studies have been performed. Based on in vitro data, pegcetacoplan has low potential for clinical drug‑drug interactions.

4.6. Fertility, pregnancy and lactation

Women of childbearing potential

It is recommended that women of childbearing potential use effective contraception methods to prevent pregnancy during treatment with pegcetacoplan and for at least 8 weeks after the last dose of pegcetacoplan. For women planning to become pregnant, the use of pegcetacoplan may be considered following an assessment of the risks and benefits (see Pregnancy).

Pregnancy

There is a limited amount of data from the use of pegcetacoplan in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3).

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

Breast‑feeding

It is unknown whether pegcetacoplan is excreted in human milk. The potential for absorption and harm to the breastfed infant is unknown. Animal data suggest a low excretion (less than 1%, not pharmacologically significant) of pegcetacoplan in monkey milk (see section 5.3). It is unlikely that a breastfed infant would have clinically relevant exposure.

It is recommended to discontinue breast‑feeding during pegcetacoplan treatment.

Fertility

No animal or human data on the effect of pegcetacoplan on fertility are available. In toxicity studies, there were no microscopic abnormalities in male or female reproductive organs in monkeys (see section 5.3).

4.7. Effects on ability to drive and use machines

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

4.8. Undesirable effects

Summary of the safety profile

PNH

The most commonly reported adverse reactions in patients with PNH treated with pegcetacoplan were injection site reactions: injection site erythema, injection site pruritus, injection site swelling, injection site pain, injection site bruising. Other adverse reactions reported in more than 10% of patients during clinical studies were upper respiratory tract infection, diarrhoea, haemolysis, abdominal pain, headache, fatigue, pyrexia, cough, urinary tract infection, vaccination complication, pain in extremity, dizziness, arthralgia, and back pain. The most commonly reported serious adverse reactions were haemolysis and sepsis.

C3G and primary IC-MPGN

The most commonly reported adverse drug reactions in patients with C3G or primary IC-MPGN treated with pegcetacoplan were infusion site reactions and upper respiratory tract infections. The most commonly reported serious adverse reactions were acute kidney injury and pneumonia.

Tabulated list of adverse reactions

Table 1 gives the adverse reactions observed from clinical studies and postmarketing experience with pegcetacoplan in patients with PNH, C3G and primary IC-MPGN. Adverse reactions are listed by MedDRA system organ class (SOC) and frequency, using the following convention: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1 000 to <1/100) or rare (≥1/10 000 to <1/1 000), very rare (<1/10 000), and not known (cannot be estimated from available data).

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 1: Adverse reactions from clinical trials1 and postmarketing experience

MedDRA System Organ Class

Adverse reaction

Frequency in PNH

Frequency in C3G or primary IC-MPGN

Infections and infestations

Influenza

Very common

Upper respiratory tract infections2

Very common

Very common

Urinary tract infection

Very common

Common

Sepsis

Common3

Opportunistic infections

Common4

COVID-19, Gastrointestinal infection, Fungal infection, Skin infection, Oral infection

Common

Ear infection

Common

Common

Infection, Respiratory tract infection5, Viral infection, Bacterial infection, Vaginal infection, Eye infection

Common

Cervicitis, Groin infection

Uncommon

Pneumonia

Uncommon

Common

Nasal abscess, Tuberculosis, Oesophageal candidiasis, COVID-19 pneumonia, Anal abscess

Uncommon

Immune system disorders

Hypersensitivity reaction

Very common6

Anaphylactic reaction7

Anaphylactic shock7

Uncommon

Blood and lymphatic system disorders

Haemolysis

Very common

Thrombocytopenia

Common

Common8

Neutropenia

Common

Common

Metabolism and nutrition disorders

Hypokalaemia

Common

Common

Nervous system disorders

Headache

Very common

Very common

Dizziness

Very common

Vascular disorders

Hypertension

Common

Respiratory, thoracic and mediastinal disorders

Cough

Very common

Common

Dyspnoea, Oropharyngeal pain, Nasal congestion

Common

Epistaxis

Common

Common

Gastrointestinal disorders

Abdominal pain

Very common

Diarrhoea

Very common

Very common

Nausea

Common

Very common

Skin and subcutaneous tissue disorders

Erythema, Rash, Urticaria

Common

Musculoskeletal and connective tissue disorders

Arthralgia, Back pain

Very common

Pain in extremity

Very common

Common

Myalgia

Common

Common

Muscle spasms

Common

Renal and urinary disorders

Acute kidney injury

Common

Very common

Chromaturia

Common

General disorders and administration site conditions

Pyrexia

Very common

Very common

Fatigue

Very common

Common

Infusion site reactions9

Very common

Very common

Investigations

Alanine aminotransferase increased, Bilirubin increased

Common

Injury, poisoning and procedural complications

Vaccination complication

Very common

1 Studies APL2-308, APL2-302, APL2-202, APL2-CP-PNH-204, and APL-CP0514 in PNH patients and Study APL2-C3G-310, APL2-C3G-314, APL2-201 and APL2-C3G-204 in C3G and primary IC-MPGN patients.

Medically similar terms are grouped, where appropriate, on the basis of similar medical concept.

2 Include nasopharyngitis, upper respiratory tract infection, pharyngitis, rhinitis and sinusitis.

3 Sepsis includes one case of septic shock and one case with non-encapsulated Neisseria meningitidis.

4Herpes zoster (including Herpes zoster meningoencephalitis), and Pneumocystis jirovecii infection.

5Include respiratory tract infection and respiratory tract infection viral.

6Include rash and eczema.'

7 Estimated from postmarketing experience.

8Includes platelet count decreased.

9PTs included in Infusion site reactions: infusion site erythema, infusion site pruritus, infusion site swelling, infusion site bruising, infusion site pain, infusion site induration.

Description of selected adverse reactions

Infections

No serious infection caused by encapsulated bacteria was reported during PNH Study APL2‑302. Forty-eight patients experienced an infection during the study. The most frequent infections in patients treated with pegcetacoplan during PNH Study APL2‑302 were upper respiratory tract infection (28 cases, 35%). Most infections reported in patients treated with pegcetacoplan during PNH study APL2-302 were non‑serious, and predominantly mild in intensity. Ten patients developed infections reported as serious including one patient who died due to COVID-19. The most frequent serious infections were sepsis (3 cases) (leading to discontinuation of pegcetacoplan in one patient) and gastroenteritis (3 cases); all of which resolved.

In C3G and primary IC‑MPGN clinical studies, four serious respiratory tract infections caused by encapsulated bacteria were reported in patients treated with pegcetacoplan: an epiglottitis, a pneumococcal pneumonia and an atypical pneumonia that led to drug interruption, and a pneumonia Haemophilus with no dose adjustment. Events recovered and resolved except for the events of pneumonia Haemophilus and the atypical pneumonia that resolved with sequelae. In addition, one serious Escherichia urinary tract infection was reported, the event recovered and resolved with no dose adjustment.

Haemolysis

Nineteen patients reported haemolysis during PNH Study APL2‑302 in patients treated with pegcetacoplan. Seven cases were reported as serious, and 5 cases led to discontinuation of pegcetacoplan and the dose of pegcetacoplan was increased in 10 patients. There were 3 cases of haemolysis during PNH Study APL2‑308 in patients treated with pegcetacoplan. None of these cases were reported as serious or led to discontinuation of pegcetacoplan. The dose of pegcetacoplan was increased in all 3 patients.

Acute kidney injury

In C3G and primary IC-MPGN clinical studies, 10 serious events of acute kidney injury were reported in 8 patients (5.7%) treated with pegcetacoplan, of which 5 events were observed in 4 post-transplant patients. Of these serious events, only 1 led to drug withdrawal and 1 to dose interruption. All events recovered and resolved, except the single event that led to drug withdrawal.

Patients with post-transplant recurrent C3G or primary IC-MPGN

In the patients with post-transplant recurrent C3G or primary IC-MPGN (N=22), included in Studies APL2-C3G-310 and APL2-C3G-204, the safety profile appeared consistent with that of the overall population, although with higher frequencies of severe and serious adverse events, as expected in this patient population.

Paediatric population

In adolescent patients with C3G or primary IC-MPGN (N=28, aged 12 years to 17 years) included in Study APL2‑C3G-310, the safety profile appeared consistent with the overall results. The most common adverse reaction reported in this patient population were infusion site reactions.

The safety of pegcetacoplan has not been studied in paediatric patients less than 12 years of age.

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.

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

4.9. Overdose

In the postmarketing setting, cases of overdose have been reported , with no new safety events observed. In case of overdose, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions and appropriate symptomatic treatment be instituted.