ASPAVELI Solution for infusion Ref.[49950] Active ingredients: Pegcetacoplan

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, 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'.

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

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 are no or 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).

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

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 the 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 trials 1 and postmarketing experience:

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.
⁴ Herpes zoster (including Herpes zoster meningoencephalitis), and Pneumocystis jirovecii infection.
⁵ Include respiratory tract infection and respiratory tract infection viral.
⁶ Include rash and eczema.
⁷ Includes platelet count decreased.
⁸ PTs 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 nonserious, 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 national reporting system listed in Appendix V.

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.