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 ASPAVELI, unless the risk of delaying therapy outweighs the risk of developing an infection.

Patients with known history of vaccination

Before receiving treatment with ASPAVELI, 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 ASPAVELI.

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 ASPAVELI. 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 ASPAVELI therapy with patients.

Hypersensitivity

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

Injection site reactions

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

PNH laboratory monitoring

Patients with PNH receiving ASPAVELI 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 ASPAVELI, 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 are familiar with the physician’s guide to prescribing. Physicians must discuss the benefits and risks of pegcetacoplan therapy with patients and provide them with a patient information brochure and a patient safety card. Patients should be instructed to seek prompt medical care if they experience any signs and symptoms of infection with encapsulated bacteria during therapy with ASPAVELI, especially if signs and symptoms are indicative of meningococcal infection.

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 ASPAVELI 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).

ASPAVELI 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

The most commonly reported adverse reactions in patients treated with ASPAVELI were injection site reactions: injection site erythema, injection site pruritus, injection site swelling, injection site pain. Other adverse reactions reported in more than 10% of patients during clinical studies were upper respiratory tract infection, abdominal pain, diarrhoea, headache, fatigue, and pyrexia. The most commonly reported serious adverse reactions were haemolysis and thrombocytopenia.

Tabulated list of adverse reactions

Table 1 gives the adverse reactions observed from the clinical studies with pegcetacoplan in patients with PNH. 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:

The ADRs listed in the table are from clinical studies APL2-302, Study 202, Study 204, and Study CP0514.
¹ Upper respiratory tract infection includes preferred terms of Upper respiratory tract infection, Nasopharyngitis, Pharyngitis, Rhinitis, Sinusitis, Tonsillitis, Tonsillitis bacterial, and Viral pharyngitis.
² Haemolysis includes preferred terms of Haemolysis, Haemolytic anaemia, and Intravascular haemolysis.
³ Thrombocytopenia includes the preferred terms of Platelet count decreased and Thrombocytopenia.
⁴ Abdominal pain includes preferred terms of Abdominal pain, Abdominal pain upper, Abdominal pain lower, and Abdominal discomfort.
⁵ Fatigue includes preferred terms of Fatigue and Asthenia.
⁶ Pyrexia includes preferred terms of Pyrexia and Body temperature increased.

Description of selected adverse reactions

Infections

Based on its mechanism of action, the use of pegcetacoplan may potentially increase the risk of infections, particularly infections caused by encapsulated bacteria including Streptococcus pneumoniae, Neisseria meningitidis types A, C, W, Y, and B, and Haemophilus influenzae (see section 4.4). No infection caused by encapsulated bacteria was reported during Study APL2-302. The most frequent infections in patients treated with pegcetacoplan during the run-in and randomised controlled periods (RCP) of Study APL-302 were upper respiratory tract infections (11 cases, 13.8%). Most infections reported in patients treated with pegcetacoplan during the run-in and RCP were non-serious, and predominantly mild in intensity. Four serious infections were reported in Study APL2-302: one bacterial infection, one viral upper respiratory tract infection, and one gastroenteritis during the RCP, and one sepsis during the run-in period in a patient with history of renal transplant. Of these, two were severe in intensity (gastroenteritis and sepsis). None of these events led to discontinuation of pegcetacoplan.

Haemolysis

Six cases of haemolysis were reported during the run-in (1 case) and RCP (5 cases) of Study APL2-302 in patients treated with pegcetacoplan. Three cases were serious in nature and severe in intensity. One of the serious episodes of haemolysis resulted in pegcetacoplan discontinuation. The remaining events were non-serious in nature and moderate in intensity; of these, 2 led to discontinuation of pegcetacoplan.

Immunogenicity

Anti-drug antibody (ADA) incidence (seroconverted ADA or boosted ADA from pre-existing level) were low, and when present, had no noticeable impact on the PK/PD, efficacy, or safety profile of pegcetacoplan. In Study APL2-302 up to Week 16, 2 out of 80 patients developed anti-pegcetacoplan peptide antibodies. Both patients also tested positive for neutralizing antibody (NAb). NAb response had no apparent impact on PK or clinical efficacy. Two out of 80 patients developed anti-PEG antibody incidence; one was seroconversion and one was treatment-boosted which was transient.

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.