1 Name of Medicine
Pegcetacoplan.
2 Qualitative and Quantitative Composition
Each 20 mL vial contains 1,080 mg pegcetacoplan in a pH 5.0, 10 mmol acetate buffer.
For the full list of excipients, see Section 6.1 List of Excipients.
3 Pharmaceutical Form
Solution for injection.
Clear, colourless to slightly yellowish aqueous solution, practically free from visible particles, to be administered by subcutaneous infusion.
Empaveli solution for injection does not contain any antimicrobial preservatives. The vial is for single use in one patient on one occasion only. Discard any residue.
4.1 Therapeutic Indications
Empaveli is indicated in the treatment of adult patients with paroxysmal nocturnal haemoglobinuria (PNH).
4.2 Dose and Method of Administration
Recommended vaccination and prophylaxis.
Before receiving treatment with Empaveli. Patients with known history of vaccination.
Ensure 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 (Hib) within 2 years prior to starting Empaveli (see Section 4.4 Special Warnings and Precautions for Use).
Patients without known history of vaccination.
Administer required vaccines at least 2 weeks prior to receiving the first dose of Empaveli (see Section 4.4 Special Warnings and Precautions for Use).
If immediate therapy with Empaveli is indicated, administer required vaccines as soon as possible and provide patients with antibacterial drug prophylaxis until 2 weeks after vaccination (see Section 4.4 Special Warnings and Precautions for Use).
Dosage.
Adult patients with PNH.
Empaveli is administered twice weekly as a 1,080 mg subcutaneous infusion with a commercially available syringe system infusion pump that can deliver doses up to 20 mL (see Method of administration). After proper training in subcutaneous infusion, a patient may self-administer, or the patient's caregiver may administer Empaveli, if a healthcare provider determines that it is appropriate.
PNH is a chronic disease and treatment with Empaveli is recommended to continue for the patient's lifetime, unless the discontinuation of Empaveli is clinically indicated (see Section 4.4 Special Warnings and Precautions for Use).
Patients switching to Empaveli from a C5 inhibitor (eculizumab rmc, ravulizumab rch).
For the first 4 weeks, Empaveli 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 treatment with the C5 inhibitor before continuing on monotherapy with Empaveli.
Dose adjustment for Empaveli.
The dosing regimen may be changed to 1,080 mg every third day if a subject has a lactate dehydrogenase (LDH) level greater than 2 x upper limit of normal (ULN).
In the event of a dose increase, monitor LDH twice weekly for at least 4 weeks.
Missed dose of Empaveli.
If a dose of Empaveli is missed, and the next scheduled dose has not been administered, the missed dose should be administered as soon as possible, and the regular schedule resumed.
Two doses should not be administered on the same day; however, it is acceptable to administer doses on 2 consecutive days.
Method of administration.
Empaveli should only be administered via subcutaneous administration using a syringe system infusion pump.
When therapy with Empaveli is initiated, the patient will be instructed by a qualified healthcare provider in infusion techniques, the use of a syringe system infusion pump, the keeping of a treatment record, the recognition of possible adverse reactions, and measures to be taken in case these occur.
Infuse Empaveli in the abdomen, thighs, hips, or upper arms. Infusion sites should be at least 7.5 cm apart from each other. Rotate infusion sites between administration. Do not infuse into areas where the skin is tender, bruised, red, or hard. Avoid infusing into tattoos, scars, or stretch marks.
The typical infusion time is approximately 30 minutes (if using two sites) or approximately 60 minutes (if using one site). The infusion should be started promptly after drawing Empaveli into the syringe. Complete the administration within 2 hours after preparing the syringe.
Renal impairment.
Renal impairment had no effect on the pharmacokinetics of pegcetacoplan; therefore, dose adjustment of Empaveli in patients with renal impairment is not necessary (see Section 5.2 Pharmacokinetic Properties). There are no data available for the use of pegcetacoplan in patients with end-stage renal disease requiring haemodialysis.
Hepatic impairment.
The safety and efficacy of Empaveli have not been studied in patients with hepatic impairment; however, population pharmacokinetic data suggest that no dose adjustment is required in patients with hepatic impairment (see Section 5.2 Pharmacokinetic Properties).4.3 Contraindications
Empaveli is contraindicated in patients with:
Hypersensitivity to pegcetacoplan or to any of the excipients;
Unresolved infection caused by encapsulated bacteria including Neisseria meningitidis, Streptococcus pneumoniae, and Haemophilus influenzae (see Section 4.4 Special Warnings and Precautions for Use).
4.4 Special Warnings and Precautions for Use
Serious infections caused by encapsulated bacteria.
The use of Empaveli may predispose individuals to serious infections caused by encapsulated bacteria including Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae. To reduce the risk of infection, all patients must be vaccinated against these bacteria according to current local guidelines at least 2 weeks prior to receiving Empaveli, unless the risk of delaying therapy with Empaveli outweighs the risk of developing an infection. Patients who initiate treatment with Empaveli less than 2 weeks after vaccination must receive treatment with appropriate prophylactic antibiotics until 2 weeks after vaccination.
Vaccination may not be sufficient to prevent serious infection. Consider official guidance on the appropriate use of antibacterial agents. Monitor all patients for early signs of serious infection, evaluate immediately if infection is suspected, and treat with appropriate antibiotics if necessary. Inform patients of these signs and symptoms and that they should seek medical care immediately.
Hypersensitivity.
Hypersensitivity reactions have been reported. If a severe hypersensitivity reaction (including anaphylaxis) occurs, discontinue infusion with Empaveli immediately and institute appropriate treatment.
Monitoring PNH manifestations after discontinuation of Empaveli.
If patients with PNH discontinue treatment with Empaveli, 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, shortness of breath (dyspnoea), major adverse vascular event (including thrombosis), dysphagia, or erectile dysfunction. If discontinuation of Empaveli is necessary, an alternate therapy should be considered because PNH is life-threatening if untreated. If serious haemolysis occurs after discontinuation, consider the following procedures/treatments: blood transfusion (packed RBCs), exchange transfusion, anticoagulation and corticosteroids. In addition, slow weaning should be considered, and patients should be closely monitored for at least 8 weeks to detect haemolysis and other reactions, as alternative complement inhibitors may not prevent haemolysis as efficiently.
PNH laboratory monitoring.
Patients with PNH receiving Empaveli 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 Dose and Method of Administration).
Excipients with known effect.
This medicinal product contains sorbitol. The additive effect of concomitantly administered products containing sorbitol (or fructose) and dietary intake of sorbitol (or fructose) should be taken into consideration for patients known or suspected to have the rare genetic disorder of hereditary fructose intolerance (HFI).
Use in the elderly.
Although there were no apparent age-related differences observed in clinical studies, the number of patients aged 65 years and over was not sufficient to determine whether they respond differently from younger subjects.
Paediatric use.
The safety and efficacy of pegcetacoplan in children with PNH from birth to less than 18 years have not been established.
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.
Effects on laboratory tests.
There may be interference between silica reagents in coagulation panels and Empaveli that results in artificially prolonged activated partial thromboplastin time (aPTT); therefore, the use of silica reagents in coagulation panels should be avoided.4.5 Interactions with Other Medicines and Other Forms of Interactions
No clinical interaction studies have been performed. Nonclinical studies showed that pegcetacoplan has a low potential for pharmacokinetic drug interactions, as it did not induce or inhibit cytochrome P450 isozyme activities or serve as a substrate and/or inhibitor for human drug transporters.
4.6 Fertility, Pregnancy and Lactation
Effects on fertility.
Effects of pegcetacoplan upon fertility have not been studied in animals. There were no microscopic abnormalities in male or female reproductive organs in toxicity studies in rabbits and monkeys dosed daily subcutaneously for up to 9 months at exposure levels up to 6 times the clinical area under the curve (AUC).
(Category B3)
There are insufficient data on Empaveli use in pregnant women to inform a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.
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. Pregnancy testing is advised for females of reproductive potential prior to treatment with Empaveli.
Use of Empaveli in pregnancy should be carefully considered, with regard to the specific risks of PNH (including maternal and neonatal death and non-live birth) and benefits for each patient. Empaveli should be used during pregnancy only if the potential benefit justifies the potential risk to the mother, fetus, and/or neonate.
Clinical considerations. Disease-associated maternal and/or fetal/neonatal risk.
In pregnancy, PNH is associated with adverse maternal outcomes, including worsening cytopenias, thrombotic events, infections, bleeding, miscarriages and increased maternal mortality, and adverse fetal outcomes, including fetal death and premature delivery.
Animal data. Animal reproduction studies with pegcetacoplan were conducted in rats, rabbits, and cynomolgus monkeys. Pegcetacoplan treatment of pregnant cynomolgus monkeys at a subcutaneous dose of 28 mg/kg/day (2.9 times the human steady-state AUC) from the gestation period through parturition resulted in a statistically significant increase in abortions or stillbirths compared to controls. The relative exposure at the no-adverse-effect level for this effect (7 mg/kg/day) was similar to that anticipated clinically (1.3 times AUC). No maternal toxicity or teratogenic effects were observed in offspring delivered at term. Additionally, no developmental effects were observed in infants up to 6 months postpartum. Minimal systemic exposure to pegcetacoplan (less than 1% of maternal exposure) was detected in fetuses from monkeys treated with 28 mg/kg/day from the period of organogenesis through the second trimester.
It is not known whether pegcetacoplan is secreted in human milk or whether there is potential for absorption and harm to the infant. Animal data and the chemical nature of pegcetacoplan suggest that the risk of clinically relevant exposure to the infant is minimal.
Minimal (less than 1%) pegcetacoplan excretion in milk has been demonstrated in monkeys; therefore, the probability of clinically relevant exposure of breastfed infant through breastmilk is considered low.
It is recommended to discontinue breast-feeding during pegcetacoplan treatment.4.7 Effects on Ability to Drive and Use Machines
Empaveli has no or negligible influence on the ability to drive and use machines.
4.8 Adverse Effects (Undesirable Effects)
Clinical trial experience in adult patients with PNH.
Study in complement inhibitor-experienced adult patients with PNH (Study APL2-302).
The data described in Table 1 reflect the exposure in 80 adult patients with PNH who received Empaveli (n=41) or eculizumab (n=39) at the recommended dosing regimens for 16 weeks in Study APL2-302.
Serious adverse events were reported in 7 (17%) patients with PNH receiving Empaveli. The most common serious adverse reaction in patients treated with Empaveli was infections (5%).
Clinically relevant adverse reactions in less than 5% of patients include: intestinal ischemia; biliary sepsis; hypersensitivity pneumonitis.
The data described in Table 2 reflect the exposure in the 80 adult patients in Study APL2-302 who received Empaveli at the recommended dosing regimens for up to 48 weeks.
Study in complement inhibitor-naïve adult patients with PNH (Study APL2-308).
The data described below reflect the exposure in adult patients with PNH who received Empaveli (n=46) or the control arm (supportive care excluding complement inhibitors) (n=18) in Study APL2-308. One patient (2%) who received Empaveli died due to septic shock. Serious adverse events were reported in 6 (13%) patients with PNH receiving Empaveli. The most common adverse events (≥ 10%) in patients treated with Empaveli were injection site reactions, infections, viral infection, pain in extremity, hypokalaemia, arthralgia, dizziness, abdominal pain, rash, and headache.
Table 3 describes the adverse events that occurred in ≥ 5% of patients treated with Empaveli in Study APL2-308.
Description of selected adverse reactions.
Injection site reactions.
Injections site reactions (e.g. erythema, swelling, induration, pruritus, and pain) have been reported during Study APL2-302 and APL2-308. These reactions were not severe and did not lead to discontinuation of treatment.
Diarrhoea.
Cases of diarrhoea have been reported during Study APL2-302 and APL2-308, none of them were severe or led to discontinuation of treatment.
Haemolysis.
Haemolysis and haemolytic anaemia have been reported during Study APL2-302 and APL2-308. In Study APL2-302, these events occurred less frequently in the Empaveli group than in the eculizumab group during the randomised controlled period (RCP) (Week 16). There were 3 cases of haemolysis during 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.
Immunogenicity.
The immunogenicity of Empaveli has been evaluated using specific anti-drug antibody (ADA) assays, one specific for the detection of ADAs against the peptide moiety of pegcetacoplan (anti-pegcetacoplan peptide) and a second one specific for ADAs against the polyethylene glycol (PEG) component of pegcetacoplan (anti-PEG).
Anti-drug antibody incidence (seroconverted ADA or boosted ADA from pre-existing level) was low, and when present, had no noticeable impact on the pharmacokinetics/pharmacodynamics (PK/PD), efficacy, or safety profile of pegcetacoplan. Throughout studies APL2-302 and APL2-308, 3 out of 126 patients who were exposed to pegcetacoplan had confirmed positive anti-pegcetacoplan peptide antibodies. All 3 patients also tested positive for neutralising antibody (NAb). NAb response had no apparent impact on PK or clinical efficacy. Eighteen out of 126 patients developed anti-PEG antibodies; nine were seroconversions and nine were treatment-boosted.
Post marketing experience.
In post marketing experience, the following additional adverse reactions have been reported:
Immune system disorders: anaphylactic reaction, anaphylactic shock.
Skin and subcutaneous tissue disorders: urticaria.
Reporting suspected adverse effects.
Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting-problems.4.9 Overdose
No case of overdose has been reported during clinical studies.
For information on the management of overdose, contact the Poison Information Centre on 13 11 26 (Australia).
5 Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmacotherapeutic group: Selective immunosuppressants, ATC code: LO4AJ03.
Mechanism of action.
Pegcetacoplan binds to complement protein C3 and its activation fragment C3b with high affinity, thereby regulating the cleavage of C3 and the generation of downstream effectors of complement activation. In PNH, extravascular haemolysis (EVH) is facilitated by C3b opsonisation while intravascular haemolysis (IVH) is mediated by the downstream membrane attack complex (MAC). Pegcetacoplan exerts broad regulation of the complement cascade by acting proximal to both C3b and MAC formation, thereby controlling the mechanisms that lead to EVH and IVH. These functions of pegcetacoplan underlie the observed sustained reduction in complement mediated haemolytic activity in patients with PNH.
Pharmacodynamic effects.
In Study APL2-302, the mean C3 concentration increased from 0.94 g/L at baseline to 3.83 g/L at Week 16 in the pegcetacoplan group and sustained through Week 48. In Study APL2-308, the mean C3 concentration increased from 0.95 g/L at baseline to 3.56 g/L at Week 26.
In Study APL2-302, the percentage of PNH Type II + III RBCs increased from 66.80% at baseline to 93.85% at Week 16 and sustained through Week 48. In Study APL2-308, the mean percentage of PNH Type II + III RBCs increased from 42.4% at baseline to 90.0% at Week 26.
In Study APL2-302, the mean percentage of PNH Type II + III RBCs with C3 deposition was decreased from 17.73% at baseline to 0.20% at Week 16 and sustained through Week 48. In Study APL2-308, the mean percentage of PNH Type II + III RBCs with C3 deposition decreased from 2.85% at baseline to 0.09% at Week 26.
Pegcetacoplan treatment of patients with PNH resulted in the improvement of haemoglobin (Hb) level and reduction of absolute reticulocyte count (ARC) and LDH (see Clinical trials).
Clinical trials.
Paroxysmal nocturnal haemoglobinuria (PNH). The efficacy and safety of Empaveli in patients with PNH was assessed in two open-label, randomised, controlled, Phase 3 studies (Study APL2-302 (NCT03500549) and Study APL2-308 (NCT04085601)). All patients who completed the studies were eligible to enroll in a separate long-term extension study.
In both studies, patients were vaccinated against Streptococcus pneumoniae, Neisseria meningitidis types A, C, W, Y and B, and Haemophilus influenzae type B (Hib), either within 2 years prior to Day 1 or within 2 weeks after starting treatment with Empaveli. Patients vaccinated after Day 1 received prophylactic treatment with appropriate antibiotics until 2 weeks after vaccination. In addition, prophylactic antibiotic therapy was administered at the discretion of the investigator in accordance with local treatment guidelines for patients with PNH who are receiving treatment with a complement inhibitor.
The dose of Empaveli was 1,080 mg twice weekly. If required, the dose of Empaveli could be adjusted to 1,080 mg every 3 days. Empaveli was administered as a subcutaneous infusion; the infusion time was approximately 20 to 40 minutes.
Study in complement inhibitor-experienced adult PNH patients (APL2-302).
This study enrolled patients with PNH who had been treated with a stable dose of eculizumab for at least the previous 3 months and with Hb levels < 10.5 g/dL. The dose of Empaveli was 1,080 mg twice weekly. Eligible patients entered a 4-week run-in period during which they received Empaveli 1,080 mg subcutaneously twice weekly in addition to their current dose of eculizumab. Patients were then randomised in a 1:1 ratio to receive either 1,080 mg of Empaveli twice weekly or their current dose of eculizumab through the duration of the 16-week randomised controlled period (RCP). If required, the dose of Empaveli could be adjusted to 1,080 mg every 3 days. Randomisation was stratified based on the number of packed red blood cell (PRBC) transfusions within the 12 months prior to Day 28 (< 4; ≥ 4) and platelet count at screening (< 100,000/mm3; ≥ 100,000/mm3). Following completion of the RCP, all patients entered a 32-week open-label period and received monotherapy with Empaveli. All patients who completed the 48-week period were eligible to enroll in a separate long-term extension study.
The primary efficacy endpoint was change from baseline to Week 16 (during RCP) in haemoglobin level. Baseline was defined as the average of measurements recorded prior to taking the first dose of Empaveli. Key secondary efficacy endpoints were transfusion avoidance, defined as the proportion of patients who did not require a transfusion during the RCP, and change from baseline to Week 16 in ARC, LDH level, and the functional assessment of chronic illness therapy (FACIT)-fatigue scale score.
A total of 80 patients were randomised to receive treatment, 41 to Empaveli and 39 to eculizumab. Demographics and baseline disease characteristics were generally well balanced between treatment groups (see Table 4). A total of 38 patients in the group treated with Empaveli and 39 patients in the eculizumab group completed the 16-week RCP and continued into the 32-week open-label period (OLP). Per protocol 15 patients had their dose adjusted to 1,080 mg every three days. Twelve patients were evaluated for benefit and 8 of the 12 patients demonstrated benefit from the dose adjustment.
Empaveli was superior to eculizumab for the primary endpoint of the haemoglobin change from baseline (P < 0.0001). The adjusted mean change from baseline in Hb level was 2.4 g/dL in the group treated with Empaveli versus -1.5 g/dL in the eculizumab group, demonstrating an adjusted mean increase of 3.8 g/dL with Empaveli compared to eculizumab at Week 16 (Figure 1). Treatment differences between the Empaveli and eculizumab groups were evident as early as Week 2 and persisted throughout the 16-week RCP.
The adjusted means, treatment difference, confidence intervals, and statistical analyses performed for the key secondary endpoints are shown in Figure 2.
In patients treated with Empaveli, primary and key secondary efficacy analyses showed no notable differences based on sex, race, or age.
Normalisation of ARC was achieved in 78% of patients in the group treated with Empaveli and in 3% in the eculizumab group. LDH normalisation was achieved in 71% of patients in the group treated with Empaveli and in 15% in the eculizumab group.
A total of 77 patients entered the 32-week OLP, during which all patients received Empaveli resulting in a total exposure of up to 48 weeks. The results at Week 48 were generally consistent with those at Week 16 and support sustained efficacy.
Study in complement inhibitor-naïve adult PNH patients (APL2-308).
Study APL2-308 was a randomised, open-label, standard of care (SOC)-controlled study that enrolled patients with PNH who had not been treated with any complement inhibitor within 3 months prior to enrolment and with Hb levels less than the lower limit of normal (LLN). Eligible patients were randomised in a 2:1 ratio to receive Empaveli or SOC excluding complement inhibitors, hereafter referred to as SOC through the duration of the 26-week treatment period.
Randomisation was stratified based on the number of packed red blood cell (PRBC) transfusions within the 12 months prior to Day 28 (< 4; ≥ 4). At any point during the study, a patient assigned to the SOC treatment group who had Hb levels ≥ 2 g/dL below baseline or presented with a PNH associated thromboembolic event was per protocol able to transition to Empaveli for the remainder of the study.
A total of 53 patients were randomised, 35 to Empaveli and 18 patients to SOC. Demographics and baseline disease characteristics were generally well balanced between treatment groups (see Table 5). Eleven of 18 patients randomised to SOC transitioned to Empaveli because their Hb levels decreased by ≥ 2 g/dL below baseline. Per protocol, 3 patients had their dose adjustment to 1,080 mg every three days.
The primary and secondary efficacy endpoints were assessed at Week 26. The two co-primary efficacy endpoints were Hb stabilisation, defined as avoidance of a > 1 g/dL decrease in Hb concentration from baseline in the absence of transfusion, and change in LDH concentration from baseline.
Empaveli was superior to SOC for the first co-primary endpoint of Hb stabilisation through Week 26 (p < 0.0001). In the group treated with Empaveli, 30 out of 35 patients (85.7%) achieved Hb stabilisation versus 0 patients in the SOC group. The adjusted difference between Empaveli and SOC was 73.1% (95% CI, 57.2% to 89.0%).
Empaveli was also superior to SOC for the second co-primary endpoint of change from baseline in LDH concentration at Week 26 (p < 0.0001). The least-square (LS) mean (SE) changes from baseline in LDH were -1870 U/L in the group treated with Empaveli versus -400 U/L in the SOC group. The difference between Empaveli and SOC was -1470 (95% CI, -2113 to -827). Treatment differences between the Empaveli and SOC groups were evident at Week 2 and were maintained through Week 26 (see Figure 3). LDH concentrations in the SOC group remained elevated.
For the secondary efficacy endpoints of change from baseline in ARC, change from baseline in Hb and transfusion avoidance, superiority was demonstrated for Empaveli versus SOC.
In the group treated with Empaveli, the mean change from baseline in ARC was -123 x 109/L versus -19 x 109/L in the SOC, demonstrating an adjusted mean decrease of 104 x 109/L compared to SOC.
In the group treated with Empaveli, the mean change from baseline in Hb was 2.94 g/dL versus 0.27 g/dL in the SOC, demonstrating an adjusted mean difference of 2.67 g/dL compared to SOC.
Transfusion avoidance was achieved in 91% of patients in the group treated with Empaveli, as compared to 6% in the SOC group.
Superiority was not demonstrated for the change from baseline in FACIT-fatigue score, however the adjusted mean change from baseline in FACIT-fatigue score was 7.8 points in the group treated with Empaveli versus 3.3 points in the SOC group, demonstrating an adjusted mean increase of 4.5 points compared to SOC.
The adjusted means, treatment differences, confidence intervals and statistical analyses performed for the selected secondary endpoints are shown in Table 6.
5.2 Pharmacokinetic Properties
Absorption.
Empaveli is administered subcutaneously and is gradually absorbed into the systemic circulation with a median Tmax between 108 and 144 hours (4.5 to 6.0 days). Steady-state serum concentrations following twice weekly dosing at 1,080 mg in PNH patients were achieved approximately 4 to 6 weeks following the first dose and therapeutic concentrations of pegcetacoplan were maintained through week 48.
Distribution.
The mean (%CV) of central volume of distribution of pegcetacoplan is approximately 3.98 L (32%) in patients with PNH.
Metabolism/excretion.
Based on its PEGylated peptide structure, the metabolism of pegcetacoplan is expected to occur via catabolic pathways and be degraded into small peptides and amino acids.
Following multiple subcutaneous dosing of pegcetacoplan, the estimated mean (CV%) of clearance (CL) is 0.015 L/hour (30%) and median effective half-life of elimination (t1/2) is 8.6 days in patients with PNH. Results of a radiolabeled study in cynomolgus monkeys suggest the primary route of elimination is via urinary excretion.
Pegcetacoplan showed no inhibition or induction of the CYP enzyme isoforms tested as demonstrated from the results of in vitro studies. Pegcetacoplan was neither a substrate not an inhibitor of the human uptake or efflux transporters.
Linearity/non-linearity.
Exposure of pegcetacoplan increases in a dose-proportional manner from 45 to 1440 mg.
Special populations.
No impact on the pharmacokinetics of pegcetacoplan was identified with age, sex, race, and hepatic function based on the results of population PK analysis.
Elderly population.
Although there were no apparent age-related differences observed in these studies, the number of patients aged 65 years and over was not sufficient to determine whether they respond differently from younger patients.
Renal insufficiency.
In a study of 8 patients with severe renal impairment, defined as creatine clearance (CrCl) less than 30 mL/min (with 4 patients with values less than 20 mL/min), renal impairment had no effect on the pharmacokinetics of pegcetacoplan (see Section 4.2 Dose and Method of Administration).
5.3 Preclinical Safety Data
Genotoxicity.
Pegcetacoplan was not mutagenic when tested in in vitro bacterial reverse mutation (Ames) assays and was not clastogenic in an in vitro assay in human TK6 cells or in an in vivo micronucleus assay in mice.
Carcinogenicity.
Long-term animal carcinogenicity studies of pegcetacoplan have not been conducted.6 Pharmaceutical Particulars
6.1 List of Excipients
Sorbitol, glacial acetic acid, sodium acetate trihydrate, sodium hydroxide, water for injections.
6.2 Incompatibilities
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
6.3 Shelf Life
In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.
6.4 Special Precautions for Storage
Store at 2°C - 8°C in a refrigerator. Do not freeze.
Keep Empaveli in its original package to protect from light.
6.5 Nature and Contents of Container
Sterile solution present in a vial (Type I glass) with a stopper (chlorobutyl or bromobutyl), and a seal (aluminium) with a flip-off cap (polypropylene).
Each 20 mL vial contains 1.3 mL overfill.
Pack sizes of 1 or 8 vials. Not all pack sizes may be marketed.
6.6 Special Precautions for Disposal
In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.
6.7 Physicochemical Properties
Pegcetacoplan, the active ingredient in Empaveli solution for subcutaneous infusion 1,080 mg/20 mL, is a symmetrical molecule comprised of two identical pentadecapeptides covalently bound to both ends of a linear polyethylene glycol (PEG) molecule. The molecular weight of pegcetacoplan is approximately 43.5 kiloDaltons (kDa). The peptide moieties bind to complement C3 and exert a broad inhibition of the complement cascade. The 40-kDa PEG moiety imparts improved solubility and longer residence time in the body after administration of the drug product. The structure of pegcetacoplan is shown below.
Chemical structure.
The chemical name is poly(oxy-1,2-ethanediyl), α-hydro, ω-hydroxy-,15,15'-diester with N-acetyl-L-isoleucyl-L-cysteinyl-L-valyl-1-methyl-L-tryptophyl-L-glutaminyl-L-α-aspartyl-L-tryptophylglycyl-L-alanyl-L-histidyl-L-arginyl-L-cysteinyl-L-threonyl-2-[2-(2-aminoethoxy)ethoxy]acetyl-N6-carboxy-L-lysinamide cyclic (2→12)-(disulfide).
The chemical formula is C170H248N50O47S4.(C2H4O)n n = 800-1100.
CAS registry number.
2019171-69-6.7 Medicine Schedule (Poisons Standard)
Schedule 4 - Prescription Only Medicine.
Summary Table of Changes
