Summary Basis of Decision for Empaveli

As described above, the clinical review of the New Drug Submission for Empaveli was conducted as per Method 3 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada .

Clinical Pharmacology

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, life-threatening hematologic disorder characterized by a deficiency of the complement regulatory proteins complement decay-accelerating factor (CD55) and membrane attack complex (MAC)-inhibitory protein (CD59) on red blood cells. This deficiency leads to chronic and/or paroxysmal hemolysis and a propensity for thrombosis, organ dysfunction, and bone marrow failure. Although current therapies have improved outcomes related to the control of intravascular hemolysis (IVH), many PNH patients who are receiving complement component 5 (C5) inhibitor therapy continue to experience extravascular hemolysis (EVH) resulting in persistent anemia and transfusion requirements.

Pegcetacoplan, the medicinal ingredient in Empaveli, inhibits the complement system upstream by binding to complement protein C3 and its activation fragment C3b, thereby regulating the cleavage of C3 and the generation of downstream effectors of complement activation. In PNH, EVH is facilitated by C3b opsonization while (IVH) is mediated by the downstream membrane attack complex (MAC). Pegcetacoplan acts proximally in the complement cascade controlling both C3b‑mediated EVH and terminal complement-mediated IVH.

Following subcutaneous infusion, pegcetacoplan is gradually absorbed reaching peak serum concentration between 4.5 and 6.0 days. The central volume of distribution for pegcetacoplan is approximately 3.9 L and it is expected to be catabolized into small peptides, amino acids, and polyethylene glycol (PEG). Urinary excretion is the primary route of elimination of the peptide moiety and PEG. The estimated clearance of pegcetacoplan is 0.015 L/hour and its half-life is 8.0 days. Exposure of pegcetacoplan increases in a dose‑proportional manner from 45 to 1,440 mg.

As biotransformation is mainly via catabolism, hepatic impairment is not expected to influence the clearance of pegcetacoplan. The results of a dedicated clinical study indicated that renal impairment had no clinically meaningful effect on pegcetacoplan pharmacokinetics. Pegcetacoplan has not been studied in patients with end-stage renal disease requiring hemodialysis.

In the pivotal Phase III clinical study (PEGASUS, described in the Clinical Efficacy section), sustained elevation of the serum C3 concentration, reduction in C3 deposition on PNH Type II and III red blood cells (RBCs), and an increase in the percentage of Type II and III RBCs were observed, supporting the mechanism of action of pegcetacoplan for the treatment of PNH.

At the recommended doses, pegcetacoplan is not predicted to cause large mean increases (i.e., greater than 20 msec) in the corrected QT interval (QTc).

Based on in vitro data, pegcetacoplan has a low potential for clinical drug-drug interactions. The bioanalytical assays for the detection of anti-pegcetacoplan peptide antidrug antibodies (ADA) and neutralizing antibodies had unacceptable tolerance for pegcetacoplan at steady-state levels. Therefore, the incidence of ADAs and their effect on the pharmacokinetics/pharmacodynamics, safety, or effectiveness of pegcetacoplan could not be determined. Redevelopment and revalidation of both assays by the sponsor are ongoing and samples from pivotal clinical studies will be reanalyzed. Health Canada will receive relevant updates on immunogenicity in Periodic Safety Update Reports.

Overall, the review of the clinical pharmacology studies did not identify issues to preclude the approval of Empaveli for the intended patient population. Key clinical pharmacology findings, relevant risks, and uncertainties are properly addressed in the Empaveli Product Monograph.

The clinical pharmacology data support the use of Empaveli for the recommended indication. For further details, please refer to the Empaveli Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The clinical efficacy of Empaveli for the treatment of adult patients with paroxysmal nocturnal hemoglobinuria (PNH) who remain anemic despite treatment with eculizumab (a complement component 5 [C5] inhibitor) was evaluated in the pivotal Phase III PEGASUS (APL2-302) study. This randomized, active-comparator controlled, open-label study assessed the efficacy of Empaveli versus (vs.) eculizumab in patients 18 years of age or older who remained anemic (continued to have hemoglobin [Hb] levels less than 10.5 g/dL [105 g/L]) despite treatment with eculizumab.

Patients enrolled in the study had a primary diagnosis of PNH (as confirmed by high-sensitivity flow cytometry) and were on treatment with eculizumab at a dosage that was stable for at least 3 months prior to the screening visit. At the screening visit, in addition to having Hb levels less than 10.5 g/dL, eligible patients were also required to have an absolute reticulocyte count (ARC) greater than 1.0 times the upper limit of normal, a platelet count greater than 50,000/mm³, and an absolute neutrophil count greater than 500/mm³. Vaccination against Neisseria meningitidis types A, C, W, Y, and B; Streptococcus pneumoniae; and Haemophilus influenzae Type B either within 2 years, or within 14 days after starting treatment with Empaveli was also required. Patients were excluded if they had an active bacterial infection or were receiving iron, folic acid, vitamin B12 or erythropoietin (unless the dosage was stable in the 4 weeks prior to screening). In addition, patients with hereditary complement deficiency or a history of bone marrow transplantation were excluded from the study.

The study treatment period consisted of three parts: a 4-week run-in period, a 16-week randomized controlled period (RCP), and a 32-week open-label period (OLP). During the 4-week run-in period (Day -28 up to and including Day 1), all patients self-administered twice‑weekly subcutaneous doses of 1,080 mg Empaveli in addition to their current dosage of eculizumab. This regimen was followed to avoid hemolysis due to the abrupt discontinuation of eculizumab and to allow Empaveli to reach steady state. Following completion of the run-in period, patients were assigned randomly (1:1) to receive either Empaveli or eculizumab for the remainder of the 16-week RCP. Randomization was stratified based on the number of packed red blood cell (PRBC) transfusions in the 12 months prior (less than four or four or greater) and platelet count at screening (less than 100,000/mm³ or greater than or equal to 100,000/mm³). After completion of the RCP, patients continued into a 32-week open-label period during which all patients received twice-weekly doses of 1,080 mg Empaveli. Patients who were in the eculizumab group during the RCP underwent another 4 weeks of combined therapy with Empaveli and eculizumab (Weeks 17 to 20) before transitioning to Empaveli monotherapy. After completion of the 52-week treatment period (Week 48), patients were offered entry into an open-label extension study.

A 16-week data analysis was completed at the end of the RCP based on the data cut-off date February 24, 2020. Subsequently, a 48-week analysis was completed to assess data from the final database lock on November 6, 2020. Efficacy and safety data from the entire study (through Week 48 and follow-up) were analyzed for the review of this New Drug Submission.

The assessment of efficacy was based on the intent-to-treat (ITT) set of 80 patients. Most patients were female (61.3%), white (61.3%), and not Hispanic or Latino (76.3%). The mean age was 48.8 years, ranging from 19 to 81 years. Approximately half of the patients were from Europe, with the remaining patients being equally from the North America and Asia-Pacific regions. The mean time since diagnosis of PNH to Day -28 was 10.18 years with this time being longer for patients in the eculizumab group than those in the Empaveli group (11.68 years vs. 8.74 years, respectively). The duration of prior treatment with eculizumab, as well as baseline mean Hb level, platelet count, absolute reticulocyte count (ARC), and Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score were generally similar between groups. Lactate dehydrogenase (LDH) levels were slightly higher in the eculizumab group than in the Empaveli group (308.64 U/L vs. 257.48 U/L, respectively).

The between-treatment-group comparisons for the primary efficacy endpoint and key secondary endpoints were performed using a mixed-effect model for repeated measures (MMRM). This model was used to address PRBC transfusions as a potential confounding factor, where post-transfusion laboratory values were set to missing. The primary efficacy endpoint was tested for superiority and key secondary endpoints were tested for noninferiority in a hierarchical manner after statistical significance was reached for the primary endpoint.

The primary efficacy endpoint of the PEGASUS study was the change from baseline (CFB) to Week 16 in Hb level, excluding data before the RCP and censored for transfusion. The least-square (LS) mean CFB in Hb at Week 16 for the Empaveli and eculizumab groups was 2.4 g/dL (24 g/L) and -1.5 g/dL (-15 g/L), respectively. Empaveli was superior to eculizumab regarding the CFB in Hb level, resulting in a statistically significant adjusted mean increase of 3.8 g/dL (38 g/L) (95% confidence interval [CI]: 2.33, 5.34; p <0.0001). The results of sensitivity and supportive analyses corroborated and confirmed the primary endpoint analysis.

Key secondary efficacy endpoints included transfusion avoidance, CFB to Week 16 in ARC, CFB to Week 16 in LDH level, and CFB to Week 16 in FACIT-Fatigue Scale score. Empaveli was noninferior to eculizumab for transfusion avoidance. A total of 85% of Empaveli patients achieved transfusion avoidance as compared to only 15% of eculizumab patients. The lower bound of the 95% CI of the 63% adjusted treatment difference (48%, 77%) was greater than the prespecified noninferiority margin (NIM) of ‑20%. Empaveli was also noninferior to eculizumab for CFB in ARC, with a LS mean difference of -164 x 10⁹ cells/L (95% CI: -189.9, -137.3). The upper bound of the 95% CI of the adjusted treatment difference was less than the prespecified NIM of 10. For LDH, the LS mean CFB at Week 16 was -15 for Empaveli and -10.0 for eculizumab, with a difference of ‑5.0 (95% CI: ‑181.3 to 172.0). The upper bound of the 95% CI of the adjusted treatment difference was not less than the prespecified NIM of 20; thus, noninferiority was not met. Due to prespecified hierarchical testing, noninferiority for the FACIT-Fatigue score was not assessed. However, the nominal adjusted mean CFB in FACIT-Fatigue score was 9.2 points in the group treated with Empaveli versus ‑2.7 points in the eculizumab group, demonstrating an adjusted mean increase of 11.9 points (95% CI: 5.49, 18.25). The lower bound of the 95% CI of the adjusted treatment difference was greater than the prespecified NIM of 3.

Data for the primary and key secondary efficacy analyses at Week 16 were censored for PRBC transfusion. In the eculizumab group, the majority of patients (84.6%) required at least one PRBC transfusion and were not included in the MMRM analysis. When all observed data were considered (no censoring), results were in keeping with the primary analysis, but the magnitude of the benefit observed with Empaveli compared to eculizumab was smaller, albeit still statistically significant and clinically relevant. The results of the key secondary analyses were consistent with the MMRM analyses in which post-transfusion data were set to missing. The consistency of these results provides strength and validity to the findings of primary and key secondary endpoint analyses.

The long-term efficacy of Empaveli was evaluated during the open-label period, during which 77 patients were treated with Empaveli monotherapy for a total exposure of up to 48 weeks. Additional secondary efficacy endpoints were assessed including the evaluation of Hb level, ARC, LDH level, FACIT-Fatigue Scale score, and number of PRBC units transfused. The benefit of Empaveli treatment was observed across all efficacy endpoints at Week 48 in patients who continued Empaveli monotherapy for an additional 32 weeks, as well as in patients who restarted Empaveli and received 28 weeks of monotherapy. In particular, Empaveli monotherapy provided sustained improvements in Hb across the entire study (mean change from baseline of 2.69 g/dL [26.9 g/L] at Week 48 for all patients on Empaveli monotherapy). Overall, the results at Week 48 were generally consistent with those at Week 16 and were supportive of sustained efficacy.

Indication

The New Drug Submission for Empaveli was filed by the sponsor with the following indication, which Health Canada subsequently approved:

Empaveli (pegcetacoplan) is a complement inhibitor indicated for the treatment of adult patients with paroxysmal nocturnal hemoglobinuria (PNH) who have an inadequate response to, or are intolerant of, a C5 inhibitor.

For more information, refer to the Empaveli Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The clinical safety of Empaveli was evaluated in the pivotal PEGASUS (APL2-302) study described in the Clinical Efficacy section. The primary safety analysis set included 80 patients (total number [n] = 41 in the Empaveli arm and n = 39 patients in the eculizumab arm) in the 16-week randomized controlled period (RCP). The mean duration of treatment for Empaveli monotherapy was 107.2 days with a mean of 31 completed Empaveli infusions. The overall 48-week study (RCP plus open-label period [OLP]) provided long-term safety data for 80 patients who were exposed to systemic Empaveli monotherapy for a mean duration of 258.3 days with a mean of 74.7 completed Empaveli infusions per patient.

During the run-in period, 80 patients received a combination of Empaveli and eculizumab and 71 patients (88.8%) experienced at least one treatment-emergent adverse event (TEAE). The most frequently reported TEAEs (occurring in 10% or more of patients) were injection site erythema (41.3%), injection site pruritis (15.0%), diarrhea (12.5%), headache (12.5%), injection site swelling (12.5%), and injection site reaction (10.0%). There were no TEAEs that led to death, study discontinuation, or study drug discontinuation during the run-in period. The co-administration of Empaveli and eculizumab was well tolerated and these data provided adequate evidence to support the recommended 4-week period of combination therapy when transitioning a patient from a C5 inhibitor to Empaveli monotherapy.

In the RCP, a similar percentage of patients in both treatment groups reported at least one TEAE, including 36 patients (87.8%) in the Empaveli group and 36 patients (92.3%) in the eculizumab group. The most frequently reported TEAEs (occurring in 10% or more of patients) for the Empaveli group were diarrhea (22.0%), injection site erythema (17.1%) and hemolysis (12.2%). Three patients (7.3%) discontinued Empaveli due to hemolysis. In patients treated with Empaveli, the most frequent adverse reactions (occurring in 5% or more of patients) as assessed by investigators were injection site erythema (14.6%), injection site reaction (9.8%), injection site swelling (9.8%) and injection site induration (7.3%). These reactions were mild to moderate in intensity and did not lead to discontinuation of treatment. A similar proportion of patients experienced serious adverse events (SAEs) during the RCP (7 patients [17.1%] in the Empaveli group vs. 5 patients [12.8 %] in the eculizumab group). The most common SAE observed in the Empaveli group was hemolysis (4.9%). One SAE in the Empaveli group (facial paralysis) was considered possibly related to the study drug. There were no adverse events (AEs) leading to death during the RCP.

During the OLP, 77 patients were treated with Empaveli and 71 (92.2%) experienced at least 1 TEAE. The most commonly reported TEAEs were hemolysis, nasopharyngitis, and diarrhea, which was consistent with the findings for the Empaveli group during the RCP. Nine patients (11.7%) reported TEAEs that led to study discontinuation and there was one severe TEAE that led to death due to coronavirus disease 2019 (COVID-19).

Serious infections caused by encapsulated bacteria and hemolysis were two key issues relevant to the evaluation of risk. Due to its mechanism of action, the use of Empaveli may predispose individuals to serious infections caused by encapsulated bacteria. For this study, vaccination against encapsulated organisms (Neisseria. meningitides, Streptococcus pneumoniae, and Haemophilus influenzae) was required within 2 years, or within 14 days after starting treatment with Empaveli. During the RCP, TEAEs of infection were equally reported between the Empaveli and eculizumab groups (12 patients [29.3%] and 11 patients [28.2%], respectively). Serious infections were reported exclusively in the Empaveli group (2 patients [4.9%]). Across the whole study (RCP plus OLP plus follow-up), 10 patients (12.5%) reported serious infections. Despite the frequency of infection, none were due to encapsulated bacteria and only one resulted in study discontinuation (death due to COVID-19, pegcetacoplan was ongoing until death). Infection risk has been addressed through appropriate labelling (a Serious Warnings and Precautions box) in the Empaveli Product Monograph. Empaveli is only available through a controlled distribution program under which prescribers must enroll patients and confirm vaccination against encapsulated bacteria. Prescribers must also counsel patients about the risk of serious infection and provide them with the patient guide and patient card.

Hemolysis is a hallmark clinical manifestation of PNH and a key risk of complement therapy. Patients are at risk of hemolysis secondary to the disease and at risk of breakthrough hemolysis while receiving complement inhibitor therapy. During the RCP, hemolysis TEAEs were reported for 5 patients (12.2%) in the Empaveli group and 10 patients (25.6%) in the eculizumab group. However, SAEs were reported in 2 patients (4.9%) in the Empaveli group and 1 patient (2.6%) in the eculizumab group. Across the whole study, 7 patients (8.8%) reported an SAE of hemolysis with 5 cases (6.3%) resulting in discontinuation of study drug.

Taken as a whole, the data from the pivotal study suggest that the safety of Empaveli is acceptable. The incidence of AEs and SAEs was similar between the Empaveli group and the eculizumab group. While some TEAEs occurred more frequently in the Empaveli group (e.g., injection site reactions and diarrhea), others occurred more frequently in the eculizumab group (e.g., hemolysis and headache). The frequency of infections was similar between both groups and there were no infections due to encapsulated bacteria. Treatment-emergent AEs that occurred more frequently in the Empaveli group did not limit overall tolerability, as none were serious, severe, or led to study drug discontinuation. Although TEAEs of hemolysis occurred more frequently in the eculizumab group, patients in the Empaveli group had more serious hemolysis events and more events that led to study drug discontinuation. During the RCP, three events occurred in the Empaveli group that led to study drug discontinuation, while discontinuation from eculizumab was not permitted under study protocol.

Overall, the safety profile of Empaveli is acceptable for the treatment of adult patients with PNH who have an inadequate response to, or are intolerant of, a C5 inhibitor. The identified safety issues can be managed through labelling and post-market pharmacovigilance.

For more information, refer to the Empaveli Product Monograph, approved by Health Canada and available through the Drug Product Database.

As described above, the review of the toxicology component of the New Drug Submission for Empaveli was conducted as per Method 3 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada.

Pegcetacoplan is a small molecule that inhibits complement protein 3 (C3). It consists of two 15–amino acid cyclic synthetic peptides conjugated to a linear 40 kDa linear polyethylene glycol (PEG) chain. The peptidic domains of the molecule are a derivative of compstatin and have been shown to bind to human C3 and C3b, resulting in broad inhibition of complement activation in a primate‑specific manner.

From in vitro studies, pegcetacoplan was shown to bind to C3 and C3b, preventing C3 cleavage to C3a and C3b with nanomolar affinity. Assays confirmed that pegcetacoplan is an inhibitor of both the classical and alternative pathways of complement activation in primate matrices. The in vivo pharmacodynamics of pegcetacoplan were also investigated. To evaluate the efficacy of pegcetacoplan in monkeys, the inhibition of complement system and the hemolysis activity were measured by alternative pathway hemolytic complement (AH50) and total complement activity (CH50) tests. At a dose of 84 mg/kg twice daily over 60 min as an intravenous injection at Day 1 and Day 2, pegcetacoplan rapidly inhibited AH50 and CH50 hemolytic activity. Furthermore, the C3a and C3 levels decreased during the first 48 hours, correlating with pegcetacoplan injection. These results demonstrated that pegcetacoplan induces an inhibition of both alternative and classical baseline complement activation in vivo.

Safety pharmacology studies indicated that pegcetacoplan does not inhibit the human ether-à-go-go-related gene (hERG; fast potassium [IKr]) channel or pose an acute cardiovascular or respiratory functional risk. A dedicated central nervous system safety pharmacology study was not conducted because pegcetacoplan did not bio-distribute to the brain in monkeys, and clinical observations throughout the toxicology program revealed no signal to suggest disturbed neurobehavioral function.

Based on pharmacokinetic results of studies with pegcetacoplan, the bioavailability (absorption) of pegcetacoplan was estimated to be greater than 85% after a single subcutaneous dose. The steady‑state half-life of pegcetacoplan was determined to be 7.5 days in monkeys. The maximum concentration (C_max) for distribution was observed at 72 hours for most of the tissues analyzed. Distribution was either not observed or below the limit of quantitation in the brain, bone, fat (white), gastrointestinal contents, and optic nerve. There was no appreciable distribution to the eye or cecal contents. Single-dose tissue distribution studies found pegcetacoplan to have the highest concentration at the subcutaneous injection sites followed by in the blood, lung, kidney, spleen, and liver. The metabolism of pegcetacoplan has not been specifically studied. Like other PEGylated peptide/protein conjugates, catabolic pathways are expected to be mainly responsible for the metabolism of pegcetacoplan. Following a subcutaneous dose of pegcetacoplan, the main route of elimination is via urinary excretion. No significant differences in pharmacokinetic parameters with varying molecular weight of pegcetacoplan was observed.

Pegcetacoplan did not induce nor inhibit cytochrome P450 (CYP) enzymes (CYP 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4/5) in vitro. Pegcetacoplan was not a substrate or an inhibitor of tested drug transporters (organic anion transporter [OAT]1, OATP1B1, OATP1B3, organic cation transporter 2, p-glycoprotein, or breast cancer resistance protein).

Toxicology

The toxicology program for pegcetacoplan included repeat-dose studies in rabbits and monkeys, in vitro and in vivo genotoxicity studies, and embryo-fetal and developmental toxicity studies in rats, rabbits, and monkeys.

Repeat dosing of pegcetacoplan up to 140 mg/kg/day for 28 days (in both rabbits and monkeys) and up to 28 mg/kg/day for 6 months (rabbits) and 9 months (monkeys) produced no unscheduled deaths and no relevant clinical observations or gross pathology findings.

Pegcetacoplan‑related histopathology findings were observed in multiple organs including bone marrow (sternum), choroid plexus of the brain, adrenal gland, pituitary gland, liver sinusoids, mandibular and mesenteric lymph node sinuses, ovary, the red pulp of the spleen, stomach, and urinary bladder. In the tissues, infiltrates of histiocytes or resident macrophages had abundant vacuolated cytoplasm with occasional flocculent material in the vacuoles. Vacuolation was also observed in epithelial cells in the choroid plexus of the brain and in the synovium of the femur. Following the recovery period, the findings were still present in several tissues. These findings were considered to be associated with PEG, were observed at exposures lower or comparable to clinical exposure and were considered non-adverse.

In the kidneys, pegcetacoplan treatment was associated with the rare presence of tubules showing minimal vacuolation of the epithelium and within these areas, minimal degeneration of tubules lined by attenuated epithelium was seen. These findings were considered adverse in nature. The no observed adverse effect level (NOAEL) for renal degeneration in monkeys was 7 mg/kg/day (corresponding to a 1.4-fold clinical exposure).

Pegcetacoplan was shown to be non-genotoxic and non-clastogenic in in vitro and in vivo studies. Based on these results, and because pegcetacoplan is pharmacologically active only in humans and non-human primates, rodent carcinogenicity studies with pegcetacoplan have not been conducted.

In pre- and post-postnatal development toxicology studies in monkeys, no pegcetacoplan-related signs of toxicity were observed in the mothers or in offspring up to 6 months post-birth, nor were there signs of teratogenic effects in the aborted fetuses and infants. A statistically significant increase in abortions/stillbirths was observed with pegcetacoplan dosed at 28 mg/kg/day from gestation day 20 to 22 until parturition. Fetal exposure to pegcetacoplan represented 0.15% of the mean maternal serum exposure. Pegcetacoplan concentration in the milk was less than 1% of serum exposure. Antidrug antibodies were not detected in serum from the mother or offspring. Based on the increased incidence of abortions and stillbirths at 28 mg/kg/day, the NOAEL was considered to be 7 mg/kg/day (corresponding to a 1.3-fold clinical exposure).

The results of the non-clinical studies as well as the potential risks to humans have been included in the Empaveli Product Monograph. In view of the intended use of Empaveli, there are no pharmacological/toxicological issues within this submission which preclude authorization of the product.

For more information, refer to the Empaveli Product Monograph, approved by Health Canada and available through the Drug Product Database.

As described above, the review of the quality component of the New Drug Submission for Empaveli was conducted as per Method 3 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada.

The chemistry and manufacturing information submitted for Empaveli has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes. Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review. Based on the stability data submitted, the proposed shelf life of 24 months is acceptable when stored at 5 °C ± 3 °C (2 °C - 8 °C) and protected from light.

Proposed limits of drug-related impurities are considered adequately qualified (i.e., within International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use [ICH]) limits and/or qualified from toxicological studies).

All sites involved in production are compliant with good manufacturing practices.

None of the non-medicinal ingredients (excipients, described earlier) found in the drug product are prohibited by the Food and Drug Regulations.

None of the excipients used in the formulation of Empaveli is of human or animal origin.