Summary Basis of Decision for Lyvdelzi

Clinical Pharmacology

Seladelpar is a potent and selective peroxisome proliferator-activated receptor delta (PPARδ) agonist. Peroxisome proliferator-activated receptor delta is a nuclear receptor expressed in the liver and other tissues. In the liver, PPARδ is expressed broadly in cells that play a key role in the pathobiology of primary biliary cholangitis (PBC), including hepatocytes, cholangiocytes, Kupffer cells, and hepatic stellate cells. Published literature show that PPARδ activation reduces bile acid synthesis in the liver through fibroblast growth factor 21 (FGF21)-dependent downregulation of cytochrome P450 (CYP) 7A1, the key enzyme for the synthesis of bile acids from cholesterol, and by decreasing cholesterol synthesis and absorption. These actions result in lower bile acid exposure in the liver and reduced circulating bile acid levels. Studies also show weak selectivity of seladelpar and its M2 metabolite (desethyl-seladelpar) for PPAR alpha (PPARα). Seladelpar also has positive effects on serum lipids and fibrosis in a carbon tetrachloride (CCl₄) liver fibrosis mouse model. It was also shown to decrease proinflammatory cytokine interleukin (IL)-1β in Tohoku Hospital Pediatrics-1 (THP-1) macrophages which may promote the anti-inflammatory M2 phenotype in Kupffer cells and macrophages.

Nineteen Phase I, Phase II, and Phase III clinical studies contributed to the characterization of the clinical pharmacology of seladelpar at single oral doses up to 360 mg, and at once-daily oral doses up to 200 mg for 21 days. A population pharmacokinetic model was built for seladelpar by pooling pharmacokinetic data from 12 Phase I, Phase II, and Phase III clinical studies.

In healthy subjects, orally administered seladelpar was quickly absorbed with a time to reach maximum concentration (t_max) of 1.5 hours. Seladelpar exposure increased dose-proportionally with doses ranging from 1 to 15 mg, although the exposure increased larger than dose-proportionally with higher doses. Seladelpar has not been administered intravenously to humans and thus its absolute bioavailability has not been determined. Seladelpar plasma protein binding was greater than 99% and was not saturable. Seladelpar is a substrate of the efflux transporters breast cancer resistance protein (BCRP) and multidrug resistance protein 1 (MDR1) and a substrate of the uptake transporters organic anion transporter (OAT) 3, organic anion transporting polypeptide (OATP) 1B1, and OATP1B3. The terminal elimination half-life was 6 hours. Steady state was reached by Day 4. Seladelpar showed no significant drug accumulation and did not exhibit time-dependent pharmacokinetics.

Seladelpar is metabolized by CYP2C9 and to a lesser extent by CYP2C8 and CYP3A4 and has three major circulating metabolites: seladelpar sulfoxide (M1), desethyl-seladelpar (M2), and desethyl-seladelpar sulfoxide (M3). Secondary metabolism included oxidation, glucuronidation, and to a lesser extent, sulfonation. The arithmetic means for the metabolite-to-parent drug exposure ratio was 0.363, 2.380, and 0.633 for metabolites M1, M2, and M3, respectively. Over 216 hours, urinary excretion was the major route of excretion, accounting for 73.4% of the dose; fecal excretion accounted for 19.5% of the dose.

The simulated median area under the concentration-time curve (AUC) and maximum concentration (C_max) at steady state in a typical patient with PBC dosed with seladelpar 10 mg was 817 ng h/mL (95% confidence interval [CI]: 431 to 1650 ng h/mL) and 90.5 ng/mL (95% CI: 44.4 to 182 ng/mL), respectively. The apparent volume of distribution of a typical patient with PBC was 110.3 L in the population pharmacokinetic model. In patients with PBC, terminal elimination half-life was 6.7 hours. The apparent total clearance was 12.6 L/h in the population pharmacokinetic model.

In healthy patients, the administration of seladelpar with a high-fat, high-calorie meal resulted in a 12% decrease in AUC to the last measurable time point (AUC_T) and a 32% decrease in C_max when compared to administration of seladelpar under fasting conditions. Furthermore, t_max was prolonged from 3.4 hours to 6.8 hours following a high-fat, high-calorie meal.

No clinically significant differences in the pharmacokinetics of seladelpar were observed based on age, body weight, sex, or race. Renal impairment is not expected to meaningfully modify the pharmacokinetics of seladelpar. The pharmacokinetics of seladelpar has not been investigated in patients requiring hemodialysis. Compared to PBC patients with mild hepatic impairment (Child-Pugh A) without portal hypertension, seladelpar exposures (C_max and AUC) were 1.7 to 1.8-fold higher in PBC patients with mild hepatic impairment with portal hypertension, and 1.6 to 1.9-fold higher in PBC patients with moderate hepatic impairment (Child-Pugh B) after a single oral dose of seladelpar 10 mg. Seladelpar plasma exposures (dose-normalized AUC_0-inf) were 18% higher in CYP2C9 intermediate metabolizers (with the *1/*2, *1/*8, *1/*3, or *2/*2 genotype; 28 subjects) compared to CYP2C9 normal metabolizers (with the *1/*1 genotype; 84 subjects) after a single dose of seladelpar (1 mg to 15 mg). No conclusions could be made for poor metabolizers, as only two subjects with the *2/*3 genotype and no subjects with the *3/*3 genotype were identified. Seladelpar is not expected to have clinically meaningful effects on the pharmacokinetics of tolbutamide (a CYP2C9 substrate), midazolam (a CYP3A4 substrate), simvastatin (a CYP3A4 and OATP substrate), atorvastatin (a CYP3A4 and OATP substrate), or rosuvastatin (a BCRP and OATP substrate). Probenecid (an OATP and OAT3 inhibitor) caused a 2- and 4.69-fold increase in seladelpar AUC and C_max, respectively. Cyclosporine (a BCRP, OATP, and CYP3A inhibitor) caused a 2.1- and 2.9-fold increase in seladelpar AUC and C_max, respectively. Fluconazole (a moderate CYP2C9 and CYP3A4 inhibitor) caused a 2.4- and 1.4-fold increase in seladelpar AUC and C_max, respectively. Carbamazepine (a CYP2C9 and strong CYP3A inducer) caused a 44% and 24% decrease in seladelpar AUC and C_max, respectively. Quinidine (a P-glycoprotein inhibitor) administration did not significantly modify the pharmacokinetics of seladelpar. There was no dedicated clinical drug-drug interaction study between seladelpar and the strong CYP2C9 inhibitors, rifampin and cholestyramine.

Overall, the clinical pharmacology data support the use of Lyvdelzi for the recommended indication.

For further details, please refer to the Product Monograph for Lyvdelzi, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The clinical efficacy of Lyvdelzi for the proposed indication was supported by the pivotal, Phase III, double-blind, placebo-controlled CB8025-32048 (RESPONSE) study. In total, 193 adults with PBC aged 18 to 75 years with inadequate responses to ursodeoxycholic acid (UDCA; 94% of patients) or intolerance to UDCA (6% of patients) were randomized 2:1 to receive Lyvdelzi 10 mg (128 patients) or placebo (65 patients) once daily for 52 weeks or more. Patients were stratified by baseline alkaline phosphatase (ALP) level (less than 350 U/L versus [vs.] 350 U/L or greater) and the presence of pruritus (baseline pruritus numerical rating scale [NRS] score less than 4 vs. 4 or greater). No patients had advanced stage disease as defined by the Rotterdam criteria for Model for End-Stage Liver Disease (MELD), and 14% of patients had compensated cirrhosis at baseline. Seladelpar or placebo was administered in combination with UDCA in 181 (93.8%) patients or as a monotherapy in 12 (6.2%) patients who were unable to tolerate UDCA. Most patients were female (94.8%), White (88.1%), and non-Hispanic or Latino (69.9%). The majority of patients had a history of pruritus (139 patients [72.0%]) and 72 patients (37.3%) had a pruritus NRS score of 4 or greater at baseline.

The pivotal study met its primary endpoint of composite biochemical response at Month 12, defined as an ALP level less than 1.67 times the upper limit of normal (ULN), an ALP level decrease of at least 15% from baseline, and a total bilirubin level less than the ULN. This endpoint is consistent with international specialty guidance, regulatory precedent, and published prognostic literature. At Month 12, 61.7% of patients who received Lyvdelzi achieved the composite biochemical response compared to 20% of patients who received placebo (p<0.0001). The response was primarily driven by patients who met the endpoint of an ALP level less than 1.67 times the ULN (65.6% of patients in the Lyvdelzi group vs. 26.2% of patients in the placebo group) and a 15% or greater decrease in ALP (83.6% of patients in the Lyvdelzi group vs. 32.3% of patients in the placebo group). At baseline, 87% of patients had a total bilirubin level less than or equal to the ULN, therefore, improvement in ALP was the main contributor to the biochemical response rate.

Prespecified key secondary endpoints included ALP normalization (an ALP level less than or equal to the ULN) at Month 12 and improvement in weekly averaged pruritus NRS score at Month 6 in patients with a baseline pruritus NRS score of 4 or greater. Treatment with Lyvdelzi led to a significantly higher percentage of patients achieving ALP normalization at Month 12 relative to placebo (25.0% vs. 0%; p<0.0001). The normalization of ALP has been associated with optimal transplant-free survival. These results offer significant support of the primary biochemical endpoint.

Pruritus is associated with significant morbidity in patients with PBC. Among the 72 patients with a baseline average pruritus NRS score of 4 or greater, treatment with Lyvdelzi led to a statistically significant improvement in pruritus NRS score vs. placebo with a mean change from baseline of ‑3.2 in the 49 patients who received Lyvdelzi vs. ‑1.7 in the 23 patients who received placebo (p = 0.0047). These results are considered statistically significant as well as clinically relevant and offer support for the clinical effectiveness of Lyvdelzi.

The main goal of the treatment of PBC is to prevent the progression to end-stage liver disease. The use of a composite biochemical response as a primary efficacy endpoint in those with PBC has been established by regulatory precedent with the support of the literature and international specialty guidelines. In PBC, bilirubin and ALP are established as independent predictors of prognosis. A log-linear association between serum ALP and risk of liver transplantation and death has been described in patients with PBC, with higher levels translating into decreased transplant-free survival. While the observed efficacy results are considered limited by the lack of demonstrable clinical outcomes measures, the significant response in biochemical endpoints is considered a surrogate endpoint reasonably likely to translate into clinical outcomes. The primary efficacy endpoint is supported by key secondary endpoints, suggesting a robust biochemical response.

Uncertainty remains regarding how biochemical surrogate endpoints may translate into meaningful clinical outcomes such as survival or liver-related outcomes. As such, the evidence is considered promising with further supportive evidence required to verify clinical outcomes.

Based on the benefit-harm-uncertainty profile of the product, it was recommended that Lyvdelzi be granted a Notice of Compliance with conditions (NOC/c) where confirmatory evidence of clinical benefit is required in order to be considered for a Notice of Compliance (NOC). The sponsor agreed to complete and provide the results of the confirmatory CB8025-41837 (AFFIRM) study. CB8025-41837 is an ongoing, 3-year fixed duration, Phase III, randomized, multicentre, placebo-controlled study designed to provide complementary safety and efficacy data in patients with PBC and compensated cirrhosis, restricted to mild or moderate (Child-Pugh A or Child-Pugh B) hepatic impairment. The primary objective of the study is to evaluate the effect of seladelpar compared to placebo on event-free survival (EFS) where EFS is defined as the time from start of treatment to the first occurrence of any of the following adjudicated events up to Week 156: death by any cause, liver transplantation, MELD score of 15 or greater, ascites requiring treatment or hospitalization due to esophageal or gastric variceal bleeding, hepatic encephalopathy, or spontaneous bacterial peritonitis.

Indication

The New Drug Submission for Lyvdelzi was filed by the sponsor with the following proposed indication:

Lyvdelzi (seladelpar) is indicated for the treatment of primary biliary cholangitis (PBC), including pruritus, in adults in combination with ursodeoxycholic acid (UDCA) who have an inadequate response to UDCA alone, or as monotherapy in those unable to tolerate UDCA.

Health Canada approved the following indication:

Lyvdelzi (seladelpar) is indicated for the treatment of primary biliary cholangitis (PBC) in combination with ursodeoxycholic acid (UDCA) in adults who have an inadequate response to UDCA alone, or as monotherapy in adults unable to tolerate UDCA.

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

Clinical Safety

The primary evidence in support of the clinical safety of Lyvdelzi was provided by the pivotal CB8025-32048 (RESPONSE) study described in the Clinical Efficacy section. In this study, 128 patients received Lyvdelzi 10 mg with a mean duration of exposure of 50.5 weeks.

The overall incidence of treatment-emergent adverse events (TEAEs) was similar between Lyvdelzi and placebo: total TEAEs (87% vs. 85%), study-drug related TEAEs (17% vs. 12%), severe TEAEs (11% vs. 8%), and serious TEAEs (7% vs. 6%). No serious adverse events (SAEs) were considered to be related to treatment. All SAEs were individually reported with the exception of coronavirus disease 2019 (COVID-19) which occurred in 1 patient in each group. Seven (3.6%) patients discontinued treatment due to TEAEs, including 4 patients (3%) in the Lyvdelzi group and 3 patients (5%) in the placebo group. There were no deaths in the study.

Adverse reactions occurring in more than 5% of patients and at a higher frequency than placebo were headache (8% vs. 3%), abdominal pain (7% vs. 2%), nausea (6% vs. 5%), and abdominal distension (6% vs. 3%). Adverse events of special interest included liver-, muscle-, renal-, and pancreatic-related TEAEs. Treatment-emergent adverse events potentially reflecting liver-related toxicity were reported in 6% of patients in the Lyvdelzi group vs. 9.2% of patients in the placebo group. Among patients with alanine aminotransferase (ALT) and aspartate aminotransferase (AST) values above the ULN at baseline, increases to more than 2 times the baseline AST or ALT values were observed in 2.3% of patients in the Lyvdelzi group compared with 6.2% of patients in the placebo group. One patient treated with Lyvdelzi was identified as a case potentially meeting Hy’s Law criteria; upon review, the liver test abnormalities were not considered consistent with drug-induced liver injury. An analysis of renal laboratory parameters demonstrated that more patients treated with Lyvdelzi had a 25% or greater decrease in estimated glomerular filtration rate compared with patients treated with placebo (9.4% vs. 1.5%). These changes were associated with comparable increases in serum creatinine; however, they were not associated with renal-related TEAEs or drug interruption. There were no muscle- or pancreas-related safety signals identified.

Patients with advanced disease, decompensated hepatic impairment (Child-Pugh B or C), complications of cirrhosis, portal hypertension, or laboratory findings that would be consistent with severe disease were excluded from the study. As such, the safety of Lyvdelzi in these populations has not been established. Given that PBC is a progressive disease, treatment discontinuation should be considered if the patient progresses to moderate hepatic impairment. Use is not recommended in patients with severe hepatic impairment.

Supportive data were provided from the uncontrolled open-label, long-term extension CB8025-31731-RE (ASSURE) study and the prematurely terminated placebo-controlled Phase III CB8025-31735 (ENHANCE) study, neither of which demonstrated additional safety signals. In total, 461 patients with PBC received at least one dose of Lyvdelzi 10 mg with a mean duration of treatment of 77.2 weeks.

Overall, based on the data reviewed, Lyvdelzi is considered to have an acceptable and manageable safety profile for the intended patient population. Further evaluation of the benefit-harm-uncertainty profile of the product will take place upon receiving the results of the confirmatory CB8025-41837 (AFFIRM) study, a Phase III, randomized, placebo-controlled clinical study evaluating the effects of Lyvdelzi on long-term clinical outcomes in adults with PBC and compensated cirrhosis.

Appropriate warnings and precautions are in place in the approved Product Monograph for Lyvdelzi to address the identified safety concerns.

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

Non-clinical pharmacology

The non-clinical pharmacology studies support the proposed mechanism of action of seladelpar as a peroxisome proliferator-activated receptor delta (PPARδ) agonist. Seladelpar and its M2 metabolite show weak selectivity for PPAR alpha (PPARα).

Based on the safety pharmacology studies, seladelpar did not have any adverse effects on the cardiovascular, nervous, or respiratory system.

The pharmacokinetics of seladelpar was evaluated by oral and intravenous administration in mice, rats, rabbits, dogs, and monkeys. Overall, the absorption, distribution, metabolism, and excretion of seladelpar has been appropriately investigated in non-clinical systems to support the clinical studies.

Seladelpar is extensively metabolized and three main metabolites were found across rat, dogs, monkey, and humans: seladelpar sulfoxide (M1), desethyl-seladelpar (M2), and desethyl-seladelpar sulfoxide (M3). There were no unique human metabolites.

Seladelpar is a reversible inhibitor of CYP2C8 (half-maximal inhibitory concentration [IC₅₀] = 12.7 μM) and CYP2C9 (IC₅₀ = 19 μM). Seladelpar could induce CYP3A4. None of the 3 principal metabolites, M1, M2, or M3, inhibited the major CYP enzymes under direct (IC₅₀ greater than 25 μM) or time-dependent inhibition conditions. Seladelpar inhibited uridine 5'-diphospho-glucuronosyltransferase (UGT) 2B7, UGT1A1, UGT1A3, UGT1A4, and UGT1A9 with IC₅₀ values of 15.9 μM, 33.5 μM, 31.6 μM, 27.2 μM, and 27.7 μM, respectively. Seladelpar is a substrate of the efflux transporters breast cancer resistance protein (BCRP) and multidrug resistance protein 1 (MDR1), and a substrate of the uptake transporters organic anion transporter (OAT) 3, OATP1B1, and OATP1B3. Seladelpar inhibited BCRP, MDR1, OATP1B1, OATP1A2, OATP1B3, and OATP2B1 with IC₅₀ values ranging from 2 to 157 μM.

Non-clinical Toxicology

In single-dose toxicity studies of seladelpar administered orally to rats and mice, the median lethal dose (LD₅₀) was 2,000 mg/kg in male rats, 1,000 mg/kg in female rats, 1,000 mg/kg in male mice, and 2,000 mg/kg in female mice.

Based on chronic repeat-dose toxicity studies in rats and monkeys, seladelpar has acceptable margins of safety for general toxicity compared to the recommended human dose (RHD) of 10 mg. The no-observed-adverse-effect level (NOAEL) in rats was 15 mg/kg/day in males (25 times the RHD) and 80 mg/kg/day (70 times the RHD) in females based on the 26-week rat toxicity study. The NOAEL in monkeys was 1 mg/kg/day in males (2 times the RHD) and 5 mg/kg/day (11 times the RHD) for females based on the 52-week monkey toxicity study.

In the repeat-dose toxicity studies, skeletal muscle degeneration, necrosis, and/or atrophy were observed in monkeys, dogs, rats, and mice.

Treatment-related effects in the liver were observed in the monkeys, rats, and mice. Liver necrosis, higher absolute/relative liver weights, and hepatocellular hypertrophy were observed in monkeys, rats, and mice. Enlarged and discoloured livers, bile duct hyperplasia, Kupffer cell pigmentation, higher CYP4A and fatty-acyl-CoA levels as well as centrilobular/portal hepatocyte alterations were observed in rats and/or mice. Bile duct hyperplasia, Kupffer cell hyperplasia, increased number of peroxisomes, lower bilirubin, mitochondria with elongated and/or cup-shaped profiles, increased size of peroxisomes, decreased lipid vacuoles, decreased zymogen, and smooth endoplasmic reticulum hypertrophy were observed in the livers of monkeys. Alterations in serum alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), cholesterol, albumin/globulins, total proteins, and triglycerides were observed in monkeys, rats, dogs, and mice. Higher serum bilirubin was observed in dogs. The alterations in the clinical chemistry parameters are likely associated with the adverse effects on the liver.

Progressive cardiomyopathy, myocardium degeneration, necrosis, and increased lipid vacuoles in the right or left ventricles were observed in rats. Increased mitochondria size in the heart and increased heart weight were also observed in monkeys.

Chronic progressive nephropathy, higher kidney weights, increased number and/or size of peroxisomes in the kidney, hyperplasia in the tubular epithelium in the pars recta, thickened mesangial matrix in the glomeruli, fusion of the glomerular foot processes, lower urine volume, higher urine specific gravity, dark yellow-coloured urine, and a higher incidence and/or severity of urine protein, ketones, and bilirubin were observed in rats. Higher kidney weights, increased number and/or size of peroxisomes and mitochondria with ring or cup-shaped profiles in the kidney were observed in monkeys. Higher kidney weights were observed in mice. Bilirubin in the urine was also observed in dogs. Higher serum creatine kinase was also observed in monkeys, dogs, and mice. Lower calcium values were observed in monkeys, rats, and dogs.

Increased adipose tissue infiltration in the bone marrow and/or decrease in the cellularity of the hematopoietic elements were observed in dogs. Erythroid hypoplasia/hypocellularity in the bone marrow and abnormal red blood cell morphology were observed in monkeys. Lower red blood cell parameters (red blood cell counts, hemoglobin, hematocrit, and mean corpuscular volume and/or reticulocytes) were also observed in monkeys, rats, and dogs.

Adrenal gland hypertrophy was observed in monkeys and rats. Increased vacuolation in the adrenal gland was also observed in rats. Higher adrenal gland weights were also observed in dogs. Thymus atrophy and lower thymus weights were observed in dogs. Thymus involution and lower thymus size and thymus weight were also observed in monkeys.

Prostate gland atrophy, degeneration of the seminiferous tubules, accumulation of luminal debris, hypospermia in the epididymis, and interstitial cell atrophy in the testis were observed in dogs. Lymphoid depletion in the popliteal and mesenteric lymph nodes were also observed in dogs.

Seladelpar is unlikely to pose a genotoxic risk to humans. Seladelpar was not mutagenic or clastogenic based on the Ames assay, in vitro mouse lymphoma assay, and an in vivo mouse micronucleus assay.

There is evidence that seladelpar is carcinogenic in rats and mice. Hepatocellular adenoma and carcinoma, non-glandular stomach squamous cell carcinoma, pancreas acinar cell adenoma, and testis interstitial cell tumours were observed in male rats at 30 mg/kg/day (65 times the RHD). Tumours were not observed in female rats. The no-observed-effect level (NOEL) for tumours were 10 mg/kg/day (11.7 times the RHD) and 30 mg/kg/day (21.7 times the RHD) in male and female rats, respectively.

No treatment-related effects on fertility were observed in pregnant rats administered 100 mg/kg/day of seladelpar. No treatment-related external, visceral, or skeletal malformations or variations were observed in rats administered 100 mg/kg/day. The rat developmental NOAEL was 100 mg/kg/day (145 times the RHD).

In the rabbit embryo-fetal development study, lower gravid uterine weights and fetal body weights were observed at a dose of 40 mg/kg/day. No adverse external, visceral, or skeletal malformations or variations were observed during necropsy. The rabbit developmental NOAEL was 10 mg/kg/day (2.4 times the RHD). The rabbit developmental lowest-observed-adverse-effect level (LOAEL) was 40 mg/kg/day (40.6 times the RHD) based on lower gravid uterine weight and lower fetal body weights.

In the rat pre- and postnatal development study, treatment-related lower pup body weights and developmental delays (time to eye opening and pinna unfolding) were observed at a dose of 5 mg/kg/day or higher. Treatment-related lower pup survival and delay in balanopreputial separation and vaginal opening were observed at a dose of 100 mg/kg/day. The rat pre- and postnatal development NOAEL was 20 mg/kg/day (15.2 times the RHD). The rat pre- and postnatal developmental LOAEL was 100 mg/kg/day (145.2 times the RHD) based on lower pup survival, lower pup body weights, and delay in time to eye opening, pinna unfolding, balanopreputial separation, and vaginal opening.

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

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

The quality (chemistry and manufacturing) information submitted for Lyvdelzi has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper pharmaceutical development and supporting studies were conducted and an adequate control strategy is in place for the commercial processes. Changes to the manufacturing process and formulation (if any) made throughout the pharmaceutical development are considered acceptable upon review. Based on the stability data submitted, the proposed shelf life of 48 months is acceptable when the drug product is stored in its original container at 15 °C to 25 °C.

The proposed drug-related impurity limits are considered adequately qualified (e.g., within International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use [ICH] limits and/or qualified from toxicological studies, as needed).

A risk assessment for the potential presence of nitrosamine impurities was conducted according to requirements outlined in Health Canada’s Guidance on Nitrosamine Impurities in Medications. The risks relating to the potential presence of nitrosamine impurities in the drug substance and/or drug product are considered negligible or have been adequately addressed (e.g., with qualified limits and a suitable control strategy).

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

None of the non-medicinal ingredients (excipients) in the drug product are prohibited for use in drug products by the Food and Drug Regulations.

One excipient in the capsule shell, gelatin, is of animal origin. A certification of analysis was provided confirming that the material was found to be compliant with requirements of several foreign regulators and is considered to be safe for human use.