Summary Basis of Decision for Zurzuvae

Clinical Pharmacology

Zuranolone, the medicinal ingredient in Zurzuvae, is an orally bioavailable, synthetic neuroactive steroid similar to the endogenous neuroactive steroid allopregnanolone, a metabolite of progesterone. Zuranolone exhibits positive allosteric modulation of the gamma-aminobutyric acid (GABA) type A (GABA_A) receptor and enhances GABA activity at synaptic and extrasynaptic GABA_A receptors. The mechanism of action of zuranolone in the treatment of postpartum depression is not fully understood but is thought to be related to its positive allosteric modulation of GABA_A receptors.

The pharmacokinetic and pharmacodynamic profiles of zuranolone were characterized based on results from 18 Phase I clinical studies conducted in healthy adults, elderly participants, and individuals with renal or hepatic impairment. Population pharmacokinetic modelling and exposure-response analyses also informed the exposure of zuranolone in patients with postpartum depression or major depressive disorder and in patients with renal impairment, as well as the estimated relative infant exposure to zuranolone resulting from breastfeeding.

Following oral administration in healthy adults, the maximum plasma concentration of zuranolone was reached in 5 to 6 hours. The effective half-life of zuranolone was estimated to be approximately 14 hours.

Zuranolone was extensively metabolized, primarily by the enzyme cytochrome P450 (CYP) 3A4. Metabolites were eliminated in comparable amounts through urine (45.1%) and feces (40.6%). A negligible amount of unchanged zuranolone was excreted in urine and less than 2% of unchanged zuranolone was excreted in feces. Zuranolone was also excreted into breast milk, resulting in a relative infant dose of less than 1%. The effect of such exposure on breastfed newborns and infants was not evaluated.

Gender, race or ethnicity, age, and body weight are not expected to have a clinically meaningful impact on the pharmacokinetics of zuranolone. However, zuranolone exposure was increased in subjects with moderate or severe renal impairment and in those with severe hepatic impairment. Therefore, a reduced dose of Zurzuvae (30 mg once daily) is recommended for these patient subpopulations.

Coadministration of zuranolone with a strong CYP3A4 inhibitor was shown to increase zuranolone exposure, which may increase the risk of zuranolone-associated adverse reactions. In addition, coadministration of zuranolone with a strong CYP3A4 inducer was shown to decrease zuranolone exposure, which may lead to reduced efficacy of zuranolone. Accordingly, it is recommended to reduce the dose of Zurzuvae to 30 mg once daily in patients who concomitantly receive strong CYP3A4 inhibitors and to avoid using strong CYP3A4 inducers during treatment with Zurzuvae. Furthermore, coadministration of repeated 50 mg daily doses of zuranolone and alprazolam (a benzodiazepine derivative) led to increased impairment in psychomotor performance. Hence, dose reduction of zuranolone should be considered if concomitant use with another central nervous system (CNS) depressant is unavoidable. The Product Monograph for Zurzuvae has included a list of established or potential drug-drug interactions, along with appropriate precautionary measures.

Based on pharmacokinetic data from a food-effect study in healthy volunteers, and consistent with its administration in the pivotal efficacy and safety studies, Zurzuvae is recommended to be taken with fat-containing food.

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

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

Clinical Efficacy

The efficacy of Zurzuvae for the treatment of postpartum depression was evaluated in two randomized, double-blind, parallel-group, placebo-controlled, multicentre studies: Study 217-PPD-301 and Study 217-PPD-201B.

Both studies enrolled female participants (aged 18 to 45 years) with severe postpartum depression, defined by a 17-item Hamilton Rating Scale for Depression (HAMD-17) total score of greater than or equal to 26 at baseline. The enrolled patients also met criteria for major depressive episode per the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), limited to onset of symptoms in the third trimester or within 4 weeks of delivery. Patients had experienced symptoms for a mean duration of approximately 4 to 5 months at baseline. Both patients with no current treatment and patients receiving stable doses of chronically administered antidepressants were allowed to enroll in the studies. Overall, 15% of patients in Study 217-PPD-301 and 19% of patients in Study 217-PPD-201B were taking stable doses of oral antidepressants at baseline. The mean age of patients was 30 years (range: 19 to 44 years) in Study 217-PPD-301 and 28 years (range: 18 to 44 years) in Study 217-PPD-201B. The majority of patients were White (70% in Study 217-PPD-301 and 56% in Study 217-PPD-201B).

In both studies, participants were randomized 1:1 to receive a single 14-day treatment course of once-daily oral zuranolone or placebo, in the evening, with food. In Study 217-PPD-301, there were 98 patients in the zuranolone group and 97 patients in the placebo group, whereas Study 217-PPD-201B included 76 patients in the zuranolone group and 74 patients in the placebo group. The studies used different doses and formulations of zuranolone. Study 217-PPD-301 evaluated the proposed 50 mg dose of the to-be-marketed Autofill capsule formulation, while Study 217-PPD-201B evaluated a 30 mg dose of the ProFill capsule formulation, which had a higher bioavailability (30 mg ProFill capsule formulation is equivalent to approximately 35 mg Autofill capsule formulation). Both study protocols allowed for a dose reduction of zuranolone, based on tolerability (to 40 mg in Study 217-PPD-301 and to 20 mg in Study 217-PPD-201B). After the 14-day treatment, participants were followed up for 31 days, leading to a 45-day period of efficacy and safety assessments.

The primary endpoint was the change from baseline in the HAMD-17 total score at the end of treatment period (Day 15). In both studies, zuranolone treatment led to statistically significant reductions in the HAMD-17 total score compared to placebo.

In Study 217-PPD-301, the 50 mg dose, compared to placebo, resulted in a least squares (LS) mean difference of -4.0 points in the HAMD-17 total score (95% confidence interval [CI]: -6.3, -1.7; p = 0.0007). This finding was consistent with the results of Study 217-PPD-201B, which showed a LS mean difference of -4.2 points in the HAMD-17 total score (95% CI: -6.9, -1.5; p = 0.0028) between the zuranolone-treated patients and those in the placebo group. The average difference of -4.0 to -4.2 points is considered clinically meaningful according to some literature sources for antidepressants used in patients with major depressive disorder.

A key clinical benefit of Zurzuvae is its rapid onset of action. In Study 217-PPD-301, zuranolone 50 mg demonstrated a statistically significant improvement over placebo in the key secondary efficacy endpoint of the change from baseline in the HAMD-17 total score at Day 3 (the LS mean difference between zuranolone 50 mg and placebo was -3.4 [95 CI: -5.4,-1.4; p = 0.0008]). An exploratory Kaplan-Meier analysis further supported this finding, showing a median time to first HAMD-17 response of 9 days in the zuranolone group, compared to 43 days for the placebo group.

Zuranolone 50 mg also showed a statistically significant improvement over placebo in the other key secondary endpoints: the change from baseline in the HAMD-17 total score at Day 28 (LS mean difference of -2.9 [95% CI: -5.4, -0.5; p = 0.0203]); the change from baseline in the HAMD-17 total score at Day 45 (LS mean difference of -3.5 [95% CI: -6.0, -1.0; p = 0.0067]); and the change from baseline in the Clinical Global Impression - Severity (CGI-S) scale score at Day 15 (LS mean difference of -0.6 [95% CI: -0.9, -0.2; p = 0.0052]).

Despite these positive findings, the review of the efficacy profile of Zurzuvae revealed some uncertainties and limitations (as discussed below) that were addressed by revising the sponsor’s initially proposed indication and by including relevant information and recommendations in the Product Monograph for Zurzuvae to mitigate the identified risks (further elaborated in the Clinical Safety section).

Based on the clinical data provided, the efficacy of zuranolone as an adjunct to stable background antidepressant therapy has not been established. The evidence to support such use of zuranolone is substantially limited by the small sample sizes, inconsistent findings between the two placebo-controlled studies, and significant methodological limitations. Study 217-PPD-301 failed to show any benefit of zuranolone over placebo in a small subgroup of 30 patients who continued to receive prior stable antidepressant therapy. Conversely, Study 217-PPD-201B showed a non-significant numerical benefit for zuranolone over placebo in 29 patients who continued to receive prior stable antidepressant therapy. The studies were not designed or statistically powered to evaluate the effects of zuranolone versus placebo as an adjunctive therapy in patients with inadequate response to an antidepressant.

In Study 217-PPD-301, the 50 mg dose of zuranolone was associated with treatment discontinuation (4.1%) and a high rate of dose reduction or interruption (16.3%) due to the characteristic CNS depressant effects (somnolence, dizziness, and sedation). This rate was higher than in the placebo group (1.0%) of the study and the 30 mg dose group (3.8%) in Study 217-PPD-201B. The imbalance in the rates of dose reduction created a significant potential for functional unblinding, which may have biased the subjective, clinician-rated assessment of the primary efficacy endpoints. Namely, there was a notable discrepancy between the robust results of the clinician-rated outcomes (measured by the HAMD-17 scale and the Montgomery-Åsberg Rating Scale [MADRS]) and the modest results of the patient-reported outcomes. At Day 15, the treatment differences between zuranolone and placebo measured by the patient-rated Edinburgh Postnatal Depression Scale (EPDS) (-2.0 points) and the 9-item Patient Health Questionnaire (PHQ-9) (-1.9 points) fell below established thresholds for minimal clinically important differences.

Importantly, the study duration of 45 days is insufficient to determine the efficacy durability or the need for retreatment over the typical 3- to 6-month course of a postpartum depression episode. The efficacy and safety of retreatment with Zurzuvae have not been studied and therefore retreatment with Zurzuvae in patients with postpartum depression is not recommended.

Both studies were designed to enroll patients with severe postpartum depression defined by a baseline HAMD-17 total score of greater than or equal to 26. The sponsor conducted post hoc subgroup analyses employing a different symptom scale (MADRS), which defined a large portion of the studied population as patients with moderate postpartum depression and demonstrated efficacy of Zurzuvae in this subgroup. Taking into consideration both the post hoc analyses using MADRS and the HAMD-17 inclusion criterion used in the studies, Health Canada categorized the postpartum depression severity in the approved indication as moderate or severe, instead of the sponsor’s initially sought broad indication for the treatment of postpartum depression in adults.

Indication

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

Zurzuvae (zuranolone) is indicated for the treatment of postpartum depression in adults.

Upon reviewing the submitted data, Health Canada revised the initially proposed indication. The intended population was limited to adults with moderate or severe postpartum depression (as elaborated above in the Clinical Efficacy section). Furthermore, the revised indication unequivocally limited the use of Zurzuvae after childbirth, taking into consideration the risk of fetal harm demonstrated in the non-clinical studies that led to implementing a contraindication for use of Zurzuvae in pregnant women, and in light of the diagnostic criteria in the DSM-5 referring to postpartum depression as the occurrence of major depressive episode with peripartum onset (i.e., during the course of pregnancy or up to 4  weeks after delivery). Accordingly, Health Canada approved the following indication:

Zurzuvae (zuranolone) is indicated for the treatment of moderate or severe postpartum depression in adults following childbirth.

Importantly, caveat statements were included to emphasize that the safety and efficacy of Zurzuvae for the treatment of postpartum depression have only been studied in patients who received Zurzuvae as a single 14-day course of treatment with a 31-day follow-up period, and that data on retreatment with Zurzuvae in case of a relapse are not available.

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

Clinical Safety

The safety profile of zuranolone was characterized using pooled data from two placebo-controlled studies (217-PPD-301 and 217-PPD-201B, described in the Clinical Efficacy section) conducted in patients with peripartum depression (a pool including 176 patients exposed to zuranolone). Additional data are provided from studies in patients with major depressive disorder (a pool including 2,476 patients exposed to zuranolone) and studies in healthy adult volunteers (a pool including 658 subjects exposed to zuranolone). Overall, the safety profile of zuranolone is dominated by dose-dependent CNS depressant effects.

In Study 217-PPD-301, which used the 50 mg dose of the to-be-marketed Autofill capsule formulation of zuranolone, the most commonly reported treatment-emergent adverse events in the zuranolone group (occurring in at least 2% of zuranolone-treated patients and at a rate greater than in the placebo group during the 14-day treatment and up to 3 days after the end of treatment) were somnolence/hypersomnia (27.6%), dizziness (13.3%), sedation (11.2%), diarrhea (6.1%), fatigue/asthenia (5.1%), urinary tract infection (5.1%), memory impairment (3.1%), abdominal pain (3.1%), myalgia (2.0%), muscle twitching (2.0%), anxiety (2.0%), hypoesthesia (2.0%), rash (2.0%), and tremor (2.0%). The events were typically mild or moderate in severity and could generally be managed with dose reductions. The CNS depressant effects led to dose adjustments (reductions or interruptions) in 16.3% of participants, while 4.1% of participants discontinued treatment entirely. Events of confusional state were also reported in the zuranolone group (1.1% versus none in the placebo group of the pool of patients with postpartum depression). One of these cases, in Study 217-PPD-201B, which used the 30 mg dose of the ProFill capsule formulation of zuranolone (equivalent to approximately 35 mg zuranolone in the to-be-marketed capsule formulation), was a serious adverse event that led to hospitalization, although it resolved the same day upon drug discontinuation.

Review of the full safety database, including dedicated clinical pharmacology studies, non-clinical data, and post-marketing reports, identified significant risks (described below) that required labelling in the Product Monograph for Zurzuvae, including a contraindication for use in pregnant women and a Serious Warnings and Precautions Box highlighting the risks of addiction, abuse and misuse; impairment of alertness and motor coordination; and suicidal thoughts and behaviour.

Zuranolone was shown to cause significant next-day impairment of psychomotor and cognitive functions. Dedicated driving simulation studies in healthy adults confirmed significant, dose-dependent, next-day driving impairment (approximately 9 hours after nighttime administration of zuranolone) that persisted after 7 days of daily 50 mg dosing. This impairment exceeded the threshold of impairment caused by a blood alcohol concentration of 0.05%. Importantly, most subjects were unable to reliably assess their own impairment (70% to 74% of the subjects felt safe to drive while impaired). The impairment of psychomotor performance may adversely affect the patient’s ability to take care of the infant. Post-marketing reports from other jurisdictions confirmed this risk; there were cases of excessive sedation persisting for more than 12 hours after a dose and difficulty taking care of an infant, necessitating assistance from others.

A dose-dependent abuse potential of zuranolone was demonstrated in a dedicated human abuse potential study in healthy individuals with a history of recreational CNS depressant use. At the supratherapeutic dose of 90 mg (less than two times the maximum recommended daily dose of 50 mg), the abuse potential of zuranolone was comparable to that of alprazolam (a benzodiazepine derivative, listed in Schedule IV of the Controlled Drugs and Substances Act).

There is some evidence suggesting a potential of zuranolone to induce physical dependence. While the aggregate patient data of the 20-item Physician Withdrawal Checklist (PWC-20) did not show withdrawal symptoms after discontinuation of zuranolone in the clinical studies in patients with postpartum depression, a number of adverse events potentially related to withdrawal effects were seen after discontinuation of zuranolone in the high-dose studies in healthy volunteers (e.g., insomnia and paranoia) and in individual case reports in the population with postpartum depression (e.g., new-onset anxiety, intermittent dizziness, and visual hallucinations). Non-clinical toxicology studies in dogs demonstrated convulsions and mortality upon abrupt discontinuation of high doses of zuranolone, consistent with severe withdrawal effects. In the pool of patients with major depressive disorder, two cases of seizures were reported after discontinuation of zuranolone. In one of the cases, the baseline encephalogram suggested pre-existing epilepsy and the other case was assessed as inconsistent with a withdrawal-type seizure.

Evidence suggests a potential risk of suicidality with the use of Zurzuvae. Although no concern was raised in the small clinical studies in patients with postpartum depression, a numerical imbalance in suicidality-related treatment-emergent adverse events was seen in the larger pool of patients with major depressive disorder (1.4% versus 0.9% in the placebo group). Since the zuranolone clinical development program excluded patients with active suicidal behaviour, psychosis, or other mental health disorders, uncertainty remains regarding the safety of Zurzuvae in these patient populations. Furthermore, the post-marketing data show that in the first year since the introduction of Zurzuvae to the United States market, suicidal ideation has been one of the most frequently reported serious adverse events. One case reported by a healthcare professional was considered "possibly related" to Zurzuvae based on the temporal relationship and the absence of other confounding factors. Given the preliminary nature of these findings and the inherent risk associated with the underlying condition, suicidality will be a subject of active monitoring through routine pharmacovigilance and adverse event follow-up.

Based on limited human data and non-clinical studies showing reproductive toxicity, including fetal skeletal malformations and mortality at doses resulting in exposures similar to or up to two times the exposures at the maximum recommended human dose, the use of Zurzuvae is contraindicated in pregnancy. Women of childbearing potential should be advised to use highly effective contraception during treatment with Zurzuvae and for at least 7 days after the final dose.

Clinical pharmacology studies demonstrated that zuranolone is excreted into breast milk at low levels (with an estimated relative infant dose of less than 1%). However, the effect on an infant is unknown. Post-marketing reports include cases of excessive sedation in breastfed infants, which suggest a potential risk to the infant. Therefore, it is recommended to discontinue breastfeeding during Zurzuvae treatment; if breastfeeding continues, close monitoring of the infant is necessary.

The risk of additive impairment of psychomotor performance when zuranolone is used concomitantly with other CNS depressants, such as alcohol, benzodiazepines, or opioids was highlighted as a serious drug interaction in the Product Monograph for Zurzuvae.

The evaluation of other safety parameters, including laboratory tests, vital signs, and electrocardiograms, did not identify significant safety concerns. In a dedicated thorough QT study in healthy adult subjects, zuranolone did not cause clinically significant prolongation of the corrected QT (QTc) interval at doses up to two times the maximum recommended human dose of 50 mg daily. Respiratory depression was not identified as a risk for zuranolone, even in cases of intentional overdose or supratherapeutic doses.

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

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

Zuranolone, the medicinal ingredient in Zurzuvae, is an orally bioavailable, synthetic neuroactive steroid that exhibits positive allosteric modulation of the gamma-aminobutyric acid (GABA) type A (GABA_A) receptor and enhances GABA activity at synaptic and extrasynaptic GABA_A receptors.

The non-clinical data package included in vitro and in vivo studies that evaluated the primary and secondary pharmacodynamics, safety pharmacology, pharmacokinetics, and toxicity of zuranolone.

In repeat-dose toxicity studies of zuranolone administered orally daily for up to 6 months in rats and up to 9 months in dogs, sedation was the primary and dose-limiting treatment-related effect, consistent with the anticipated pharmacological activity of zuranolone via the GABA_A receptors. Light sedation (drowsiness and ataxia) was noted at doses producing plasma exposures that were slightly lower than the exposure at the maximum recommended human dose (MRHD) of 50 mg daily. The sedation increased in incidence and severity in a dose-dependent manner and was long-lasting in the animals administered high doses of zuranolone.

A notable sex difference in systemic exposures was observed in the rat studies of zuranolone, as female rats showed higher exposure values across the evaluated dose ranges, compared to male rats. Therefore, the dose levels administered were lower in female rats (2.6 to 12 times lower in studies reviewed) than those administered to male rats. The no-adverse-effect levels (NOAELs) of 10 mg/kg/day in males and 5 mg/kg/day in females in the 6-month rat study provided safety margins of 3.4 and 5.6 times, respectively, the expected human exposure at the MRHD of 50 mg daily.

Convulsions and early mortalities observed in the repeat-dose toxicity studies in dogs administered high doses of zuranolone (2 mg/kg/day and 2.5 mg/kg/day) are consistent with withdrawal-type effects seen following termination of chronic dosing of other GABA-modulating compounds in dogs. Plasma exposures at the NOAEL in dogs after 9 months of repeat dosing and after 14 days of repeat dosing were 4.7 times and 3 times higher, respectively, than the human exposure at the MRHD of 50 mg daily.

Zuranolone did not exhibit genotoxicity and carcinogenicity potential in the genotoxicity and carcinogenicity studies.

In fertility and early embryonic development studies in rats, dose-dependent serious clinical signs (hyperreactivity, sedation, ataxia, and twitching) and drug-related deaths were observed in both males and females treated with zuranolone. There were increases in the number of female rats exhibiting persistent diestrus and an associated reduction in the number of estrous stages, and dose-related increases in postimplantation loss and non-viable embryos. The NOAELs for toxicity in male and female rats were determined to be 3 mg/kg/day and 1 mg/kg/day, respectively, while the NOAELs for fertility and toxicity were determined to be 30 mg/kg/day in male rats and 3 mg/kg/day in female rats, respectively. The safety margin for fertility and reproductive toxicity corresponds to 2.6 times and 3.8 times the expected exposure at the MHRD of 50 mg daily, in male and female rats, respectively (with the caveat that less than dose-proportional exposure was observed in the studies).

The embryo-fetal development study of zuranolone in pregnant rats highlighted similar serious drug-related observations, including deaths at the highest dose administered. Surviving rats from the high-dose group had a higher number of early resorptions, increased postimplantation loss, and lower gravid uterine weights. Fetal body weights were also reduced. Higher numbers of external and skeletal malformations and skeletal variations, not secondary to maternal toxicity, were reported in multiple litters from the dams in the high-dose group. These included absent limbs, herniated umbilicus, absent ribs, arches and vertebrae. The lack of dose-proportional exposure and the fewer surviving animals in the high-dose group hindered the identification of the threshold toxicity dose. The NOAELs for maternal toxicity and developmental toxicity in rats were determined to be the lowest dose tested of 2.5 mg/kg/day (providing a safety margin of 2.7 times the expected exposure at the MHRD of 50 mg daily).

An embryo-fetal development study of zuranolone in pregnant rabbits was considered inadequate due to the high interindividual variability in plasma concentrations reached and the high number of drug-related deaths.

In a prenatal and postnatal study in rats, drug-related mortality of mothers was observed in the groups of animals administered mid-doses and high doses of zuranolone (greater than or equal to 4 mg/kg/day). In the surviving animals in all treated groups, serious, toxicologically relevant and dose-related clinical observations were reported, including hyperreactivity and tremors, convulsions, lower body weights and food intake, reduced pup viability index and fewer pups per litter, and total litter loss. Pup weights decreased prior to weaning and the reductions in male pup weights persisted at least through to postnatal Day 71. The NOAEL for both maternal and developmental toxicity was determined to be 1 mg/kg/day, which produced systemic exposures corresponding to 1.4 times the exposures at the MRHD of 50 mg daily.

Administration of zuranolone to juvenile rats for 7 weeks was associated with severe clinical signs and mortality. Dose levels of zuranolone were decreased for all treated females because of the higher rate of drug-related mortality. Based on the severity of the findings, the changes observed for multiple endpoints (growth, sexual maturation, behaviour, and learning and memory) and the gender difference in toxicokinetics, the NOAEL was determined to be 10 mg/kg/day for males and 3 or 1 mg/kg/day for females. These values are associated with exposures corresponding to 2.8 times (male rats) and 1.9 times (female rats) the expected exposure at the MHRD of 50 mg daily.

A study in rats aimed to characterize the potential of zuranolone to cause neurodegeneration when administered once on postnatal Day 7. The brain development on postnatal Day 7 in rats corresponds to a period of brain development that begins during the third trimester of pregnancy in humans and continues up to a few years after birth. Histological examination identified the subiculum (an area involved in memory consolidation and learning) as an area where drug-related increases in neuronal apoptosis were observed in the brains of the treated rats. Given the study design, it is difficult to draw strong conclusions on the clinical relevance of these findings; however, a potential impact of exposure to zuranolone on the developing fetus cannot be disregarded.

Based on the risks identified in the reproductive and developmental toxicology studies of zuranolone, the Product Monograph for Zurzuvae includes a contraindication for use during pregnancy and a recommendation that women of childbearing potential use effective contraception while taking Zurzuvae and at least 7 days after the last dose.

Non-clinical abuse potential studies showed no off-target activity of zuranolone on other dependence-related receptors. Zuranolone had a similar or possibly lower abuse potential compared to benzodiazepines based on interoceptive and reinforcing effects in rats. Mild withdrawal effects were observed in female rats following discontinuation of zuranolone, at a plasma concentration that was approximately 7.4 times higher than the clinical human exposure at the MHRD of 50 mg daily.

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

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

The quality (chemistry and manufacturing) information submitted for Zurzuvae has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper pharmaceutical development studies were conducted and an adequate control strategy is in place for the commercial processes. Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable. Based on the stability data submitted, the proposed shelf life of 36 months is acceptable when the drug product is stored at room temperature (15 ºC to 25 ºC).

The 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 limits and/or qualified from toxicological studies). 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 Zurzuvae are prohibited for use in drug products by the Food and Drug Regulations. The gelatin present in the hard capsule shells is of animal origin. Relevant information has been provided to demonstrate the safety of this excipient with respect to the risk of introduction of transmissible spongiform encephalopathy agents. No other excipient in the drug product formulation is of animal or human origin.