Summary Basis of Decision for Nextstellis

Review decision

The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.


Product type:

Drug

Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Nextstellis is located below.

Recent Activity for Nextstellis

SBDs written for eligible drugs approved after September 1, 2012 will be updated to include post-authorization information. This information will be compiled in a Post-Authorization Activity Table (PAAT). The PAAT will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. PAATs will be updated regularly with post-authorization activity throughout the product's life cycle.

The following table describes post-authorization activity for Nextstellis, a product which contains the medicinal ingredients estetrol monohydrate and drospirenone. For more information on the type of information found in PAATs, please refer to the Frequently Asked Questions: Summary Basis of Decision (SBD) Project: Phase II and to the list of abbreviations that are found in PAATs.

For additional information about the drug submission process, refer to the AnchorAnchorManagement of Drug Submissions and Applications Guidance.

Updated: 2023-07-21

Drug Identification Number (DIN):

DIN 02513218 – 15 mg estetrol monohydrate and 3 mg drospirenone, tablets, oral administration

Post-Authorization Activity Table (PAAT)

Activity/submission type, control number Date submitted Decision and date Summary of activities
Drug product (DIN 02513218) market notification Not applicable Date of first sale: 2021-06-15 The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
NDS # 236197 2020-02-18 Issued NOC 2021-03-05 NOC issued for New Drug Submission.
Summary Basis of Decision (SBD) for Nextstellis

Date SBD issued: 2021-06-16

The following information relates to the New Drug Submission for Nextstellis.

Estetrol monohydrate and drospirenone

Drug Identification Number (DIN):

  • DIN 02513218 - 15 mg estetrol monohydrate and 3 mg drospirenone, tablets, oral administration

Searchlight Pharma Inc.

New Drug Submission Control Number: 236197

On March 5, 2021, Health Canada issued a Notice of Compliance to Searchlight Pharma Inc. for the drug product Nextstellis.

The market authorization was based on quality (chemistry and manufacturing), non‑clinical (pharmacology and toxicology), and clinical (pharmacology, safety, and efficacy) information submitted. Based on Health Canada’s review, the benefit‑harm-uncertainty profile of Nextstellis is favourable for prevention of pregnancy.

1 What was approved?

Nextstellis, an oral contraceptive, was authorized for prevention of pregnancy.

The safety and efficacy of Nextstellis have been studied in women between 16 and 50 years of age. No data in women under 16 years of age were available to Health Canada at the time of authorization, therefore, an indication for pediatric use has not been authorized. Use of this product before menarche is not indicated. In addition, Health Canada has not authorized an indication in women over 50 years of age. Nextstellis is not indicated for use in postmenopausal women.

Nextstellis is contraindicated for subjects who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container.

Nextstellis should not be used in women with the following conditions:

  • a history of or actual thrombophlebitis or thromboembolic disorders (such as deep vein thrombosis or pulmonary embolism);
  • presence of severe or multiple risk factor(s) for arterial or venous or thrombosis such as:
    • hypertension
    • hereditary or acquired predisposition for venous or arterial thrombosis, such as Factor V Leiden mutation and activated protein C (APC-) resistance, antithrombin-III-deficiency, protein C deficiency, protein S deficiency, hyperhomocysteinemia and antiphospholipid-antibodies (anticardiolipin antibodies, lupus anticoagulant) and prothrombin mutation G20210A
    • severe dyslipoproteinemia
    • diabetes mellitus with vascular involvement
    • increasing age, particularly above 50 years
    • obesity
    • other medical conditions associated with venous thromboembolism or other adverse vascular events
    • positive family history (arterial thromboembolism in a sibling or parent especially at relatively early age, e.g., below 50)
    • prolonged immobilization, major surgery, any surgery to the legs or pelvis, neurosurgery, or major trauma
    • smoking, particularly in women who are over 35 years of age
  • a history of or actual cerebrovascular disorders;
  • a history of or actual myocardial infarction or coronary artery disease;
  • valvular heart disease with complications;
  • history of or actual prodromi of a thrombosis (e.g., transient ischaemic attack, angina pectoris);
  • active liver disease, or history of or actual benign or malignant liver tumours;
  • known or suspected carcinoma of the breast;
  • carcinoma of the endometrium or other known or suspected estrogen-dependent neoplasia;
  • undiagnosed abnormal vaginal bleeding;
  • steroid-dependent jaundice, cholestatic jaundice, history of jaundice of pregnancy;
  • any ocular lesion arising from ophthalmic vascular disease, such as partial or complete loss of vision or defect in visual fields;
  • known or suspected pregnancy;
  • current or history of migraine with focal aura;
  • history of or actual pancreatitis if associated with severe hypertriglyceridaemia;
  • renal insufficiency;
  • hepatic dysfunction;
  • adrenal insufficiency.

Nextstellis was approved for use under the conditions stated in its Product Monograph taking into consideration the potential risks associated with the administration of this drug product.

Nextstellis (15 mg estetrol monohydrate and 3 mg drospirenone) is presented as tablets. In addition to the medicinal ingredients, each tablet contains:

  • Pink (active) tablets: cottonseed oil (hydrogenated), hydroxypropylcellulose, hydroxypropylmethylcellulose, iron oxide red (E172), lactose monohydrate, magnesium stearate, maize starch, povidone, sodium starch glycolate, talc, and titanium dioxide (E171)
  • White (inert) tablets: cottonseed oil, hydrogenated, hydroxypropylcellulose, hydroxypropylmethylcellulose, lactose monohydrate, magnesium stearate (E572), maize starch, talc, and titanium dioxide (E171)

For more information, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

Additional information may be found in the Nextstellis Product Monograph, approved by Health Canada and available through the Drug Product Database.

2 Why was Nextstellis approved?

Health Canada considers that the benefit-harm-uncertainty profile of Nextstellis is favourable for prevention of pregnancy.

Combined oral contraceptives are an effective method of pregnancy prevention and are widely used in the industrialized world. A combined oral contraceptive includes a progestin and an estrogen. The progestin primarily prevents pregnancy by decreasing luteinizing hormone secretion via the pituitary gland, which results in the inhibition of ovulation. The estrogen contributes contraceptive activity by inhibiting the secretion of follicle-stimulating hormone, thereby affecting ovarian follicle development. Estrogen provides stability to the endometrium (in balance with the progestin) and consequently an acceptable cycle control and bleeding pattern.

Nextstellis is a new combined oral contraceptive containing estrogen (estetrol monohydrate - 15 mg) and progestin (drospirenone ‑ 3 mg). Estetrol monohydrate is a new active substance. It is a synthetic form of natural estrogen produced by the human fetal liver during pregnancy. Drospirenone is a well-characterized and widely used contraceptive progestin. In Canada, drospirenone has been available in combination with ethinyl estradiol as an oral contraceptive since 2004.

Nextstellis has been shown to be efficacious in preventing pregnancy. The market authorization was primarily based on two pivotal Phase III multicentre, open-label, single-arm clinical studies (Study C302 and Study C301). Study C302 was conducted in the United States and Canada and included 1,864 healthy female subjects between the ages of 16 and 50 years. Study C301 was conducted in Europe and Russia and included 1,553 healthy female subjects between the ages of 18 and 50 years. The primary efficacy endpoint for both studies was the number of on-treatment pregnancies in the intent‑to‑treat (ITT) population of women aged 16 to 35 years for Study C302 and 18 to 35 years for Study C301. On-treatment pregnancies were assessed using the Pearl Index (PI), a validated, reliable measurement of pregnancy rate. Life table analysis provided cumulative on-treatment pregnancy rates over one year. The key secondary efficacy endpoint for both studies was the PI in the overall ITT population.

For Study C302, the primary analysis was performed on 12,763 at-risk cycles from 1,524 women 16 to 35 years of age. The results of this analysis determined that the PI for this group was 2.65 (95% Confidence Interval [CI]: 1.73-3.88) and the cumulative on-treatment pregnancy rate was 2.06% (95% CI: 1.40-3.04%), corresponding to approximately 97.9% contraceptive protection over 1 year. The overall PI for subjects 16 to 50 years of age was 2.52 (95% CI: 1.68-3.64) with a cumulative on-treatment pregnancy rate of 2.00% (95% CI: 1.38-2.91%). 

For Study C301, the primary analysis was performed on 13,692 at-risk cycles from 1,313 women 18 to 35 years of age. The results of this analysis determined that the PI in this group was 0.47 (95% CI: 0.15-1.11) and the cumulative on-treatment pregnancy rate was 0.45% (95% CI: 0.19-1.09%), corresponding to approximately 99.6% contraceptive protection over 1 year. The overall PI for women 18 to 50 years of age was 0.41 (95% CI: 0.13-0.96) with a cumulative on-treatment pregnancy rate of 0.39% (95% CI: 0.16-0.94%).

Data was pooled from these two pivotal studies to obtain a PI for women 16 to 35 years of age. The pooled PI was 1.52 (95% CI: 1.04, 2.16) and the pooled cumulative on-treatment pregnancy rate was 1.28% (95% CI 0.83, 1.73%), corresponding to approximately 98.8% contraceptive protection over 1 year.

To assess the safety of Nextstellis, data were pooled from the two Phase III studies and from three Phase II studies. These studies were conducted in the target population (i.e., healthy pre-menopausal women between 16 to 50 years of age) with a duration of study at least three 28-day cycles. The safety analysis included safety data from 3,790 subjects. A total of 2,212 subjects completed 13 cycles of treatment in the two Phase III studies. Treated subjects contributed a total of 2,735 woman-years or 35,677 cycles of exposure.

Approximately 50% of the subjects reported a Treatment-Emergent Adverse Event (TEAE), of which approximately half were related to Nextstellis. Less than 10% of TEAEs resulted in premature discontinuation. The most frequently reported adverse reactions (≥1%) were metrorrhagia (4.3%), headache (3.2%), acne (3.2%), vaginal hemorrhage (2.7%), dysmenorrhea (2.4%), breast pain (2.1%), weight increased (2.0%), breast pain/tenderness (1.8%), libido decreased (1.5%), nausea (1.4%), menorrhagia (1.3%) and mood swings (1.3%). In subjects between 16 and 35 years of age, the reported rates of TEAEs were similar to that of the all-subjects population. Forty-five serious TEAEs (regardless of causality) were reported by 41 subjects (1.1%) in the safety population. These included nine cases of spontaneous abortion, two cases of ectopic pregnancy, seven cases of psychiatric disorders, two cases of depression, one case of vascular disorder, and one case of venous thrombosis. Three of the serious TEAEs (ectopic pregnancy, depression and venous thrombosis) were associated with the treatment of Nextstellis.

The identified safety concerns include an increased risk of serious cardiovascular events associated with the use of hormonal contraceptives and cigarette smoking. The risk increases with age, particularly in women over 35 years of age, and with the number of cigarettes smoked. For this reason, Nextstellis should not be used by women who are over 35 years of age and smoke. In addition, subjects should be counselled that birth control pills do not protect against sexually transmitted infections including human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS). Both of these concerns are listed in a Serious Warnings and Precautions box in the Nextstellis Product Monograph.

The safety of Nextstellis was not evaluated in women with hypertension, with a history or risk factors of venous thromboembolism (VTE) or arterial thromboembolism (ATE), and beyond 13 cycles. Potential drug-drug interactions (DDIs) were not evaluated (except one DDI study that assessed the effect of a strong uridine 5'-diphospho-glucuronosyltransferase 2B7 [UGT2B7] inhibitor). All potential DDIs are adequately labelled. Potential risks of serious adverse events such as ectopic pregnancy, depression/psychiatric disorders, and VTE/ATE should be further characterized in post-marketing surveillance activities.

A Risk Management Plan (RMP) for Nextstellis was submitted by Searchlight Pharma Inc. to Health Canada. Upon review, the RMP was considered to be acceptable. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will be put in place to minimize risks associated with the product.

In the RMP, VTE and ATE were considered important identified risks. The sponsor proposed routine pharmacovigilance activities and routine risk minimization measures (labelling) for these risks. The European Medicine Agency (EMA) requested an additional non-interventional post-authorization safety study (PASS) be carried out to further characterize the risk of VTE and ATE associated with Nextstellis in comparison with a marketed combined oral contraceptive. In this regard, Health Canada recommended that safety findings from post-marketing pharmacovigilance commitments, including the PASS required by the EMA, be submitted to Health Canada.

The submitted inner and outer labels, package insert and Patient Medication Information section of the Nextstellis Product Monograph meet the necessary regulatory labelling, plain language and design element requirements.

A review of the submitted brand name assessment, including testing for Look‑alike Sound‑alike attributes, was conducted and the proposed name Nextstellis was accepted.

Nextstellis has been shown to have a favourable benefit-harm-uncertainty profile based on non-clinical and clinical studies. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Nextstellis Product Monograph to address the identified safety concerns.

This New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations. For more information, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

3 What steps led to the approval of Nextstellis?

Submission Milestones: Nextstellis

Submission Milestone Date
Pre-submission meeting 2019-10-10
New Drug Submission filed 2020-02-18
Screening  
Screening Deficiency Notice issued 2020-04-01
Response filed 2020-04-17
Screening Acceptance Letter issued 2020-05-12
Review  
Review of Risk Management Plan complete 2020-12-15
Biopharmaceutics Evaluation complete 2021-02-03
Non-Clinical Evaluation complete 2021-02-23
Quality Evaluation complete 2021-02-26
Labelling Review complete 2021-03-01
Clinical/Medical Evaluation complete 2021-03-05
Notice of Compliance issued by Director General, Therapeutic Products Directorate 2021-03-05

For additional information about the drug submission process, refer to the Management of Drug Submissions and Applications Guidance.

4 What follow-up measures will the company take?

Requirements for post-market commitments are outlined in the Food and Drugs Act and Regulations. As part of the marketing authorization for Nextstellis, Health Canada requested and the sponsor agreed to several commitments to be addressed post-market. In the Risk Management Plan, venous thromboembolism (VTE) and arterial thromboembolism (ATE) were considered important identified risks. The sponsor proposed routine pharmacovigilance activities and routine risk minimization measures (labelling) for these risks. The European Medicines Agency (EMA) requested an additional non-interventional post-authorization safety study (PASS) be carried out to further characterize the risk of VTE and ATE associated with Nextstellis in comparison with a marketed combined oral contraceptive. In this regard, Health Canada recommended that safety findings from post-marketing pharmacovigilance commitments including the PASS required by the EMA, should be submitted to Health Canada.

5 What post-authorization activity has taken place for Nextstellis?

Summary Basis of Decision documents (SBDs) for eligible drugs authorized after September 1, 2012 will include post-authorization information in a table format. The Post-Authorization Activity Table (PAAT) will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada’s decisions were negative or positive. The PAAT will continue to be updated during the product life cycle.

The PAAT for Nextstellis is found above.

For the latest advisories, warnings and recalls for marketed products, see MedEffect Canada.

6 What other information is available about drugs?

Up to date information on drug products can be found at the following links:

7 What was the scientific rationale for Health Canada's decision?
7.1 Clinical Basis for Decision

Clinical Pharmacology

Nextstellis is a monophasic, combination oral contraceptive that contains 15 mg of the estrogen estetrol monohydrateand 3.0 mg of the progestin drospirenone. Combination oral contraceptives act by suppressing the release of gonadotropins. Although the primary mechanism of action is inhibition of ovulation, combinations of estrogens and progestins also produce changes in the cervical mucus, the uterine endometrium, and in motility and secretion in the uterine tube.

Drospirenone is a spironolactone analogue with antimineralocorticoid activity. In humans, estetrol is only produced by the fetal liver during pregnancy and reaches the maternal circulation through the placenta. The estetrol monohydrate in Nextstellis is synthesized from a plant source.

Estetrol displays a high selectivity for estrogen receptors (ERs) and binds to both ERα and ERβ, with a 4‑ to 5‑times higher affinity for ERα compared to ERβ. Estrogenic properties of estetrol were confirmed in several in vivo pharmacodynamic models. Estetrol acts as an estrogen agonist on the vagina, the uterus and the endometrium, the bones and the brain, and as an antagonist in breast tissues. Estetrol as monotherapy suppresses ovarian activity and inhibits ovulation dose-dependently; however, complete ovarian suppression is only obtained when estetrol is combined with a progestin.

Pharmacodynamics

Biochemical assays showed that estetrol is a weak estrogen displaying a highly selective binding to ER and a lower potency compared to estradiol and ethinyl estradiol. Estetrol demonstrated anti-gonadotropic activity characterized by a dose-dependent decrease in both serum follicle stimulating hormone and luteinizing hormone levels, while it stimulated the endometrium. Both main metabolites, estetrol-3-glucuronide and estetrol-16-glucoronide showed a weak estrogenic activity with potencies several hundred‑fold lower than estetrol. Based on literature, it was established that drospirenone is a spironolactone analogue with antimineralocorticoid activity but without androgenic, estrogenic, glucocorticoid or anti-glucocorticoid properties.

Pharmacokinetics

Estetrol and drospirenone were both rapidly absorbed after ingestion, about 1-3 hours and 0.5‑2 hours, respectively. Bioavailability was estimated around 70% for estetrol and 76‑85% for drospirenone. Steady state of estetrol and drospirenone was achieved after about 5-6 days and 8-10 days, respectively, of dosing with estetrol/drospirenone 15/3 mg. Maximum plasma concentration (Cmax) and area under the concentration time curve (AUC) of estetrol alone or in combination with drospirenone increased in a dose-proportional manner over the range of 15 mg to 75 mg estetrol following a multiple dose of 15/3 mg to 75/15 mg once daily. The elimination half-life of estetrol and drospirenone was calculated to be approximately 25.0h ± 6.6 and 35.7h respectively under steady state conditions. The apparent steady state volume of distribution (Vd) of estetrol and drospirenone was approximately 6,000-10,000 L and 3.7 L, respectively. The high Vd of estetrol indicated that the component is widely distributed in tissues with only a limited amount in plasma.

Level of Sex Hormone Binding Globulin (SHBG) was a predictive marker for the risk of venous thromboembolism. In vitro binding affinity study showed that estetrol did not bind to SHBG. Estetrol displayed moderate binding to human plasma proteins (45.5%‑50.4%) and human serum albumin (58.6%) whereas drospirenone was known to be bound 97% to plasma proteins. There was limited distribution of estetrol into red blood cells.

After oral administration in humans, it has been shown that estetrol undergoes extensive Phase II metabolism to form glucuronide and sulphate conjugates. The uridine 5'-diphospho-glucuronosyltransferase (UGT) isoform UGT2B7 is the dominant UGT isoform involved in the biotransformation of estetrol into a direct glucuronide. Estetrol undergoes sulfation, mainly by estrogen sulfotransferase (SULT1E1). Approximately 69% of the administered dose of estetrol was eliminated in the urine as inactive metabolites. Therefore, most of the estetrol was excreted as metabolites with negligible estrogenic activity. Based on literature, it is well established that drospirenone is extensively metabolized as only trace amounts of drospirenone were excreted unchanged in urine and feces. Drospirenone is also subject to oxidative metabolism catalyzed by cytochrome P450 (CYP) 3A4 (CYP3A4).

Drug-Drug Interactions

Results from in vitro studies showed that estetrol exhibited low inhibitory properties towards human UGT1A9 and UGT2B7. One drug-drug interactions study was submitted. The purpose of the study was to determine whether a strong UGT2B7 inhibitor affects the pharmacokinetic parameters of estetrol/drospirenone. The results of this study showed that the inhibitor valproic acid increased the mean maximum concentration (Cmax) of estetrol by 35.5%, AUC from time 0 up to the last measurable concentration (AUC0-tlast) by 25.5% and AUC to infinite time (AUC0-inf) by 13.1%, while no effect was observed on drospirenone. The increases in the pharmacokinetic parameters of estetrol were not considered clinically relevant.

The results of in vitro metabolism studies showed that estetrol did not inhibit the major CYP450 isoforms. Thus, the effect of estetrol on drugs metabolized primarily by CYP450 is expected to be limited but the risk cannot be ruled out.

In vitro permeability and uptake/efflux transporters studies showed that an inhibitory signal was detected for the organic anion transporter 3 (OAT3) with estetrol. While it cannot be entirely excluded that estetrol acts as a substrate for OAT3, the risk of a potential drug interaction with other drugs affecting the OAT3 transporter cannot be ruled out. Moreover, the effect of estetrol as a potential substrate for efflux ABC transporters was assessed and findings implied that estetrol acts as a P-glycoprotein and Breast Cancer Resistance Protein (BCRP) substrate. Since estetrol is highly permeable and highly soluble, estetrol may not be significantly affected by BCRP-mediated efflux but the risk cannot be ruled out.

A class labelling exists for all combined oral contraceptives to include potential drug-drug interactions including those not well established. This class labelling also applies to Nextstellis as the sponsor did not carry out relevant drug-drug interaction studies.

Special Populations

No dedicated studies were conducted to evaluate the pharmacokinetics of estetrol in patients with renal or hepatic impairment. Nextstellis is contraindicated in subjects with renal impairment and liver disease. Based on pharmacokinetic analysis, no dose adjustment of Nextstellis is recommended for age, ethnicity, bodyweight or gender.

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

Clinical Efficacy

The market authorization for Nextstellis was based primarily on the results of two pivotal Phase III studies (Study C302 and Study C301) with supportive data provided from the Phase II studies ES-C02, C202, and C201.

Pivotal Studies

The contraceptive efficacy of Nextstellis (15 mg estetrol [E4] monohydrate/3 mg drospirenone [DRSP]) was evaluated in two Phase III, multicentre, open-label, single-arm clinical studies (Study C302 and Study C301) conducted in healthy, heterosexually active pre-menopausal women. Subjects were excluded from the studies if they were smokers ≥35 years of age; had a body mass index >35 kg/m2; had hypertension or a history of deep vein thrombosis, pulmonary embolism, angina pectoris, ischemic heart disease, or cerebral stroke; had risk factors for venous thromboembolism (VTE) or arterial thromboembolism (ATE); or had a history of hormone-related malignancy.

Participants in the both studies received Nextstellis (E4/DRSP 15/3 mg) supplied in blister packs containing 24 active (hormone-containing) pink tablets and 4 white inert (hormone-free) tablets. Nextstellis was administered orally once daily for 13 consecutive 28-day cycles. The treatment was taken at approximately the same time of day in a 24/4‑day regimen (one active pink tablet taken each day for 24 consecutive days, followed by one inert white tablet for 4 days).

The primary efficacy endpoint for both studies was the number of on-treatment pregnancies assessed by the Pearl Index (PI) in the intent-to-treat (ITT) Population of women aged 16 to 35 years for Study C302 and 18 to 35 years of age for Study C301. The primary analysis was conducted in subjects with at least one at-risk cycle (cycles in which no other methods of birth control were used and during which the subjects confirmed that sexual intercourse had occurred). The PI is a validated, reliable measurement of pregnancy rate and includes women who did not take the drug correctly. Life table analysis provided a cumulative on-treatment pregnancy rate over one year. A key secondary efficacy endpoint for both studies was the PI in the overall ITT population.

Study C302 enrolled women between the ages of 16 and 50 years in the United States and Canada. A total of 1,864 subjects received the treatment including 1,674 women 16 to 35 years of age. The primary analysis was performed on 12,763 at-risk cycles from 1,524 subjects 16 to 35 years of age. In this group, twenty-six on-treatment pregnancies occurred, resulting in a PI of 2.65 (95% confidence interval [CI]: 1.73-3.88). Life table analyses were consistent with the PI, resulting in a cumulative on-treatment pregnancy rate of 2.06% (95% CI: 1.40-3.04%), corresponding to approximately 97.9% contraceptive protection over 1 year. Among women 36 to 50 years of age, two on-treatment pregnancies occurred, resulting in an overall PI of 2.52 (95% CI: 1.68-3.64) for women 16 to 50 years of age (the overall ITT population) based on a total of 14,437 at-risk cycles. The life-table pregnancy rate for women 16 to 50 years of age was 2.00% (95% CI: 1.38-2.91%).

Study C301 enrolled women between the ages of 18 and 50 years of age in Europe and Russia. A total of 1,553 women received the treatment including 1,353 women 18 to 35 years of age. The primary analysis for Study C301 was performed on 13,692 at-risk cycles from 1,313 subjects 18 to 35 years of age. In this group, five on-treatment pregnancies occurred, resulting in a PI of 0.47 (95% CI: 0.15-1.11). Life table analyses were consistent with the PI, giving a cumulative on-treatment pregnancy rate of 0.45% (95% CI: 0.19-1.09%) for subjects aged 18 to 35 years, corresponding to approximately 99.6% contraceptive protection over 1 year. There were no on-treatment pregnancies among women aged 36 to 50 years, which resulted in an overall PI of 0.41 (95% CI: 0.13-0.96) for women 18 to 50 years (the overall ITT population) based on a total of 15,849 at-risk cycles. The life-table pregnancy rate for women 18 to 50 years was 0.39% (95% CI: 0.16-0.94%).

The pooled PI from the two pivotal studies for women 16 to 35 years of age was 1.52 (95% CI: 1.04, 2.16) based on a total of 2,837 subjects with 26,455 at-risk cycles and 31 on-treatment pregnancies. The pooled cumulative on-treatment pregnancy rate for women 16 to 35 years of age was 1.28% (95% CI: 0.83, 1.73%), corresponding to approximately 98.8% contraceptive protection over 1 year.

Cycle control and bleeding patterns were evaluated as secondary objectives in the pivotal studies. In pooled data from Studies C301 and C302, after an initial incidence of 27.1% in Cycle 1, the overall incidence of unscheduled bleeding and/or spotting ranged between 15% and 20% per cycle. The majority of bleeding and/or spotting episodes concerned spotting-only, implying that in each cycle, approximately 90% of the subjects did not experience unscheduled bleeding requiring the use of sanitary protection. The predictability of vaginal bleeding can be expressed by the occurrence of scheduled bleeding, or by its undesirable complement absence of scheduled bleeding. Absence of scheduled bleeding occurred in 9.7% to 11.3% of subjects per cycle, implying that 88.7% to 90.3% of the women had their scheduled withdrawal bleeding. There were on average 4.9 to 5.6 scheduled bleeding-spotting days in a cycle, consisting of equal numbers of bleeding and spotting days. The median number of bleeding-spotting days in scheduled episodes was 4.0 to 5.0 days.

Supportive Studies

Study ES-C02 was a multicentre, randomized, open-label, dose-finding study designed to select the optimal combination of E4 plus DRSP or levonorgestrel for the Phase III clinical program, with a group using estradiol Qlaira (valerate/dienogest) as reference therapy. Altogether, 389 young, healthy female volunteers (mean age 24.1 years, range: 18-35 years) received one of five treatments for six treatment cycles of 28 days each. The primary endpoints of the study were vaginal bleeding patterns (cycle controls) by measuring the occurrence of unscheduled bleeding/spotting and absence of withdrawal bleeding. The results of this study showed that the incidence of subjects with unscheduled bleeding/spotting was generally lower in the E4/DRSP groups across the primary cycles than in the other treatment groups. By Cycle 6, the 15 mg/3 mg E4/DRSP group had the lowest incidence (33.8%) of unscheduled bleeding/spotting among all groups. An absence of withdrawal bleeding occurred in <20% of subjects in all E4 treatment groups. At Cycle 6, the 15 mg/3 mg E4/DRSP group had the lowest incidence (3.5%) of absence of withdrawal bleeding among all groups.

Study C202 was a single-centre, randomized, open-label, two-arm study to evaluate the effects of 15 mg/3 mg E4/DRSP and 20 µg ethinylestradiol/3 mg DRSP combination as reference on ovarian function inhibition at Treatment Cycle 1 and Treatment Cycle 3. A total of 82 female subjects between 19 and 35 years of age and with a body mass index between 18.6 and 34.9 kg/m2 participated in the study. The primary endpoint was Hoogland score (a measurement of ovarian activity) at Treatment Cycle 1 and Treatment Cycle 3 based on follicular size assessed by transvaginal ultrasonography and endogenous hormone levels: serum estradiol and serum progesterone. The results of Study C202 showed that ovarian function inhibition was adequate in both treatment groups. The overall Hoogland scores for both treatments were similar in Treatment Cycle 1. In Treatment Cycle 3, a higher percentage (20%) of subjects treated with 15 mg E4/3 mg DRSP having a Hoogland score of 4 when compared with those treated with 20 µg ethinylestradiol/3 mg DRSP (4.9%).

Study C201 was a single-centre, randomized, open-label, three-arm study to evaluate the effect of 15 mg E4/3 mg DRSP and of two reference combined oral contraceptives containing either ethinylestradiol (30 µg) and levonorgestrel (150 µg) or ethinylestradiol (20 µg) and DRSP (3 mg) on endocrine function, metabolic control and hemostasis during 6 treatment cycles. A total of 101 healthy female subjects were randomized. No clear changes between baseline and Cycle 6 were observed for endocrine parameters such as dehydroepiandrosterone sulfate (DHEAS), dihydrotestosterone (DHT), testosterone, prolactin, free triiodothyronine, free thyroxine and thyrotropin, and cortisol. Treatment with 15 mg E4/3 mg DRSP did not result in an apparent decrease in follicle stimulating hormone and luteinizing hormone levels. There were small increases from baseline to Cycle 6 with respect to liver protein such as angiotensinogen. There was no apparent change for C-reactive protein. Additionally, there were little changes from baseline to Cycle 6 in lipid profile parameters such as cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, lipoprotein-a, and triglycerides. There were also no obvious changes from baseline to Cycle 6 with respect to glucose metabolism parameters such as insulin and glucose level. In subjects treated with 15 mg E4/3 mg DRSP, no obvious changes from baseline to Cycle 6 were observed for hemostasis parameters such as fibrinogen, factor VIII activity, von Willebrand factor, plasminogen activator-1 (PAI‑1), soluble E-selectin, prothrombin fragments 1+2, prothrombin activity (factor II), antithrombin, protein C activity (Factor XIV), Tissue Factor Pathway Inhibitor (TFPI), activated protein C (APC) resistance activated partial thromboplastin time (APTT) and D-dimer.

Indication

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

  • Nextstellis (estetrol monohydrate and drospirenone) is indicated for prevention of pregnancy.
     
  • Pediatrics (<16 years of age): No data are available to Health Canada. Therefore, Health Canada has not authorized an indication for pediatric use.
     
  • Geriatrics (>65 years of age): Nextstellis is not indicated for use in postmenopausal women.

Health Canada approved the following indication:

  • Nextstellis (estetrol monohydrate and drospirenone) is indicated for prevention of pregnancy.
     
  • Pediatrics (< 16 years of age): Safety and efficacy have been studied in women between 16 and 50 years old. No data in women under 16 are available to Health Canada. Therefore, Health Canada has not authorized an indication for pediatric use. Use of this product before menarche is not indicated.
     
  • Geriatrics: No data are available to Health Canada; therefore, Health Canada has not authorized an indication for women over 50 years of age. Nextstellis is not indicated for use in postmenopausal women.

Overall Analysis of Efficacy

During the review of the submission, a discrepancy was noted in the results of the pivotal studies. In Study C302, which was conducted in the United States and Canada, the PI for women 16 to 35 years of age was 2.65 (95% CI: 1.73-3.88). In Study C301, conducted in Europe and Russia, the PI for women 18 to 35 years of age was 0.47 (95% CI: 0.15-1.11). Similar patterns existed for the overall PI and the cumulative on‑treatment pregnancy rates (life-table analysis). It is possible that lower compliance among subjects in the United States/Canada study compared to those in the Europe/Russian study may have contributed significantly to these discrepancies. Differences in demographics between the two pivotal studies may have also have played important roles. In the primary population, the proportion of African American/black subjects was 19.5% and 0.6% in Study C302 and Study C301, respectively; and the proportion of Hispanic/Latino subjects was 26% and 0.8%, respectively. Published literature have reported a lower compliance of oral contraceptive among Hispanic/Latino subjects. Furthermore, subjects in the United States/Canada study were more likely to be starters (58% vs. 38%) and had a higher body mass index (median 25.3 vs. 22.3) than subjects in Europe/Russia study. Both factors might have affected the PI results.

The totality of evidence submitted support the efficacy of Nextstellis for the indication of prevention of pregnancy in women 16 and 50 years of age. For more information, refer to the Nextstellis Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The safety of Nextstellis for the proposed indication was evaluated in the clinical studies described in the Clinical Efficacy section. Data were pooled from the two Phase III studies (Study C301 and C302) and the three Phase II studies (Studies C201, C202 and ES-C02). These studies were conducted in the target population (i.e., healthy pre-menopausal women between 16 to 50 years of age) with a study duration of at least three 28-day cycles and included the dosage and regimen of Nextstellis (15 mg E4/3 mg DRSP). The safety analysis included safety data from 3,790 subjects. A total of 2,212 subjects completed 13 cycles of treatment in the two Phase III studies. Treated subjects contributed a total of 2,735 woman-years or 35,677 cycles of exposure. Within the treated population, 3,181 women aged 16 to 35 years contributed 31,412 cycles, while 394 women aged 36 to 50 years contributed 4,266 cycles. The safety population (number [n] = 3,790) also included 215 subjects who were dispensed study medication, but for whom the actual intake of study medication was not confirmed.

Approximately 50% of subjects reported a Treatment-Emergent Adverse Event (TEAE), of which approximately half were related to Nextstellis. Less than 10% of TEAEs resulted in premature discontinuation. The most frequently reported adverse reactions (≥1%) were metrorrhagia (4.3%), headache (3.2%), acne (3.2%), vaginal hemorrhage (2.7%), dysmenorrhea (2.4%), breast pain (2.1%), weight increased (2.0%), breast pain/tenderness (1.8%), libido decreased (1.5%), nausea (1.4%), menorrhagia (1.3%) and mood swings (1.3%). In subjects 16 to 35 years of age, the reported rates of TEAEs were similar to that of in the all-subjects population. Forty-five serious TEAEs (regardless of causality) were reported by 41 subjects (1.1%) in the safety population. These included nine cases of spontaneous abortion, two cases of ectopic pregnancy, seven cases of psychiatric disorders, two cases of depression, one case of vascular disorder, and one case of venous thrombosis. Three of the serious TEAEs (ectopic pregnancy, depression, and venous thrombosis) were associated with the treatment of Nextstellis.

The safety of Nextstellis was not evaluated in women with hypertension or with a history or risk factors of venous thromboembolism (VTE) or arterial thromboembolism (ATE). In addition, safety was not evaluated and beyond 13 cycles. The European Medicine Agency (EMA) requested an additional non-interventional post-authorization safety study (PASS) be carried out to further characterize the risk of VTE and ATE associated with Nextstellis in comparison with a marketed combined oral contraceptive. In this regard, Health Canada recommended that safety findings from post-marketing pharmacovigilance commitments, including the PASS required by the EMA, be submitted to Health Canada.

Potential drug-drug interactions were not evaluated (except one drug-drug interaction study that assessed the effect of a strong UGT2B7 inhibitor). All potential drug-drug interactions are adequately labelled. Potential risks of serious adverse events such as ectopic pregnancy, depression/psychiatric disorders, and VTE/ATE should be further characterized in post-marketing surveillance activities.

The identified safety concerns include an increased risk of serious cardiovascular events associated with the use of hormonal contraceptives and cigarette smoking. This risk increases with age, particularly in women over 35 years of age, and with the number of cigarettes smoked. For this reason, Nextstellis should not be used by women who are over 35 years of age and smoke. In addition, subjects should be counselled that birth control pills do not protect against sexually transmitted infections including human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS). Both of these concerns are listed in a Serious Warnings and Precautions box in the Nextstellis Product Monograph.

The totality of evidence submitted supports the safety of Nextstellis for the indication of prevention of pregnancy in women 16 and 50 years of age. The benefit-risk profile of Nextstellis for the recommended indication and dosage is favorable. For more information, refer to the Nextstellis Product Monograph, approved by Health Canada and available through the Drug Product Database.

7.2 Non-Clinical Basis for Decision

At the time of review, Nextstellis had not been approved or marketed anywhere in the world. Nextstellis is a combined oral contraceptive containing 15 mg of the new active substance estetrol monohydrate as the estrogen, as well as 3 mg of the progestogen drospirenone, which is already used at this dosage in approved combined oral contraceptives. Non-clinical studies were conducted with estetrol alone to characterize its pharmacological properties, pharmacokinetic characteristics, and safety profile. Non-clinical studies were not conducted with drospirenone alone, with the exception of one toxicity study conducted with estetrol monohydrate/drospirenone in female monkeys. Additional non-clinical and safety data for drospirenone were submitted in the form of published sources and the Yasmin Product Monograph.

Toxicology studies performed with estetrol included single-dose toxicity, repeat-dose toxicity, genotoxicity, carcinogenicity, and reproductive toxicity, together with supplementary studies to investigate the generation of reactive oxygen species (ROS). Given the established use of drospirenone, toxicology studies with drospirenone alone or with estetrol and drospirenone in combination were not conducted, except for one 13‑week oral repeat-dose toxicity study in female cynomolgus monkeys conducted with estetrol/drospirenone that included a drospirenone-only group. The long-term toxicity of estetrol alone was also investigated in multiple repeat-dose studies.

The toxicity profile of estetrol is mainly driven by the estrogenic properties of the substance with changes in reproductive tissues, lymphoid tissues, liver (rats), adrenals and pituitary (monkey). Changes observed following administration of estetrol alone included: changes in reproductive tissues weight, generally accompanied by macroscopic and/or microscopic observations (mice, rats, monkeys); minimal to moderate decrease in red blood cell parameters (mice, rats, monkeys) and decrease in white blood cell parameters (rats); decreased thymus weight, associated with lymphoid atrophy (mice, rats, monkeys); increased liver weight (mice, rats) accompanied by microscopic changes and decreased glycogen content (monkeys); changes in adrenals (mice, rats, monkeys). No treatment-related mortality occurred. All the observations were consistent with the estrogenic properties of estetrol and displayed evidence of reversibility upon cessation of treatment, although full recovery to control values was not always reached.

Estetrol and drospirenone in combination induced reversible but adverse hyperglycemia in female monkeys. Hyperglycemia determined the no observed adverse effect level (NOAEL) in the repeat-dose toxicity study with the estetrol/drospirenone combination (3/0.6 mg/kg/day).

In addition, at exposures exceedingly higher compared to the human therapeutic dose, ventricular histological changes, without clinical effects, were observed in monkeys after repeated administration of the combination. Spontaneous ventricular changes are a common observation in the monkey strain used in the study and the observations are possibly related to the genetic background of these monkeys.

Toxicokinetic monitoring showed that, on the basis of area under the plasma concentration-time curve over the last 24 hours dosing interval (AUC[0-24h]) values, the highest doses of estetrol used in rats after 26 weeks of treatment (5 mg/kg/day) and in monkeys after 39 weeks of treatment (3 mg/kg/day), which did not lead to overt signs of toxicity, led to 12‑times (rats) and 5.5‑times (monkeys) higher systemic exposure as compared to human exposure at the therapeutic dose. The NOAEL determined in monkeys after 13 weeks of treatment with the combination (3/0.6 mg/kg/day) led to 8 times higher systemic exposure as compared to human exposure to estetrol at the therapeutic dose.

Additionally, estetrol induced maternal toxicity and embryotoxicity (total embryo-fetal loss or abortion) in embryo-fetal development studies in the rat (3 mg/kg/day) and rabbit (≥0.15 mg/kg/day). Fetal development delays were noted in both species, but there was no evidence of teratogenic properties.

The non‑clinical studies performed to date provided an adequate data set to evaluate the safety of estetrol in combination with drospirenone in the context of the proposed treatment regimen of estetrol/drospirenone 15/3 mg daily tablets for 24 days, followed by placebo daily tablets for 4 days. The results of the non-clinical studies as well as the potential risks to humans have been included in the Nextstellis Product Monograph. In view of the intended use of Nextstellis, there are no pharmacological/toxicological issues within this submission which preclude authorization of the product.

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

7.3 Quality Basis for Decision

The Chemistry and Manufacturing information submitted for Nextstellis 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 48 months is acceptable when the drug product is stored at room temperature (15 ºC to 30 ºC).

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

All sites involved in production are compliant with Good Manufacturing Practices.

All non-medicinal ingredients (described earlier) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations. The biologic raw materials used during manufacturing originate from sources with no or minimal risk of transmissible spongiform encephalopathy (TSE) or other human pathogens.

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