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Drugs and Health Products

Summary Basis of Decision (SBD) for PrVISANNE®

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Contact: Bureau of Metabolism, Oncology and Reproductive Sciences (BMORS)

PrVISANNE®

Dienogest, 2 mg tablet
Bayer Inc.
Submission Control Number 132174
Date Issued 2012/02/14

Foreword

Health Canada's Summary Basis of Decision (SBD) documents outline the scientific and regulatory considerations that factor into Health Canada regulatory decisions related to drugs and medical devices. SBDs are written in technical language for stakeholders interested in product-specific Health Canada decisions, and are a direct reflection of observations detailed within the evaluation reports. As such, SBDs are intended to complement and not duplicate information provided within the Product Monograph.

Readers are encouraged to consult the 'Reader's Guide to the Summary Basis of Decision - Drugs' to assist with interpretation of terms and acronyms referred to herein. In addition, a brief overview of the drug submission review process is provided in the Fact Sheet entitled 'How Drugs are Reviewed in Canada'. This Fact Sheet describes the factors considered by Health Canada during the review and authorization process of a drug submission. Readers should also consult the 'Summary Basis of Decision Initiative - Frequently Asked Questions' document.

The SBD reflects the information available to Health Canada regulators at the time a decision has been rendered. Subsequent submissions reviewed for additional uses will not be captured under Phase I of the SBD implementation strategy. For up-to-date information on a particular product, readers should refer to the most recent Product Monograph for a product. For information related to advisories, warnings and recalls as a result of adverse events (AE), interested parties are advised to access the Health Canada Website.

For further information on a particular product, readers may also access websites of other regulatory jurisdictions. The information received in support of a Canadian drug submission may not be identical to that received by other jurisdictions.

Other Policies and Guidance

Readers should consult the Health Canada Web site for other drug policies and guidance documents. In particular, readers may wish to refer to the 'Management of Drug Submissions Guidance'.

Table Of Contents

Table of Contents

1 Product And Submission Information

Brand Name:
PrVISANNE®
Manufacturer/Sponsor:
Bayer Inc.
Medicinal Ingredient:
Dienogest
International Non-proprietary Name:
Dienogest
Strength:
2mg
Dosage form:
Tablet
Route of Administration:
Oral
Drug Identification Numbers (DINs):
02374900
Therapeutic Classification:
Progestin
Non-medicinal Ingredients:
Crospovidone, lactose monohydrate, magnesium stearate, microcrystalline cellulose, potato starch, povidone K 25, and talc.
Submission Type and Control Number: Control Number 132174
New Drug Submission,
Control Number: 107792
Date of Submission:
2009/08/21
Date of Authorization:
2011/10/12
®VISANNE is a trademark used under license by Bayer Inc.

2 Notice Of Decision

On October 12, 2011, Health Canada issued a Notice of Compliance to Bayer Inc. for the drug product, Visanne.

Visanne contains the medicinal ingredient dienogest which is a progestin.

Visanne is indicated for the management of pelvic pain associated with endometriosis. The efficacy of Visanne has not been tested beyond 15 months.

Endometriosis is a gynaecological disease where endometrial tissue is found outside the uterine cavity, most commonly on the ovaries and the peritoneal surface. This tissue can cause inflammation and adhesions which result in chronic pelvic pain and often infertility. The cause of endometriosis remains unknown. Visanne reduces the endogenous production of estradiol and thereby suppresses the trophic effects of estradiol on both the eutopic and ectopic endometrium. When given continously, Visanne leads to a hyperprogestogenic and moderately hypoestrogenic endocrine environment causing initial decidualization of endometrial tissue. In addition to the estradiol-mediated effects Visanne also has direct antiproliferative, immunologic and antiangiogenic effects that contribute to the reduction of pelvic pain associated with endometriosis.

The market authorization was based on quality, non-clinical, and clinical information submitted. The efficacy and safety of Visanne were demonstrated primarily in three multicentre Phase III studies. All three studies enrolled patients with a confirmed diagnosis of endometriosis with various stages of disease severity. Assessment of pelvic pain associated with endometriosis was determined by using a visual analog scale (0-100 mm, where 0 mm represents no pain and 100 mm represents severe pain). The first study was a double-blind placebo-controlled study where 102 patients were treated orally (PO) with a Visanne 2 mg tablet once daily (OD) compared to 96 patients who were treated with a placebo, over a 12 week period. The second study was an open-label extension to the placebo-controlled study. The extension study included 168 women; 87 previously treated with Visanne (2 mg, PO, OD) and 81 previously treated with placebo. All 168 women received Visanne (2 mg, PO, OD) for an additional 52 weeks to assess the long-term efficacy of Visanne treatment. The third study compared Visanne (2 mg, PO, OD) to 3.75 mg leuprolide acetate administered intramuscularly every four weeks, where 120 patients received Visanne treatment and 128 patients received leuprolide acetate, for a 24-week treatment period. Results from all three studies demonstrated that treatment with Visanne produced clinically significant reductions in pelvic pain compared to baseline values. In the placebo-controlled study, following 12 weeks of treatment with Visanne, the mean reduction of pelvic pain compared to baseline was 27.4 ▒ 22.9 mm. The open-label extension study showed continued improvement in pelvic pain for up to 15 months. In the third active comparator study, Visanne demonstrated efficacy similar to leuprolide acetate in reducing pelvic pain associated with endometriosis. In all clinical studies, Visanne was generally well-tolerated.

Visanne (2 mg, dienogest) is provided in tablet form. The recommended dose of Visanne is one oral tablet per day, preferably taken at the same time each day, with some liquid as needed. Visanne tablets are intended for continuous administration regardless of any vaginal bleeding. Dosing guidelines are available in the Product Monograph.

Visanne is contraindicated in women with any of the conditions listed below, which are partially derived from information on other progestin-only preparations. Should any of the conditions appear during the use of Visanne, treatment must be discontinued immediately:

  • Known or suspected pregnancy;
  • Lactation;
  • Active venous thromboembolic disorder;
  • Arterial and cardiovascular disease, past or present [for example (e.g.) myocardial infarction, cerebrovascular accident, ischaemic heart disease];
  • Diabetes mellitus with vascular involvement;
  • Presence or history of severe hepatic disease as long as liver function values have not returned to normal;
  • Presence or history of liver tumours (benign or malignant);
  • Known or suspected sex hormone-dependent malignancies;
  • Undiagnosed abnormal vaginal bleeding;
  • Any ocular lesion arising from ophthalmic vascular disease, such as partial or complete loss of vision or defect in visual fields;
  • Current or history of migraine with focal aura;
  • Hypersensitivity to dienogest or to any ingredient in the formulation or component of the container.

Visanne should be administered under the conditions stated in the Product Monograph taking into consideration the potential risks associated with the administration of this drug product. Detailed conditions for the use of Visanne are described in the Product Monograph.

Based on the Health Canada review of data on quality, safety, and efficacy, Health Canada considers that the benefit/risk profile of Visanne is favourable for the indication stated above.

3 Scientific And Regulatory Basis For Decision

A New Drug Submission (NDS) for Visanne (dienogest) was filed with Health Canada on August 21, 2009. Upon review, Health Canada concluded that there were several deficiencies in the clinical data, including insufficient data to support the indication for the treatment of endometriosis. On July 30, 2010, the submission received a Notice of Deficiency (NOD). A response to the NOD was filed on October 29, 2010. The sponsor revised the indication and addressed the deficiencies and the safety concerns raised in the NOD. The outstanding issues were adequately addressed and a Notice of Compliance (NOC) was issued for Visanne on October 12, 2011. A timeline of these events are reported in section 4 Submission Milestones.

3.1 Quality Basis for Decision

3.1.1 Drug Substance (Medicinal Ingredient)
General Information

Dienogest, the medicinal ingredient of Visanne, is a synthetic steroid and belongs to the class of progestin drugs. Dienogest has estradiol-mediated effects, as well as direct antiproliferative, immunologic, and antiangiogenic effects that contribute to the reduction of pelvic pain associated with endometriosis.

Manufacturing Process and Process Controls

Dienogest is manufactured via a multi-step synthesis. Each step of the manufacturing process is considered to be controlled within acceptable limits:

  • The sponsor has provided information on the quality and controls for all materials used in the manufacture of the drug substance.
  • The drug substance specifications are found to be satisfactory. Impurity limits meet International Conference on Harmonisation (ICH) requirements.
  • The processing steps have been evaluated and the appropriate ranges for process parameters have been established.
Characterization

The structure of dienogest has been adequately elucidated and the representative spectra have been provided. Physical and chemical properties have been described and were found to be satisfactory.

Impurities and degradation products arising from manufacturing and/or storage were reported and characterized. These products were found to be within ICH-established limits and/or were qualified from batch analysis, or toxicological studies and therefore, are considered to be acceptable
Control of Drug Substance

The drug substance specifications and analytical methods used for quality control of dienogest are considered acceptable.

Validation reports are considered satisfactory for all analytical procedures used for in-process, release, and stability testing of the drug substance.

Data from the batch analyses were reviewed and are within the proposed acceptance criteria.

The drug substance packaging is considered acceptable.

Stability

Based on the long-term, real-time, and accelerated stability data submitted, the proposed retest period and storage conditions for the drug substance were supported and are considered satisfactory.

3.1.2 Drug Product
Description and Composition

Visanne (dienogest) is available as white to off-white, round, flat-faced, bevelled-edged tablets with a diameter of 7 mm and an embossed "B" on one side.

Each tablet contains 2 mg dienogest and the following non-medicinal ingredients: crospovidone; lactose monohydrate; magnesium stearate; microcrystalline cellulose; potato starch; povidone K 25; and talc.

Visanne tablets are packaged in blister packs of 28 tablets. All non-medicinal ingredients (excipients) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations. The compatibility of dienogest with the excipients is demonstrated by the stability data presented on the proposed commercial formulation.

Pharmaceutical Development

Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review.

Manufacturing Process and Process Controls

The method of manufacturing is considered acceptable and the process is considered adequately controlled within justified limits.

Control of Drug Product

Visanne is tested to verify that its identity, appearance, content uniformity, assay, and levels of degradation products and microbiological impurities are within acceptance criteria. The test specifications and analytical methods are considered acceptable; the shelf-life and the release limits, for individual and total degradation products, are within acceptable limits.

Copies of the analytical methods and, where appropriate, validation reports were provided and are considered satisfactory for all analytical procedures used for release and stability testing of Visanne. Data from final batch analyses were reviewed and are considered to be acceptable according to the specifications of the drug product.

Stability

Based on the real-time, long-term, and accelerated stability data submitted, the proposed 5-year shelf-life at 15°C-30°C for Visanne is considered acceptable. The compatibility of the drug product with the container closure system was demonstrated through stability studies. The container closure system met all validation test acceptance criteria.

3.1.3 Facilities and Equipment

The design, operations, and controls of the facilities and equipment that are involved in the production of Visanne are considered suitable for the activities and products manufactured.

All sites are compliant with Good Manufacturing Practices.

3.1.4 Adventitious Agents Safety Evaluation

The excipient, lactose monohydrate, is derived from milk sourced from healthy animals in the same conditions as milk is collected for human consumption.

Magnesium stearate (used as an excipient) is exclusively of vegetable origin.

3.1.5 Conclusion

The Chemistry and Manufacturing information submitted for Visanne 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.

3.2 Non-clinical Basis for Decision

3.2.1 Pharmacodynamics

The pharmacological studies were primarily performed in mice, rats, and rabbits but also in guinea pigs, dogs, and monkeys. In vitro studies using human biomaterial were also analyzed. In vitro studies revealed a low relative binding affinity (less than 20%) of dienogest to the progesterone receptor of rat or rabbit uterus cytosol compared with progesterone.

In vitro studies demonstrated a dose-dependent inhibition of cell proliferation of human endometrial stromal cells in the presence of estradiol and dienogest. In addition, dienogest induced a statistically significant reduction of cell proliferation in endometrial stromal cells isolated from human endometriotic lesions.

In vivo studies with dienogest revealed a strong progestational activity in the endometrial transformation assay in rabbits after oral and subcutaneous administration of doses ≥0.01 mg/kg. In rats, the oral administration of dienogest (0.3 mg/kg/day) resulted in a statistically significant reduction in the area of endometriotic lesions. Orally administered dienogest had only marginal androgenic activity and no anabolic, glucocorticoid, or mineralocorticoid activity in rats at doses up to 100 mg/kg.

Dienogest exhibited considerable estrogenic activity in mice and rats, which may be due to the aromatic metabolite which was demonstrated as a main plasma metabolite in rats.

Orally administered dienogest showed antiprogestogenic activity in female rabbits at doses up to 10 mg/kg and some antigonadotropic activity in female rats at doses ≥20.7 mg/kg.

The conclusion drawn from the detailed endocrinological characterization of dienogest is that this drug substance has a potent progestational activity in the endometrial transformation assay in rabbits and in pregnancy maintenance tests in rats and rabbits, and a medium antigonadotropic/antiovulatory activity in rats. A moderate antiandrogenic activity was observed in mice and rats, and only low androgenic activity was noted. The estrogenic activity of dienogest observed in rats and mice was considered to represent a species-specific response related to the presence of an aromatic dienogest metabolite that occurs only in these species.

Dienogest was well-tolerated in the safety pharmacology studies that evaluated the impact of dienogest on the central nervous system, and on the cardiovascular (including electrocardiogram), respiratory, renal, and gastrointestinal functions. No safety concerns were noted.

3.2.2 Pharmacokinetics
Absorption

Dienogest was rapidly and completely absorbed after oral administration in all of the species studied. A high bioavailability after oral administration was found, with values of approximately 70% in rats, 85% in baboons, 85% in dogs and 90% in rabbits.

In rats, the systemic exposure [area under the curve (AUC)] after multiple dosing for 13 weeks to 1 year was approximately twice the concentration compared to levels found after a single dose.

Distribution

Dienogest is distributed throughout the whole body. At 24 hours after single oral and repeated administration, the highest concentrations were observed in the adrenals and the liver. Dienogest and/or its metabolites pass the blood-brain-barrier, enter the foetus and are excreted in milk.

The protein binding of dienogest in plasma of female rats, dogs, monkeys and healthy human volunteers was concentration independent and similar between the species in the range of 90% to 94%. The main binding protein in plasma was albumin. The volume of distribution among the species tested ranged from 0.6 L/kg in rats and dogs to 3.2 L/kg in rabbits.

Metabolism

The metabolism of dienogest is very extensive. Several hydroxylated and one aromatic metabolite have been identified. Because these metabolites were found to be excreted very quickly, unchanged dienogest was the dominating fraction in plasma. In plasma of humans, monkeys and rabbits, only unchanged dienogest was detected. Whereas in rat plasma, hydroxylated metabolites and the aromatic dienogest metabolite were found. The hydroxylation leads to an inactivation of dienogest, whereas the aromatic metabolite possesses estrogenic and antiprogestational properties. This aromatic metabolite did not occur in human plasma.

The cytochrome (CYP) P450 isoenzyme CYP3A4 was identified as the predominant isoenzyme catalyzing the metabolism of dienogest. Therefore, CYP3A4 inducers and inhibitors may affect dienogest plasma levels. At multiples of clinically relevant concentrations, dienogest did not inhibit CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4 in vitro.

Excretion

Dienogest is extensively metabolized and only trace amounts of unchanged dienogest are excreted. In female rats, monkeys, and rabbits, the renal excretion of dienogest metabolites was predominant.

3.2.3 Toxicology
Single-Dose Toxicity

Single-dose toxicity studies were conducted in several species including mice, rabbits, rats, and dogs. All of the studies revealed a very low toxicity of dienogest after single oral or parenteral administration. Non-lethal doses were between 1,000 and 4,000 mg/kg with the exception of male rabbits where it was below but close to 1,000 mg/kg. Toxic signs observed at high doses were central depression in mice; anorexia weight loss and convulsions in rabbits; and a transient increase in serum glutamic pyruvic transaminase (SGPT) in dogs without histopathological findings. There were no toxic signs observed in rats.

Repeat-Dose Toxicity

The repeat-dose toxicity studies were conducted in different animal species (up to 13 weeks in mice; 12 months in rats; 6 months in dogs;, and up to 12 months in monkeys). The one-year repeat-dose oral toxicity studies in rats and monkeys were performed under Good Laboratory Practice (GLP) and were considered the pivotal systemic toxicity studies with dienogest. The findings mainly involved changes in reproductive organs and can be attributed to the pharmacological profile of the drug.

In the rat studies, dienogest was well-tolerated and was non-lethal when administered orally once daily for 3 months at dose levels up to 30 mg/kg or for 6 and 12 months at doses up to 10 mg/kg/day. In the 3-month study, 3.0 mg/kg/day was identified as the
no-observable-adverse-effect-level (NOAEL). In the 12-month study, 1.0 mg/kg/day was identified as the NOAEL. A 29-fold multiple of human exposure to dienogest was achieved in the 3-month studies in female rats and a 12-fold exposure was achieved in the pivotal 1-year study in terms of AUC(0-24hours). Compared with controls, changes observed across the rat studies were predominantly pharmacological in nature and included persistent diestrus; lower than average serum total cholesterol and alanine and/or aspartate aminotransferase values; slightly higher serum triglyceride and non-esterified fatty acid values; alterations in coagulation parameters (higher platelet counts, fibrinogen values or longer prothrombin times); higher absolute and relative liver weights; and microscopic changes in target organs (ovaries, uterus and vagina) at most dose levels ≥1.0 mg/kg/day. Slightly lower erythrocytic parameters (typically erythrocyte counts, haemoglobin and haematocrit) compared with controls were also observed in some of the studies. Microscopic liver changes including basophilic foci of cellular alteration, periportal fat deposition and vacuolated hepatocytes were observed after oral administration of 10 mg/kg/day for 12 months. The liver changes seen only in this chronic study probably reflect earlier onset of age-related changes in female rats.

In the repeat-dose studies in female monkeys, dienogest was orally (intragastrically) administered at dose levels of 0.1, 1, and 10 mg/kg/day for 3 or 12 months. After administration of 10 mg/kg/day, alterations in coagulation parameters (such as increases in fibrinogen and plasminogen activity but without effect on coagulation times or thromboelastograms) and intimal thickening and hypertrophy of the uterus were observed in each study. Furthermore, apart from a two-fold increase in glutamate pyruvate transaminase (GPT) in a single high-dose monkey and only in Week 4 (as compared to the mean in controls) of the 3-month study, there was no indication of liver toxicity in any of the three monkey studies. The highest dose of 10 mg/kg in the pivotal 1-year monkey study corresponds to 75 times the human dienogest exposure.

Genotoxicity

Dienogest was found to be non-genotoxic in a large battery of mutagenicity and genotoxicity assays.

Carcinogenicity

Slightly increased incidences of malignant lymphomas and pituitary adenomas were seen in male mice during a 2-year carcinogenicity study. Female mice showed an increased incidence of uterine stromal polyps at the highest tested dose level. These findings are considered to be related to the weak partial estrogenic activity of dienogest in rodents. In one of the two carcinogenicity studies in rats, there was an increased incidence of pituitary adenomas and fibroepithelial tumours of the mammary gland in male animals. There was no change in tumour incidence in female rats in both studies. These observations do not suggest particular human risks apart from those which are generally assumed for the use of progestogenic compounds and which are addressed in the Product Monograph.

Reproductive and Developmental Toxicity

Reproductive toxicity studies with dienogest gave no indication of a teratogenic potential up to embryolethal doses. The inhibition of implantation in rats might be due to an estrogenic effect and the impairment of tubal transport of ova and the postimplantational losses further indicate a disturbance of the endocrine milieu. The fertility of female offspring was impaired after high doses of dienogest were administered during late pregnancy and lactation. Overall, the results of reproductive toxicity testing with dienogest do not differentiate this drug from other progestins.

3.2.4 Summary and Conclusion

The non-clinical studies for this drug submission are considered acceptable. The pharmacology and toxicology program for Visanne (dienogest) demonstrated that the compound is relatively safe for humans. Dienogest was well-tolerated up to high doses in animals and raised no safety concerns with regard to its use in endometriosis. Overall, the non-clinical data revealed no special risk for the use of 2 mg oral dienogest recommended for the treatment of endometriosis in women.

3.3 Clinical Basis for Decision

3.3.1 Pharmacodynamics

Dienogest binds to the progesterone receptor of the human uterus with only 10% of the relative affinity of progesterone. Despite its low affinity to the progesterone receptor, dienogest has a strong peripheral progestogenic effect. Two studies characterized the progestogenic activity of dienogest by determination of the transformation dose in estrogen-deficient women who were treated with ethinylestradiol for 2 weeks and with a combination of ethinylestradiol and dienogest for 2 consecutive weeks. The transformation dose was found to be 6.3 mg per cycle [that is (i.e), 0.45 mg per day). The results of a second study suggested that dienogest produces clear progestogenic effects at a dose of 0.25 mg per day. However, a complete transformation of the endometrium in 100% of the volunteers could not be documented at any of the doses tested up to 0.55 mg dienogest. This may have been due to the low number of women enrolled in the studies, who were, furthermore, post-menopausal and received estrogen pre-treatments that were of insufficient duration to develop adequate endometrial proliferation.

Dienogest acts on endometriosis by abolishing the trophic effects of estradiol on both the eutopic and ectopic endometrium. When given continuously, dienogest leads to a hyperprogestogenic and moderately hypoestrogenic endocrine environment causing decidualization of endometrial tissue. Additional properties, such as immunologic and antiangiogenic effects, seem to contribute to the inhibitory action of dienogest on cell proliferation.

The antigonadotropic effects of daily, oral administration of Visanne (2 mg dienogest) alone and in combination with 0.03 mg ethinylestradiol for 21 days on gonadotropin [luteinizing hormone (LH), follicle-stimulating hormone (FSH)] secretion and its pulsatile characteristics were investigated in healthy young women. As secondary variables the concentrations of estradiol and progesterone in serum were determined, and follicular growth was measured by transvaginal ultrasound. With 2 mg dienogest alone neither the pulsatility nor the hypophyseal gonadotropin secretion were altered. None of the volunteers ovulated, but follicular growth was only stopped at a size of 10 mm.

The effect of dienogest on ovulation inhibition was investigated and doses ≥1 mg dienogest per day inhibited ovulation. However, follicular maturation processes evident by a rise in serum estradiol levels were not completely suppressed even with the highest dose of 2 mg dienogest.

Dienogest at doses up to 10 mg did not delay cardiac repolarization as measured by QT/QTc prolongation.

In summary, it appears that at a dose of 2 mg dienogest per day, ovulation is inhibited but ovarian hormone production is not completely suppressed. Thus, compared to other endometriosis treatments, estrogen-deficiency related side effects are expected to be of low intensity with 2 mg dienogest. Compared with its ovulation inhibitory potency, the effect of dienogest on the endometrium is relatively strong as indicated by the low doses required for endometrial transformation.
3.3.2 Pharmacokinetics
Absorption

After oral administration of dienogest either as immediate-release tablets or as a microcrystalline suspension, the absorption of the drug was rapid as indicated by the short time of 0.67 to 2 hours to reach maximum concentrations of dienogest in serum or plasma. Maximum serum concentrations of 52 ng/mL at steady-state were reached at approximately 1.3 hours after the oral administration of Visanne to young female women. The absolute bioavailability of 2 mg dienogest was determined to be 91% in males, indicating almost complete absorption and a lack of a first-pass effect.

Dose linearity of dienogest pharmacokinetics was observed following single oral administration of 1 to 8 mg dienogest to young Caucasian women.

Minor accumulation occurred with daily administration of 2 mg dienogest and neither the time to maximum plasma concentration nor the terminal half-life were altered compared to single-dose administration; steady-state was reached on treatment Day 4.

Concomitant food intake has no clinically relevant effects on the pharmacokinetics of dienogest; therefore, no special recommendation concerning food intake is considered to be necessary regarding the patient information.

Distribution

In plasma, approximately 10% was unbound dienogest whereas the remaining 90% was bound nonspecifically to plasma albumin. Dienogest does not bind to sex hormone-binding globulin (SHBG) or cortisol-binding globulin (CBG). Therefore, dienogest pharmacokinetics are not influenced by changes of SHBG or CBG concentrations, and displacement of testosterone from SHBG or cortisol from CBG by dienogest is unlikely.

The volume of distribution at steady-state was approximately 50 L.

Metabolism

Dienogest is extensively metabolized by the known pathways of steroid metabolism, i.e., hydroxylation at different positions, and conjugation of dienogest and its hydroxylated metabolites. The metabolites are excreted very quickly, and therefore unchanged dienogest is the dominating fraction in the plasma.

In human urine, the hydroxylated metabolites: 6β-OH-DNG; 1α-OH-DNG; and 11β-OH-DNG were the predominant metabolites. All other metabolites were of minor quantity.

Excretion

The main route of excretion was via urine. Dienogest was extensively metabolized and only trace amounts were excreted unchanged via urine. Excretion was fast and largely complete after 5-6 days. The mean total clearance was approximately 1 mL/minutes/kg.

Drug Interactions Studies

Interactions can occur with drugs that induce cytochrome P450 enzymes [for example (e.g.), phenytoin, barbiturates, primidone, carbamazepine, rifampicin, and possibly oxcarbazepine, topiramate, felbamate, griseofulvin, nevirapine and products containing St. John's Wort], and can result in increased clearance of sex hormones.

In a study in healthy postmenopausal women receiving the combination of dienogest and estradiol valerate, co-administration of the CYP3A4 inducer rifampin resulted in a decrease in steady-state systemic exposure of dienogest by 83%.

Known CYP3A4 inhibitors like azole antifungals (e.g., ketoconazole, itraconazole, fluconazole), cimetidine, verapamil, macrolides (e.g., erythromycin, clarithromycin, roxithromycin), diltiazem, protease inhibitors (e.g., ritonavir, saquinavir, indinavir, nelfinavir), antidepressants (e.g., nefazodone, fluvoxamine, fluoxetine), and grapefruit juice may increase plasma levels of dienogest. In a study investigating the effect of CYP3A4 inhibitors (ketoconazole, erythromycin), steady-state dienogest serum levels were increased. Co-administration of the strong CYP3A4 inhibitor ketoconazole resulted in an increase in dienogest exposure of 183% and co-administration of the moderate inhibitor erythromycin resulted in an increase in dienogest exposure of 62%.

In a drug-drug interaction study it was shown that combined administration of estradiol valerate together with dienogest has no effect on the pharmacokinetics of estradiol valerate. In another drug-drug interaction study with dienogest in combination with ethinylestradiol and nifedipine, it was shown that the metabolism of nifedipine was not influenced by dienogest/ethinylestradiol. However, the AUC of the metabolite, dehydronifedipine, was decreased by about 25%. The reasons for these contradictory results are not clear. However, apart from this rather small effect on the pharmacokinetics of the nifedipine metabolite, there are no indications to modify the statement that dienogest does not affect the metabolism of other drugs at clinically relevant doses.
Special Populations

No studies were performed in patients with impaired renal function. No studies were performed in patients with impaired liver function. Visanne is contraindicated for patients with present or past severe hepatic disease. To date, no specific studies have been performed in children or adolescents.

3.3.3 Clinical Efficacy

In the original drug submission, clinical studies were submitted to support the use of Visanne for the treatment of pelvic endometriosis and associated pain. However, during the initial review, Health Canada decided that there was very little evidence to support the indication for treatment of endometriotic lesions. As a result, this part of the indication was removed and the indication was revised based on the data to support the efficacy of Visanne in the management of pelvic pain associated with endometriosis.

Three Phase III studies (Studies 307041, 307059, and 97085) assessed the use of Visanne for pelvic pain associated with endometriosis using a visual analog scale (VAS). Patients with a confirmed diagnosis of endometriosis assessed by laparoscopy or laparotomy prior to treatment were included. These studies included patients with all stages of disease severity based on the revised American Society for Reproductive Medicine classification systems.

Study 307041 was a multicentre, double-blind, placebo-controlled, randomized study where 198 patients with endometriosis were treated over a period of 3 months. An open-label extension to this placebo-controlled study included a total of 168 women to assess the long-term efficacy of continued Visanne treatment (Study 307059). In Study 307059, patients previously treated with either placebo or Visanne in Study 307041 received Visanne for an additional 52 weeks. The third pivotal study, Study 97085, assessed pelvic pain associated with endometriosis in a 6-month noninferiority study comparing Visanne and the gonadotropin releasing hormone (GnRH) analog, leuprolide acetate, in 248 patients with endometriosis. According to the protocol, only 90 Visanne-treated patients and 96 patients treated with leuprolide acetate were included in the per protocol set (PPS). Within the three pivotal studies, the longest treatment duration was 64 weeks with the recommended daily oral dosage of a single Visanne 2 mg tablet.

In Study 307041, the VAS for pelvic pain at 12 weeks of treatment compared to baseline showed a mean decrease of 27.4 mm in the Visanne group and of 15.1 mm in the placebo group, which reached statistical significance and indicates a clinically meaningful improvement of pain. Use of rescue medication was similarly low in both treatment groups. The results of the responder analysis and the VAS adjustment analysis were in clear support of the primary results, i.e., Visanne was more effective than placebo. The separate time course analyses of VAS and rescue medication through the study visits confirmed the progressive decline of VAS in favour of Visanne and the modest decrease of rescue medication. The analyses of the Biberoglu and Behrman (B&B) severity profile for symptoms and findings score showed favourable effects of Visanne on pelvic pain, dysmenorrhea, dyspareunia, and pelvic tenderness compared to placebo, whereas for induration there were basically no differences detected between Visanne and placebo. The SF-36 questionnaires and the Clinical Global Impression (CGI) questionnaire resulted in favourable effects for Visanne.

In Study 307059 (the open-label extension to Study 307041), a continuous improvement of mean VAS was observed up to a treatment duration of approximately 1 year. Afterwards, a low and stable level of pain was maintained up to the maximum observed treatment duration of 64 weeks.

In Study 97085, VAS at 24 weeks of treatment compared to baseline showed a mean decrease of 47.5 mm in the Visanne group and of 46 mm in the leuprolide acetate group. The difference between the two treatment groups amounted to -1.5 mm (95% confidence interval: -9.25, 6.25). Thus, non-inferiority of Visanne compared to leuprolide acetate was demonstrated based on the pre-defined margin of 15 mm. In both treatment groups, the number of women with symptoms or findings according to the B&B score and the intensity of these symptoms/findings markedly decreased over time in all items and scales assessed. This was particularly obvious in the average total symptoms and severity signs scores which improved from severe intensity at screening to mild intensity at the final visit. Relevant differences between the treatment groups were not observed.

The clinical study evaluating the efficacy of Visanne to reduce the size of endometriotic lesions did not conform to the criteria of a pivotal study. Therefore, this study was insufficient to support the indication of treatment of endometriosis (reduction of endometriotic lesions) and this indication was not approved. The study did not conform to the criteria of a pivotal study: the treatment follow-up was short in duration (24 weeks), the study had very few patients, there was no control group, and the dienogest formulation was not identical to Visanne.

3.3.4 Clinical Safety

Dienogest, the active ingredient of Visanne, has been extensively studied over many decades in Europe.

Based on nine clinical Phase II and Phase III studies to investigate the safety of Visanne for the treatment of endometriosis, more than 700 patients have been exposed to dienogest at daily doses of 2 mg or more. Data from these studies showed a favourable safety profile of Visanne, which is characterized by the absence of androgenic effects (no unfavourable effects on lipid metabolism) and only minor estrogen deficiency effects (some hot flushes, but much less than with GnRH analogues) without reduction in bone mineral density (BMD). No decrease in BMD was observed after 6 months of treatment, compared to a 4% reduction with leuprolide acetate. It was noted that 6 months was not sufficient to establish effects on BMD, but this was outweighed by the favourable safety profile compared to current treatment standards. Dienogest was also safe and well-tolerated at doses of 4 mg per day and 20 mg per day for 24 weeks.

In the pivotal studies, the most frequently reported adverse drug reactions (ADRs) during treatment with Visanne were headache (6.6%); breast discomfort (5.3%); nausea (3.6%); increased weight (3.6%); and depressed mood (3.0%). Like other progestins, treatment with Visanne may also cause irregular bleeding or spotting, however it may also shorten the duration of menstruation and improve dysmenorrhea. Of these ADRs, depression/depressive mood is of potential concern and is addressed in the Product Monograph.

Dienogest is also contained in the combined oral contraceptive Valette (dienogest 2 mg and ethinylestradiol 0.03 mg) and the hormone therapy replacement preparations Climodien/Lafamme 2/2 mg (estradiol valerate 2 mg and dienogest 2 mg) and Lafamme 1 mg/2 mg (estradiol valerate 1 mg and dienogest 2 mg) which have been extensively studied in Europe, and showed that dienogest is a safe and effective progestin for oral contraception and hormone therapy. In summary, Visanne appears to be safe and well-tolerated and can be used for the management of pelvic pain associated with endometriosis.

3.4 Benefit/Risk Assessment and Recommendation

3.4.1 Benefit/Risk Assessment

Efficacy of Visanne in the management of pelvic pain associated with endometriosis was based on clinical studies to demonstrate reduction of endometriosis-associated pelvic pain. Visanne showed efficacy on pain reduction that was superior to placebo and non-inferior to leuprolide acetate, a drug which can be considered the current standard of medical treatment for endometriosis. During continuous treatment with Visanne, low and stable pain levels were maintained throughout the treatment duration of up to 64 weeks, suggesting that patients benefit from long-term treatment. Their low pain levels were maintained for a period of up to 24 weeks after cessation of treatment.

In contrast to GnRH analogues which are currently considered the most effective medical treatment for endometriosis, Visanne does not induce a massive reduction but rather a moderate decrease of endogenous estrogen levels. As a consequence, unfavourable symptoms (hot flushes) and metabolic effects (BMD reduction) that are caused by low estrogen levels are less frequent and less severe with Visanne.

The ADRs seen during treatment with Visanne are mainly effects that are known from other progestins. Tolerability issues like breast discomfort and irregular bleeding will have to be considered by each patient and her physician against the achieved improvement of pain.

Breast exams were not performed using the preferred methodology. They were performed by palpation and not ultrasound. However, the available data and dienogest's mode of action does not give rise to any specific concerns at the level of the breast. Appropriate warnings for this drug class were applied to the labelling and Product Monograph.

Occurrence of depressive mood or depression will have to be carefully judged, in light of the high prevalence of this condition in endometriosis patients, by the treating physician.

In summary, the benefit of Visanne has been clearly demonstrated in patients seeking to manage pelvic pain associated with endometriosis. While some serious risks associated with progestin administration (such as decreased BMD, endometrial hyperplasia and breast cancer) cannot be entirely ruled out, the data to date show Visanne to compare favourably to current treatment standards, and overall, have a satisfactory safety profile.

3.4.2 Recommendation

Based on the Health Canada review of data on quality, safety and efficacy, Health Canada considers that the benefit/risk profile of Visanne is favourable for the management of pelvic pain associated with endometriosis. The 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.

4 Submission Milestones
Submission Milestone Date
Pre-submission meeting: 2008/11/27
Submission filed: 2009/08/21
Screening 1
Screening Deficiency Notice issued: 2009/10/07
Review 1
Quality Evaluation complete: 2010/07/14
Clinical Evaluation complete: 2010/07/27
Notice of Decision issued by Director General: 2010/07/30
Response filed: 2010/10/29
Screening 2
Screening Acceptance Letter issued: 2010/12/16
Review 2
Quality Evaluation complete: 2011/10/03
Clinical Evaluation complete: 2011/10/12
Labelling Review complete: 2011/10/12
Notice of Compliance issued by Director General: 2011/10/12