SPC

Visanne®: Summary of Product Characteristics

(based on European approved Labelling 2009)

1. Name of the medicinal product

Visanne® 2 mg tablets.

2. Qualitative and quantitative composition

Each tablet contains 2 mg dienogest.
Excipient: each tablet contains 62.8 mg lactose monohydrate.
For a full list of excipients, see section 6.1 in the Chapter Summary of Product Characteristics.

3. Pharmaceutical form

Tablet
White to off-white, round, flat-faced, bevelled-edge tablets with an embossed ‘B’ on one side and a diameter of 7 mm.

4. Clinical particulars

4.1 Therapeutic indications

Treatment of endometriosis.

4.2 Posology and method of administration

Method of administration

For oral use.

Posology

The dosage of Visanne® is one tablet daily without any break, taken preferably at the same time each day with some liquid as needed. The tablet can be taken with or without food.
Tablets must be taken continuously without regard to vaginal bleeding. When a pack is finished the next one should be started without interruption.
There is no experience with Visanne® treatment >15 months in patients with endometriosis.
Treatment can be started on any day of the menstrual cycle.
Any hormonal contraception needs to be stopped prior to initiation of Visanne®. If contraception is required, non-hormonal methods of contraception should be used (e.g. barrier method).

Management of missed tablets:

The efficacy of Visanne® may be reduced in the event of missed tablets, vomiting and/or diarrhea (if occurring within 3–4 hours after tablet taking). In the event of one or more missed tablets, the woman should take one tablet only, as soon as she remembers, and should then continue the next day at her usual time. A tablet not absorbed due to vomiting or diarrhea should likewise be replaced by one tablet.

Additional information on special populations

Paediatric population

Visanne® is not indicated in children prior to menarche. The safety and efficacy of Visanne® in adolescents (menarche to 18 years) has not yet been established.

Geriatric population

There is no relevant indication for use of Visanne® in the geriatric population.

Patients with hepatic impairment

Visanne® is contraindicated in patients with present or past severe hepatic disease (see section 4.3 in the Chapter Summary of Product Characteristics).

Patients with renal impairment

There are no data suggesting the need for a dosage adjustment in patients with renal impairment.

4.3 Contraindications

Visanne® should not be used in the presence of any of the conditions listed below, which are partially derived from information on other progesteron-only preparations. Should any of the conditions appear during the use of Visanne®, treatment must be discontinued immediately:

  • Active venous thromboembolic disorder
  • Arterial and cardiovascular disease, past or present (e.g. myocardial infarction, cerebrovascular accident, ischemic 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 vaginal bleeding
  • Hypersensitivity to the active substance or to any of the excipients.

4.4 Special warnings and precautions for use

As Visanne® is a progestogen-only preparation it can be assumed that the special warnings and precautions for use of progestogen-only preparations are also valid for the use of Visanne®; although not all of the warnings and precautions are based on respective findings in the clinical studies with Visanne®.
If any of the conditions/risk factors mentioned below is present or deteriorates, an individual risk-benefit analysis should be done before treatment with Visanne® can be started or continued.

Serious uterine bleeding

Uterine bleeding, for example in women with adenomyosis uteri or uterine leiomyomata, may be aggravated with the use of Visanne®. If bleeding is heavy and continuous over time, this may lead to anemia (severe in some cases). In the event of anemia, discontinuation of Visanne ® should be considered.

Changes in bleeding pattern

The majority of patients treated with Visanne® experience changes in their menstrual bleeding pattern (see section 4.8 in the Chapter Summary of Product Characteristics).

Circulatory disorders

From epidemiological studies there is little evidence for an association between progestogenonly preparations and an increased risk of myocardial infarction or cerebral thromboembolism.
Rather, the risk of cardiovascular and cerebral events is related to increasing age, hypertension and smoking. In women with hypertension the risk of stroke may be slightly enhanced by progestogen-only preparations.
Although not statistically significant, some studies indicate that there may be a slightly increased risk of venous thromboembolism (VTE; deep venous thrombosis, pulmonary embolism) associated with the use of progestogen-only preparations. Generally recognized risk factors for VTE include a positive personal or family history (VTE in a sibling or a parent at a relatively early age), age, obesity, prolonged immobilisation, major surgery, or major trauma. In case of long-term immobilisation it is advisable to discontinue the use of Visanne® (in the case of elective surgery at least 4 weeks in advance) and not to resume treatment until 2 weeks after complete remobilisation.
The increased risk of thromboembolism in the puerperium must be considered.
Treatment should be stopped at once if there are symptoms of an arterial or venous thrombotic event or suspicion thereof.

Tumours

A meta-analysis from 54 epidemiological studies reported that there is a slightly increased relative risk (relative risk = 1.24) of having breast cancer diagnosed in women who are currently using oral contraceptives, mainly using estrogen-progestogen preparations. The excess risk gradually disappears during the course of the 10 years after cessation of COC use. Because breast cancer is rare in women under 40 years of age, the excess number of breast cancer diagnoses in current and recent COC users is small in relation to the overall risk of breast cancer. The risk of having breast cancer diagnosed in users of progestogenonly preparations is possibly of similar magnitude to that associated with COC. However, for progestogen-only preparations, the evidence is based on much smaller populations of users and so is less conclusive than that for COCs. These studies do not provide evidence for causation. The observed pattern of increased risk may be due to an earlier diagnosis of breast cancer in oral contraceptive users, the biological effects of oral contraceptives or a combination of both. The breast cancers diagnosed in users of oral contraceptives tend to be less advanced clinically than the cancers diagnosed in those who have never used oral contraceptives.
In rare cases, benign liver tumours, and even more rarely, malignant liver tumours have been reported in users of hormonal substances such as the one contained in Visanne®. In isolated cases, these tumours have led to life-threatening intra-abdominal haemorrhages.
A hepatic tumour should be considered in the differential diagnosis when severe upper abdominal pain, liver enlargement or signs of intra-abdominal haemorrhage occur in women taking Visanne®.

Osteoporosis

In patients who are at an increased risk of osteoporosis a careful risk-benefit assessment should be performed before starting Visanne® because endogenous estrogen levels are moderately decreased during treatment with Visanne® (see section 5.1 in the Chapter Summary of Product Characteristics).

Other conditions

Patients who have a history of depression should be carefully observed and the drug should be discontinued if the depression recurs to a serious degree.
Dienogest generally does not appear to affect blood pressure in normotensive women.
However, if a sustained clinically significant hypertension develops during the use of Visanne®, it is advisable to withdraw Visanne ® and treat the hypertension.
Recurrence of cholestatic jaundice and/or pruritus which occurred first during pregnancy or previous use of sex steroids necessitates the discontinuation of Visanne®.
Dienogest may have a slight effect on peripheral insulin resistance and glucose tolerance.
Diabetic women, especially those with a history of gestational diabetes mellitus, should be carefully observed while taking Visanne®.
Chloasma may occasionally occur, especially in women with a history of chloasma gravidarum. Women with a tendency to chloasma should avoid exposure to the sun or ultraviolet radiation whilst taking Visanne®.
Pregnancies that occur among users of progestogen-only preparations used for contraception are more likely to be ectopic than are pregnancies among users of COCs. Therefore, in women with a history of extrauterine pregnancy or an impairment of tube function, the use of Visanne® should be decided on only after carefully weighing the benefits against the risks.
Persistent ovarian follicles (often referred to as functional ovarian cysts) may occur during the use of Visanne®. Most of these follicles are asymptomatic, although some may be accompanied by pelvic pain.

Lactose

Each Visanne® tablet contains 62.8 mg of lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, lapp lactase deficiency, or glucose-galactose malabsorption who are on a lactose-free diet should consider the amount contained in Visanne®.

4.5 Interaction with other medicinal products and other forms of interaction

Effects of other medication on Visanne®

Individual enzyme-inducers or inhibitors (CYP3A4)

Progestogens including dienogest are metabolised mainly by the CYP3A4 system located both in the intestinal mucosa and in the liver. Therefore, inducers or inhibitors of CYP3A4 may affect the progestogen drug metabolism.
An increased clearance of sex hormones due to enzyme induction may reduce the therapeutic effect of Visanne® and may result in undesirable effects (e.g. changes in the uterine bleeding profile).
A reduced clearance of sex hormones due to enzyme inhibition may increase the exposure to dienogest and may result in undesirable effects.

Substances with enzyme-inducing properties

Interactions can occur with drugs (e.g. phenytoin, barbiturates, primidone, carbamazepine, rifampicin, and possibly also oxcarbazepine, topiramate, felbamate, griseofulvin, nevirapine and products containing St. John’s wort (Hypericum perforatum)) that induce microsomal enzymes (e.g. cytochrome P450 enzymes) which can result in increased clearance of sex hormones.
Maximum enzyme induction is generally not seen for 2–3 weeks but may then be sustained for at least 4 weeks after the cessation of therapy.
The effect of the CYP 3A4 inducer rifampicin was studied in healthy postmenopausal women.
Co-administration of rifampicin with estradiol valerate/dienogest tablets led to significant decreases in steady state concentrations and systemic exposures of dienogest and estradiol.
The systemic exposure of dienogest and estradiol at steady state, measured by AUC (0–24 hours) were decreased by 83% and 44%, respectively.

Substances with enzyme-inhibiting properties

Known CYP3A4 inhibitors such as azole antifungals (e.g. ketoconazole, itraconazole, fluconazole), cimetidine, verapamil, macrolides (e.g. erythromycin, clarithromycin and roxithromycin), diltiazem, protease inhibitors (e.g. ritonavir, saquinavir, indinavir, nelfinavir), antidepressants (e.g. nefazodone, fluvoxamine, fluoxetine), and grapefruit juice may increase plasma levels of progestogens and result in undesirable effects.
In a study investigating the effect of CYP3A4 inhibitors (ketoconazole, erythromycin) on the combination of estradiol valerate/dienogest, steady state dienogest plasma levels were increased. Co-administration with the strong inhibitor ketoconazole resulted in a 186% increase of AUC (0–24 hours) at steady state for dienogest. When co-administered with the moderate inhibitor erythromycin, the AUC (0–24 hours) of dienogest at steady state were increased by 62%.
The clinical relevance of these interactions is unknown.

Effects of dienogest on other medication

Based on in vitro inhibition studies, a clinically relevant interaction of dienogest with the cytochrome P450 enzyme mediated metabolism of other medication is unlikely.
Note: The prescribing information of concomitant medication should be consulted to identify potential interactions.

Interaction with food

A standardized high fat meal did not affect the bioavailability of Visanne®.

Laboratory tests

The use of progestogens may influence the results of certain laboratory tests, including biochemical parameters of liver, thyroid, adrenal and renal function, plasma levels of (carrier) proteins (e.g. corticosteroid binding globulin and lipid/lipoprotein fractions), parameters of carbohydrate metabolism and parameters of coagulation and fibrinolysis. Changes generally remain within the normal laboratory range.

4.6 Pregnancy and lactation

Pregnancy

There is limited data from the use of dienogest in pregnant women.
Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see Chapter 5.3 in the Summary of Product Characteristics).
Visanne® must not be administered to pregnant women because there is no need to treat endometriosis during pregnancy.

Lactation

Treatment with Visanne® during lactation is not recommended.
It is unknown whether dienogest is excreted in human milk. Data in animals have shown excretion of dienogest in rat milk.
A decision must be made whether to discontinue breast-feeding or to abstain from Visanne® therapy taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.

Fertility

Based on the available data, ovulation is inhibited in the majority of patients during treatment with Visanne®. However, Visanne® is not a contraceptive.
If contraception is required a non-hormonal method should be used (see section 4.2 in the Chapter Summary of Product Characteristics).
Based on available data, the menstrual cycle returns to normal within 2 months after cessation of treatment with Visanne®.

4.7 Effects on ability to drive and use machines

No effects on the ability to drive and use machines have been observed in users of products containing dienogest.

4.8 Undesirable effects

Undesirable effects are more common during the first months after the start of treatment with Visanne®, and subside with continued treatment. There may be changes in bleeding pattern, such as spotting, irregular bleeding or amenorrhea. The following undesirable effects have been reported in users of Visanne®.
The most frequently reported undesirable effects under treatment with Visanne® are headache (9.0%), breast discomfort (5.4%), depressed mood (5.1%), and acne (5.1%).
In addition, the majority of patients treated with Visanne® experience changes in their menstrual bleeding pattern. Menstrual bleeding patterns were assessed systematically using patient diaries and were analyzed using the WHO 90-days reference period method. During the first 90 days of treatment with Visanne® the following bleeding patterns were observed (n=290; 100%): amenorrhea (1.7%), infrequent bleeding (27.2%), frequent bleeding (13.4%), irregular bleeding (35.2%), prolonged bleeding (38.3%), normal bleeding, i.e. none of the previous categories (19.7%). During the fourth reference period the following bleeding patterns were observed (n=149; 100%): amenorrhea (28.2%), infrequent bleeding (24.2%), frequent bleeding (2.7%), irregular bleeding (21.5%), prolonged bleeding (4.0%), normal bleeding, i.e. none of the previous categories (22.8%). Changes in menstrual bleeding patterns were only occasionally reported as adverse event by the patients (see adverse event table).
The frequencies of adverse drug reactions (ADRs) by MedDRA system organ classes (MedDRA SOCs) reported with Visanne® are summarized in the table below. Within each frequency grouping, undesirable effects are presented in order of decreasing frequency.
Frequencies are defined as common (≥1/100 to <1/10) and uncommon (≥1/1,000 to <1/100). The frequencies are based on pooled data of four clinical trials, including 332 patients (100%).

Table 1: Adverse reactions table, phase III clinical trials, N=332

System Organ Class Common Uncommon
Blood and lymphatic
system disorders
  Anemia
Metabolism and
nutrition disorders
Weight increase Weight decrease
Increased appetite
Psychiatric disorders Depressed mood
Sleep disorder
Nervousness
Loss of libido
Altered mood
Anxiety
Depression
Mood swings
Nervous system
disorders
Headache
Migraine
Autonomic nervous system
imbalance
Disturbance in attention
Eye disorders   Dry eye
Ear and labyrinth
disorders
  Tinnitus
Cardiac disorders   Unspecific circulatory system disorder
Palpitations
Vascular disorders   Hypotension
Respiratory, thoracic and mediastinal disorders   Dyspnea
Gastrointestinal disorders Nausea
Abdominal pain
Flatulence
Abdominal distension
Vomiting
Diarrhea
Constipation
Abdominal discomfort
Gastrointestinal inflammation
Gingivitis
Skin and subcutaneous
tissue disorders
Acne
Alopecia
Dry skin
Hyperhidrosis
Pruritus
Hirsutism
Onychoclasis
Dandruff
Dermatitis
Abnormal hair growth
Photosensitivity reaction
pigmentation disorder
Musculoskeletal and connective tissue disorders Back pain Bone pain
Muscle spasms
Pain in extremities
Heaviness in extremities
Renal and urinary disorders   Urinary tract infection
Reproductive system and breast disorders Breast discomfort
Ovarian cyst
Hot flushes
Uterine/vaginal bleeding including spotting
Vaginal candidiasis
Vulvovaginal dryness
Genital discharge
Pelvic pain
Atrophic vulvovaginitis
Breast mass
Fibrocystic breast disease
Breast induration
General disorders and administration site conditions Asthenic conditions
Irritability
Edema

4.9 Overdose

Acute toxicity studies performed with dienogest did not indicate a risk of acute adverse effects in case of inadvertent intake of a multiple of the daily therapeutic dose. There is no specific antidote. A daily intake of 20–30 mg dienogest (10 to 15 times higher dose than in Visanne®) over 24 weeks of use was very well tolerated.

5. Pharmacological properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: progestogens; ATC code: G03D.

Dienogest is a nortestosterone derivative with no androgenic but rather an anti-androgenic activity of approximately one-third of that of cyproterone acetate. 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 progestogenic effect in vivo. Dienogest has no significant androgenic, mineralocorticoid or glucocorticoid activity in vivo.

Dienogest acts on endometriosis by reducing the endogenous production of oestradiol and thereby suppresses the trophic effects of estradiol on both the eutopic and ectopic endometrium. When given continuously, dienogest leads to a hypoestrogenic, hypergestagenic endocrine environment causing initial decidualization of endometrial tissue followed by atrophy of endometriotic lesions.

Data on efficacy

Superiority of Visanne® over placebo was demonstrated in a 3-month study including 198 patients with endometriosis. EAPP was measured on a VAS (0–100 mm). After 3 months of treatment with Visanne® a statistically significant difference compared to placebo (Δ = 12.3 mm; 95%CI: 6.4–18.1; P < 0.0001) and a clinically meaningful reduction of pain compared to baseline (mean reduction = 27.4 mm ± 22.9) were demonstrated.

After 3 months of treatment, reduction of EAPP by 50% or more without relevant increase of concomitant pain medication was achieved in 37.3% of patients on Visanne® (placebo: 19.8%); a reduction of EAPP by 75% or more without relevant increase of concomitant pain medication was achieved in 18.6% of patients on Visanne® (placebo: 7.3%).

The open-label extension to this placebo-controlled study suggested a continued improvement of EAPP for a treatment duration of up to 15 months.
The placebo controlled results were supported by the results obtained in a 6-month, active controlled study versus a GnRH agonist including 252 patients with endometriosis.
Three studies including a total of 252 patients who received a daily dose of 2 mg dienogest demonstrated a substantial reduction of endometriotic lesions after 6 months of treatment.
In a small study (n=8 per dose group), a daily dose of 1 mg dienogest has been shown to induce an anovulatory state after 1 month of treatment. Visanne ® has not been tested for contraceptive efficacy in larger studies.

Data on safety

Endogenous estrogen levels are moderately suppressed during treatment with Visanne®.
Currently, long-term data on BMD and risk of fractures in users of Visanne® are not available.
BMD was assessed in 21 patients before and after 6 months of treatment with Visanne® and there was no reduction of mean BMD. In 29 patients treated with LA, a mean reduction of 4.04% ± 4.84 was noted after the same period (between groups = 4.29%; 95%CI: 1.93–6.66; P<0.0003).
No significant changes of the mean values of standard laboratory parameters (including haematology, blood chemistry, liver enzymes, lipids, and HbA1C) were observed during treatment with Visanne® for up to 15 months (n=168).

5.2 Pharmacokinetic properties

Absorption

Orally administered dienogest is rapidly and almost completely absorbed. Peak serum concentrations of 47 ng/ml are reached at about 1.5 hours after single ingestion. Bioavailability is about 91%. The pharmacokinetics of dienogest are dose-proportional within the dose range of 1–8 mg.

Distribution

Dienogest is bound to serum albumin and does not bind to SHBG or corticoid binding globulin. 10% of the total serum drug concentration is present as free steroid, 90% is nonspecifically bound to albumin.
The apparent volume of distribution (Vd/F) of dienogest is 40 l.

Metabolism

Dienogest is completely metabolized by the known pathways of steroid metabolism, with the formation of endocrinologically mostly inactive metabolites. Based on in vitro and in vivo studies, CYP3A4 is the major enzyme involved in the metabolism of dienogest.
The metabolites are excreted very quickly so that in plasma unchanged dienogest is the dominating fraction.

The metabolic clearance rate from serum Cl/F is 64 ml/min.

Elimination

Dienogest serum levels decrease in two phases. The terminal disposition phase is characterized by a half-life of approximately 9–10 hours. Dienogest is excreted in form of metabolites which are excreted at a urinary to faecal ratio of about 3:1 after oral administration of 0.1 mg/ kg.

The half-life of urinary metabolites excretion is 14 hours. Following oral administration approximately 86% of the dose administered is eliminated within 6 days, the bulk of this amount excreted within the first 24 hours, mostly with the urine .

Steady-state conditions

Pharmacokinetics of dienogest are not influenced by SHBG levels. Following daily ingestion drug serum levels increase about 1.24-fold reaching steady-state conditions after 4 days of treatment. The pharmacokinetics of dienogest after repeated administration of Visanne® can be predicted from single dose pharmacokinetics.

Pharmacokinetics in special populations

Visanne® has not been studied specifically in renally impaired subjects.
Visanne® has not been studied in subjects with hepatic impairment.

5.3 Preclinical safety data

Preclinical data reveal no special risks for humans based on conventional studies of repeated dose toxicity, genotoxicity, carcinogenic potential and toxicity to reproduction. However, it should be borne in mind that sex steroids can promote the growth of certain hormonedependent tissues and tumours.

6. Pharmaceutical particulars

6.1 List of excipients

  • Crospovidone
  • Lactose monohydrate
  • Magnesium stearate
  • Microcrystalline cellulose
  • Potato starch
  • Povidone K 25
  • Talc

6.2 Incompatibilities

Not applicable

6.3 Shelf life

5 years.

6.4 Special precautions for storage

Store in the original packaging to protect from light.

6.5 Nature and contents of container

The tablets are contained in blister packs consisting of green transparent films made of polyvinyl chloride (PVC) and metallic foils made of aluminum (mat side hot sealable).
Pack sizes: 28, 84, and 168 tablets.
Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements

News

About Visanne®

Visanne® provides highly effective pain relief combined with a favourable safety and tolerability profile that allows for extended use in the treatment of endometriosis.

This section provides detailed information on the efficacy and safety profile of Visanne®, its ease of use and the extensive clinical trial program supporting the use of Visanne® in endometriosis.

About Visanne
 

This animation video will highlight the pharmacological properties and clinical profile of Visanne in the treatment of endometriosis.

Visanne Video