Nora-BE(Progesterone)

Treatment of infertility due to inadequate luteal phase.

For use during in-vitro fertilisation, where infertility is mainly due to tubal, idiopathic or endometriosis linked sterility associated with normal ovulatory cycles.

Nora-BE(Progesterone) is indicated for adjunctive use with estrogen in post-menopausal women with an intact uterus, as hormone replacement therapy (HRT).

Posology

Intravaginal application

Treatment of infertility due to inadequate luteal phase

One application (1.125g 8% gel) every day, starting after documented ovulation or arbitrarily on the 18^th - 21^st day of the cycle.

Use during in-vitro fertilisation

Daily application of Crinone 8% gel should be continued for 30 days if there is laboratory evidence of pregnancy.

Paediatric population

Not applicable

Older people

Not applicable

Method of Administration

Crinone is applied directly from the specially designed sealed applicator into the vagina. The applicator should be removed from the sealed wrapper. The twist-off cap should not be removed at this time.

1. The applicator should be gripped firmly by the thick end. It should be shaken down like a thermometer to ensure that the contents are at the thin end.

2. The tab should be twisted off and discarded.

3. The applicator may be inserted while patient is in a sitting position or when lying on her back with the knees bent. The thin end of applicator should be gently inserted well into the vagina.

4. The thick end of the applicator should be pressed firmly to deposit gel. The applicator should be removed and discarded in a waste container.

Posology

In women receiving estrogen replacement therapy there is an increased risk of endometrial cancer which can be countered by progesterone administration.

The recommended dose is 200 mg daily at bedtime, for twelve days in the last half of each therapeutic cycle (beginning on Day 15 of the cycle and ending on Day 26). Withdrawal bleeding may occur in the following week.

Alternatively 100 mg can be given at bedtime from Day 1 to Day 25 of each therapeutic cycle, withdrawal bleeding being less with this treatment schedule.

Paediatric population

There is no relevant use of Nora-BE(Progesterone) in the paediatric population.

Older people

As for adults

Method of Administration:

Oral

Nora-BE(Progesterone) 100mg Capsules should not be taken with food and should be taken at bedtime.

Concomitant food ingestion increases the bioavailability of micronized progesterone.

2. Undiagnosed vaginal bleeding

3. Known or suspected Nora-BE(Progesterone)-sensitive malignant tumours

4. Porphyria

5. Thrombophlebitis, thromboembolic disorder, cerebral apoplexy, or patients with an history of these conditions

6. Missed abortion

- Porphyria

- Cerebral haemorrhage

The pre-treatment physical examination should include special reference to breast and pelvic organs, as well as Papanicolaou smear.

Cautious use in severe hepatic insufficiency.

In cases of breakthrough bleeding, as in all cases of irregular vaginal bleeding, non-functional causes should be considered. In cases of undiagnosed vaginal bleeding, adequate diagnostic measures should be undertaken.

Crinone is not indicated in threatened abortion. Treatment should be discontinued in the event of a missed abortion.

The physician should be alert to the early manifestations of thrombotic disorders (thrombophlebitis, cerebrovascular disorder, pulmonary embolism and retinal thrombosis). Should any of these symptoms occur or be suspected, the drug should be discontinued immediately. Patients who have risk factors for thrombotic disorders should be kept under careful observation.

Although risk of thromboembolism has been associated with estrogens, a link with progestins remains questionable. Therefore, in women with generally recognised risk factors for thrombo-embolic events, such as personal or family history, treatment with Crinone may further increase the risk. In these women, the benefits of Crinone administration need to be weighed against the risks. It should be noted however, that pregnancy itself carries an increased risk of thrombo-embolic events.

Because progestogens may cause some degree of fluid retention, conditions that might be influenced by this factor (e.g, epilepsy, migraine, asthma, cardiac or renal dysfunction) require careful observation.

Patients who have a history of depression should be carefully observed and the drug discontinued if the depression recurs to a serious degree.

A decrease in glucose tolerance has been observed in a small number of patients on oestrogen- progestin combination drugs. The mechanism of this decrease is not known. For this reason, diabetic patients should be carefully observed while receiving progestin therapy.

The excipient sorbic acid may cause local skin reactions (e.g. contact dermatitis) or vaginal irritation.

Warnings:

- For the treatment of postmenopausal symptoms, HRT should only be initiated for symptoms that adversely affect quality of life. In all cases, a careful appraisal of the risks and benefits should be undertaken at least annually and HRT should only be continued as long as the benefit outweighs the risk.

- Evidence regarding the risks associated with HRT in the treatment of premature menopause is limited. Due to the low level of absolute risk in younger women, however, the balance of benefits and risks for these women may be more favourable than in older women.

Nora-BE(Progesterone) 100 mg Capsules are not suitable:

- in the treatment of premature labour, or

- as a contraceptive.

Precautions

Medical examination/follow-up

Before initiating or reinstituting HRT, a complete personal and family medical history should be taken. Physical (including pelvic and breast) examination should be guided by this and by the contraindications and warnings for use. During treatment, periodic check-ups are recommended of a frequency and nature adapted to the individual woman. Women should be advised what changes in their breasts should be reported to their doctor or nurse (see 'Breast cancer' below). Investigations, including appropriate imaging tools, e.g. mammography, should be carried out in accordance with currently accepted screening practices, modified to the clinical needs of the individual.

Conditions which need supervision

If any of the following conditions are present, have occurred previously, and/or have been aggravated during pregnancy or previous hormone treatment, the patient should be closely supervised. It should be taken into account that these conditions may recur or be aggravated during treatment with Nora-BE(Progesterone) 100 mg Capsules, in particular:

- Leiomyoma (uterine fibroids) or endometriosis

- Risk factors for thromboembolic disorders (see below)

- Risk factors for estrogen dependent tumours, e.g. 1st degree heredity for breast cancer

- Hypertension

- Liver disorders (e.g. liver adenoma)

- Diabetes mellitus with or without vascular involvement

- Cholelithiasis

- Migraine or (severe) headache

- Systemic lupus erythematosus.

- A history of endometrial hyperplasia (see below)

- Epilepsy

- Asthma

- Otosclerosis

- Fluid retention (e.g. cardiac disease, renal disease)

- Depression

- Photosensitivity

Reasons for immediate withdrawal of therapy

Therapy should be discontinued in case a contra-indication is discovered and in the following situations:

- Jaundice or deterioration in liver function

- Significant increase in blood pressure

- New onset of migraine-type headache

- Sudden or gradual, partial or complete loss of vision

- Proptosis or diplopia

- Papilloedema

- Retinal vascular lesions

Endometrial hyperplasia and carcinoma

In women with an intact uterus the risk of endometrial hyperplasia and carcinoma is increased when estrogens are administered alone for prolonged periods. The reported increase in endometrial cancer risk among estrogen-only users varies from 2-to 12-fold greater compared with non-users, depending on the duration of treatment and estrogen dose. After stopping treatment risk may remain elevated for at least 10 years.

The addition of progesterone for at least 12 days per month/28 day cycle or continuous combined estrogen-progestagen therapy in non-hysterectomised women prevents the excess risk associated with estrogen-only HRT.

Breakthrough bleeding and spotting may occur during the first months of treatment. If breakthrough bleeding persists, a lower dose of Nora-BE(Progesterone) for 25 days per cycle could be considered.

If breakthrough bleeding or spotting appears after some time on therapy, or continues after treatment has been discontinued, the reason should be investigated, which may include endometrial biopsy to exclude endometrial malignancy.

Breast cancer

The overall evidence suggests an increased risk of breast cancer in women taking combined estrogen-progestagen and possibly also estrogen-only HRT, that is dependent on the duration of taking HRT.

Combined estrogen-progestagen therapy

- The randomised placebo-controlled trial the (Women's Health Initiative study (WHI), and epidemiological studies are consistent in finding an increased risk of breast cancer in women taking combined estrogen-progestagen for HRT that becomes apparent after about 3 years.

The excess risk becomes apparent within a few years of use but returns to baseline within a few (at most five) years after stopping treatment.

HRT, especially estrogen-progestagen combined treatment, increases the density of mammographic images which may adversely affect the radiological detection of breast cancer.

Ovarian cancer

Ovarian cancer is much rarer than breast cancer. Long-term (at least 5-10 years) use of estrogen-only HRT products has been associated with a slightly increased risk of ovarian cancer. Some studies including the WHI trial suggest that the long-term use of combined HRTs may confer a similar, or slightly smaller, risk.

Venous thromboembolism

HRT is associated with a 1.3-3 fold risk of developing venous thromboembolism (VTE), i.e. deep vein thrombosis or pulmonary embolism. The occurrence of such an event is more likely in the first year of HRT than later.

Patients with known thrombophilic states have an increased risk of VTE and HRT may add to this risk. HRT is therefore contraindicated in these patients.

Generally recognised risk factors for VTE include, use of estrogens, older age, major surgery, prolonged immobilisation, obesity (BMI > 30 kg/m2), pregnancy/postpartum period, systemic lupus erythematosus (SLE), and cancer. There is no consensus about the possible role of varicose veins in VTE.

As in all postoperative patients, prophylactic measures need be considered to prevent VTE following surgery. If prolonged immobilisation is to follow elective surgery temporarily stopping HRT 4 to 6 weeks earlier is recommended. Treatment should not be restarted until the woman is completely mobilised.

In women with no personal history of VTE but with a first degree relative with a history of thrombosis at young age, screening may be offered after careful counselling regarding its limitations (only a proportion of thrombophilic defects are identified by screening).

If a thrombophilic defect is identified which segregates with thrombosis in family members or if the defect is 'severe' (e.g, antithrombin, protein S, or protein C deficiencies or a combination of defects) HRT is contraindicated.

Women already on chronic anticoagulant treatment require careful consideration of the benefit-risk of use of HRT.

If VTE develops after initiating therapy, the drug should be discontinued. Patients should be told to contact their doctors immediately when they are aware of a potential thromboembolic symptom (e.g. painful swelling of a leg, sudden pain in the chest, dyspnoea).

Coronary artery disease (CAD)

There is no evidence from randomised controlled trials of protection against myocardial infarction in women with or without existing CAD who received combined oestrogen-progestagen or oestrogen-only HRT.

Combined oestrogen-progestagen therapy

- The relative risk of CAD during use of combined oestrogen+progestagen HRT is slightly increased. As the baseline absolute risk of CAD is strongly dependent on age, the number of extra cases of CAD due to oestrogen+progestagen use is very low in healthy women close to menopause, but will rise with more advanced age.

Ischaemic stroke

Combined estrogen-progestagen and estrogen-only therapy are associated with an up to 1.5-fold increase in risk of ischaemic stroke. The relative risk does not change with age or time since menopause. However, as the baseline risk of stroke is strongly age-dependent, the overall risk of stroke in women who use HRT will increase with age.

Other conditions

HRT use does not improve cognitive function. There is some evidence of increased risk of probable dementia in women who start using continuous combined or estrogen-only HRT after the age of 65.

Drivers and users of machines are warned that risk of somnolence may occur.

Nora-BE(Progesterone) 100mg Capsules may cause drowsiness and/or dizziness in a minority of patients; therefore caution is advised in drivers and users of machines. Taking the capsules at bedtime should reduce these effects during the day.

The adverse reactions reported below are classified according to frequency of occurrence as follows:

Crinone is generally well-tolerated. In clinical studies, the following adverse events have been reported during Crinone therapy. Most adverse events observed in clinical studies cannot be distinguished from the symptoms common in early pregnancy.

Common

Headache, somnolence, abdominal pain, breast tenderness, itching or burning.

Post Marketing Reports

In addition, intermenstrual bleeding (spotting), vaginal irritation, hypersensitivity reactions usually manifesting as skin rash, and other mild application site reactions have been reported post-marketing.

Rare events of urticaria and pruritis were noted.

For adverse reactions identified during post-marketing surveillance, quantification of frequency has not been attempted, but it is most likely uncommon to very rare.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme at www.mhra.gov.uk/yellowcard.

The information given below is based on extensive post marketing experience, primarily from oral administration of progesterone.

Somnolence or transient dizziness may occur 1 to 3 hours after intake of the drug. Bedtime dosing and reduction of the dose may reduce these effects.

When used in conjunction with oestrogen, the following apply.

Breast cancer risk

An up to 2-fold increased risk of having breast cancer diagnosed is reported in women taking combined estrogen-progestagen therapy for more than 5 years.

Any increased risk in users of estrogen-only therapy is substantially lower than that seen in users of estrogen-progestagen combinations.

The level of risk is dependent on the duration of use.

Results of the largest randomised placebo-controlled trial (WHI-study) and largest epidemiological study (MWS) are presented.

Million Women study- Estimated additional risk of breast cancer after 5 years' use

US WHI studies - additional risk of breast cancer after 5 years' use

‡When the analysis was restricted to women who had not used HRT prior to the study there was no increased risk apparent during the first 5 years of treatment: after 5 years the risk was higher than in non-users.

2 *Taken from baseline incidence rates in developed countries

3 *WHI study in women with no uterus, which did not show an increase in risk of breast cancer

Endometrial cancer risk

Postmenopausal women with an uterus.

The endometrial cancer risk is about 5 in every 1000 women with an uterus not using HRT.

In women with a uterus, use of estrogen-only HRT is not recommended because it increases the risk of endometrial cancer.

Depending on the duration of estrogen-only use and estrogen dose, the increase in risk of endometrial cancer in epidemiology studies varied from between 5 and 55 extra cases diagnosed in every 1000 women between the ages of 50 and 65.

Adding progesterone to estrogen-only therapy for at least 12 days per cycle can prevent this increased risk. In the Million Women Study (MWS) the use of five years of combined (sequential or continuous) HRT did not increase risk of endometrial cancer (RR of 1.0 (0.8-1.2)).

Ovarian cancer

Long-term use of estrogen-only and combined estrogen-progestagen HRT has been associated with a slightly increased risk of ovarian cancer. In the Million Women Study 5 years of HRT resulted in 1 extra case per 2500 users.

Risk of venous thromboembolism

HRT is associated with a 1.3-3-fold increased relative risk of developing venous thromboembolism (VTE), i.e. deep vein thrombosis or pulmonary embolism. The occurrence of such an event is more likely in the first year of using HT. Results of the WHI studies are presented:

WHI Studies - Additional risk of VTE over 5 years' use

4 *Study in women with no uterus

Risk of coronary artery disease

The risk of coronary artery disease is slightly increased in users of combined estrogen-progestagen HRT over the age of 60.

Risk of ischaemic stroke

The use of estrogen-only and estrogen + progestagen therapy is associated with an up to 1.5 fold increased relative risk of ischaemic stroke.

WHI studies combined - Additional risk of ischaemic stroke*5 over 5 years' use

5*no differentiation was made between ischaemic and haemorrhagic stroke.

Other adverse reactions that have been reported in association with estrogen / progestagen treatment

- Rashes,

- Weight changes,

- Changes in libido,

- Skin and subcutaneous disorders: erythema multiforme, erythema nodosum, vascular purpura.

- Pyrexia,

- Insomnia,

- Alopecia,

- Hirsutism;

- Gall bladder disease.

- Probable dementia over the age of 65.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the website www.mhra.gov.uk/yellowcard.

Not applicable

Symptoms of overdosage may include somnolence, dizziness, euphoria or dysmenorrhoea. Treatment is observation and, if necessary, symptomatic and supportive measures should be provided.

Pharmacotherapeutic group: Sex hormones, ATC code: G03DA04

The pharmacological particulars of the product are those of the naturally occurring Nora-BE(Progesterone) with induction of a full secretory endometrium.

Pharmacotherapeutic group (ATC code: G03DA): Progestagens

Mechanism of action

Progesterone is a natural progestogen, the main hormone of the corpus luteum and the placenta. It acts on the endometrium by converting the proliferating phase to the secretory phase. Nora-BE(Progesterone) 100mg Capsules have all the properties of endogenous progesterone with induction of a full secretory endometrium and in particular gestagenic, antiestrogenic, slightly anti-androgenic and antialdosterone effects.

Clinical efficacy and safety

As estrogens promote the growth of the endometrium, unopposed estrogens increase the risk of endometrial hyperplasia and cancer. The addition of progesterone greatly reduces the estrogen-induced risk of endometrial hyperplasia in non-hysterectomised women.

The Nora-BE(Progesterone) vaginal gel is based on a polycarbophil delivery system which attaches to the vaginal mucosa and provides a prolonged release of Nora-BE(Progesterone) for at least three days.

Absorption

Micronised progesterone is absorbed by the digestive tract. Pharmacokinetic studies conducted in healthy volunteers have shown that after oral administration of 2 capsules (200mg), plasma progesterone levels increased to reach the Cmax of 13.8ng/ml +/- 2.9ng/ml in 2.2 +/- 1.4 hours. The elimination half-life observed was 16.8+/- 2.3 hours.

Distribution

Progesterone is approximately 96%-99% bound to serum proteins, primarily to serum albumin (50%-54%) and transcortin (43%-48%).

Elimination

Urinary elimination is observed for 95% in the form of glycuroconjugated metabolites, mainly 3 α, 5 β-pregnanediol (pregnandiol).

Biotransformation

Progesterone is metabolised primarily by the liver. The main plasma metabolites are 20 α hydroxy- ∆ 4 α- prenolone and 5 α-dihydroprogesterone. Some progesterone metabolites are excreted in the bile and these may be deconjugated and further metabolised in the gut via reduction, dehydroxylation and epimerisation. The main plasma and urinary metabolites are similar to those found during the physiological secretion of the corpus luteum.

Linearity/non-linearity

The pharmacokinetics of micronized progesterone is independent of the dose administered. Although there were some inter-individuals variations, the same individual pharmacokinetic characteristics were maintained over several months permitting appropriate individual adaptation of the posology and indicating predictable responses to the drug.

Older people

As per adults above

In rabbits, Crinone was an eye irritant categorised class IV (minimal effects clearing in less than 24 hours), but not a dermal irritant.

A moderate vaginal irritation was found in rabbits after application of 2.0 ml/day of 8% gel for 5 days.

Nonclinical data revealed no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction and development.

No incompatibilities were found with the usual contraceptive devices.

Not applicable.

No special requirements

Any unused product or waste material should be disposed of in accordance with local requirements.