1. Name Of The Medicinal Product
EVOREL® CONTI
EVOREL®SEQUI
2. Qualitative And Quantitative Composition
EVOREL CONTI and SEQUI are both Transdermal Delivery Systems (TDS).
EVOREL CONTI contains:
3.2 mg of estradiol hemihydrate
11.2 mg of norethisterone acetate
EVORELSEQUI consists of:
a) 4 EVOREL50 TDSs, each containing:
3.2 mg of estradiol hemihydrate
b) 4 EVORELCONTI TDSs, each containing:
3.2 mg of estradiol hemihydrate
11.2 mg of norethisterone acetate
3. Pharmaceutical Form
EVOREL 50, EVOREL CONTI and EVOREL SEQUI are Transdermal Delivery Systems (TDS), or transdermal patches, composed of a flat two
EVOREL CONTI has a surface area of 16 sq cm and contains 3.2 mg of estradiol corresponding to a nominal release of 50 micrograms of estradiol per 24 hours and 11.2 mg of norethisterone acetate corresponding to a nominal release of 170 micrograms of norethisterone acetate per 24 hours. Each TDS is marked in the centre of the lower margin on the outside of the backing film: CEN1.
EVOREL50 has a surface area of 16 sq cm and contains 3.2 mg of estradiol corresponding to a nominal release of 50 micrograms of estradiol per 24 hours. The release liner of EVOREL 50 is aluminised on one side. Each TDS is marked in the centre of the lower margin of the outside of the backing film: CE50.
4. Clinical Particulars
4.1 Therapeutic Indications
Hormone replacement therapy for the relief of menopausal symptoms.
Second line therapy for prevention of osteoporosis in postmenopausal women at high risk of future fractures who are intolerant of, or contraindicated for, other medicinal products approved for the prevention of osteoporosis.
4.2 Posology And Method Of Administration
Adults
Menopausal symptoms
EVOREL CONTI
EVOREL CONTI TDS should be applied individually without interruption.
Each EVOREL CONTI TDS should be applied twice weekly, every three to four days, to the trunk below the waist.
Insufficient data are available to guide dose adjustments for patients with severe liver or kidney function impairment.
EVOREL SEQUI
EVOREL SEQUI comprises four EVOREL 50 TDSs and four EVOREL CONTI TDSs.
EVOREL 50 and EVOREL CONTI should be applied individually in the following sequence: four EVOREL50 TDSs followed by four EVORELCONTI TDSs. This cycle should be repeated without interruption. TDSs should be applied twice weekly, every three to four days, to the trunk below the waist.
Insufficient data are available to guide dose adjustments for patients with severe liver or kidney function impairment.
It is important that the TDS be used in the correct sequence to ensure regular cyclic bleeding. Most patients will experience vaginal bleeding after the start of the progestogen therapy.
Post menopausal osteoporosis
Evorel Conti and Sequi are recommended as an effective bone-sparing dose, with lower doses of estradiol slowing but not halting bone loss.
Children
EVOREL CONTI and EVOREL SEQUI (EVOREL 50 and EVOREL CONTI) are not indicated in children.
Elderly
Data are insufficient in regard to the use of EVOREL CONTI and EVOREL SEQUI in the elderly >65 years old).
Administration
The sachet containing one TDS should be opened and one part of the protective foil removed at the SEVOREL CONTI and SEQUI should not be applied on or near the breasts.
Should a TDS fall off, it should be replaced immediately with a new equivalent EVOREL 50 or EVOREL CONTI TDS. However, the usual day of changing TDSs should be maintained.
4.3 Contraindications
• Hypersensitivity to any component of this product
• Known or suspected malignant tumours of the breast
• Genital tract or other oestrogen
• Undiagnosed vaginal bleeding
• Pregnancy or lactation
• Severe hepatic or renal disease
• Active thrombophlebitis
• Active deep venous thrombosis, thrombo-embolic disorders, or a history of confirmed venous thrombo-embolism
• Endometriosis
4.4 Special Warnings And Precautions For Use
Assessment of each woman prior to using hormone replacement therapy (and at regular intervals thereafter) should include a personal and family medical history. Physical examination should be guided by this and by the Contra-indications (Section 4.3) and Warnings (Section 4.4) for this product. During assessment of each individual woman clinical examination of the breasts and pelvic examination should be performed where clinically indicated rather than as a routine procedure. Women should be encouraged to participate in the national breast cancer screening programme (mammography) and the national cervical cancer screening programme (cervical cytology) as appropriate for their age. Breast awareness should also be encouraged and women advised to report any changes in their breasts to their doctor or nurse. Repeated breakthrough bleeding, unexplained vaginal bleeding and changes noticed during breast examination require further evaluation
A re-analysis of original data from 51 epidemiological studies reported a small or moderate increase in the probability of having breast cancer diagnosed in women currently or recently using HRT. The findings may be due to biological effects of HRT, earlier diagnosis, or a combination of both. The relative risk increased with duration of treatment (by 2.3% per year of use) and returned to normal in the course of five years after cessation of HRT use. This is comparable to the increase in relative risk when natural menopause is delayed in the absence of HRT. Breast cancers diagnosed in current or recent users of HRT are more likely to be localised to the breast than those found in non-users. HRT use may not be associated with increased mortality from breast cancer.
Between the ages of 50 and 70, about 45 women in every 1,000 not using HRT will have breast cancer diagnosed. It is estimated that among those who use HRT for 5 years starting at age 50, 2 extra cases of breast cancer will be detected by age 70 in every 1,000 women. For those who use HRT for 10 years, there will be 6 extra cases of breast cancer, and for 15 years use, 12 extra cases of breast cancer in every 1,000 women during the 20 year period until age 70.
It is important that the increased risk of being diagnosed with breast cancer is discussed with the patient and weighed against the known benefits of HRT.
Epidemiological studies have suggested that hormone replacement therapy (HRT) is associated with an increased relative risk of developing venous thrombo-embolism (VTE), ie deep vein thrombosis or pulmonary embolism. The studies find a 2-3 fold increase for users compared with non-users which for healthy women amounts to a low risk of one extra case of VTE each year for every 5,000 patients taking HRT.
Generally recognised risk factors for VTE include a personal or family history and severe obesity (body mass index>30 kg/m2). In women with these factors the benefits of treatment with HRT need to be carefully weighed against risks.
The risk of VTE may be temporarily increased with prolonged immobilisation, major trauma or major surgery. In women on HRT scrupulous attention should be given to prophylactic measures to prevent VTE following surgery. Where prolonged immobilisation is liable to follow elective surgery, particularly abdominal or orthopaedic surgery to the lower limbs, consideration should be given to temporarily stopping HRT 4 weeks earlier, if this is possible.
If venous thrombo-embolism develops after initiating therapy the drug should be discontinued.
Appropriate monitoring is recommended in patients with cardiac impairment, epilepsy, diabetes mellitus, hypertension, disturbances or impairment of liver or kidney function, mastopathy, a family history of breast cancer, or a history of cholestatic jaundice.
Administration of unopposed oestrogen in patients with an intact uterus has been reported to increase the risk of endometrial hyperplasia and of endometrial carcinoma. Therefore oestrogen in combination with continuous administration of a progestogen as in EVOREL CONTI, or with sequential administration of a progestogen as in EVOREL SEQUI, is recommended in women with an intact uterus in order to reduce the risk of hyperplasia or endometrial carcinoma.
EVOREL CONTI and EVOREL SEQUI are not to be used as contraception.
The TDSs should be kept away from children and pets.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
Drugs which induce microsomal liver enzyme activity may alter oestrogen and progestogen metabolism. Examples of such drugs are barbiturates, hydantoins, carbamazepine, meprobamate, phenylbutazone and rifampicin. On a theoretical basis, the effects of liver enzyme induction on the metabolism of transdermally administered estradiol and norethisterone acetate should be minimised by the avoidance of the first pass liver metabolism.
4.6 Pregnancy And Lactation
The use of EVOREL CONTI and EVOREL SEQUI is contra-indicated in pregnancy and lactation.
4.7 Effects On Ability To Drive And Use Machines
There are no known data on the effects of EVOREL CONTI and EVOREL SEQUI on the ability to drive or use machinery.
4.8 Undesirable Effects
The most commonly reported adverse events reported in clinical trials with EVOREL CONTI and EVOREL SEQUI include vaginal bleeding, spotting, breast tenderness, headache and abdominal cramps/bloating. These adverse events reflect the known profile of oestrogen or oestrogen/progestogen therapy.
Skin reactions reported include transient erythema and irritation with or without pruritus at the site of TDS application. Very rarely, contact dermatitis, reversible post-inflammatory pigmentation, generalised pruritus and exanthema occurred in studies with EVOREL50.
Rare adverse events reported in association with oral progestogen or oestrogen replacement therapy include: thrombo-embolic events, cholestasis, benign or malignant breast disease, uterine carcinoma, aggravation of epilepsy, liver adenoma and galactorrhoea. If such events occur, EVOREL CONTI and EVOREL SEQUI should be discontinued immediately.
4.9 Overdose
Symptoms of overdose of oestrogen and progestogen therapy may include nausea, break
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
EVOREL CONTI and EVOREL SEQUI belong to pharmacotherapeutic class G 03 F B 05, according to the ATC classification.
The active hormone of EVOREL CONTI and EVOREL SEQUI is 17β-estradiol, the biologically most potent oestrogen produced by the ovary. Its synthesis in the ovarian follicles is regulated by pituitary hormones. Like all steroid hormones, estradiol diffuses freely into target cells, where it binds to specific macromolecules (receptors). The estradiol-receptor complex then interacts with genomic DNA to alter transcriptional activity. This results in increases or decreases in protein synthesis and in changes of cellular functions.
Estradiol is secreted at different rates during the menstrual cycle. The endometrium is highly sensitive to estradiol, which regulates endometrial proliferation during the follicular phase of the cycle and together with progesterone, induces secretory changes during the luteal phase. Around the menopause estradiol secretion becomes irregular and eventually ceases altogether. The absence of estradiol is associated with menopausal symptoms such as vasomotor instability, sleep disturbances, depressive mood, signs of vulvovaginal and urogenital atrophy and with increased bone loss. In addition, there is growing evidence for an increased incidence in cardiovascular disease in the absence of oestrogen.
Oestrogen replacement therapy has been found effective in most postmenopausal women to compensate for the endogenous oestrogen depletion. It has been demonstrated that transdermal estradiol administration of 50 micrograms/day is effective in the treatment of menopausal symptoms and of postmenopausal bone loss.
In postmenopausal women, EVOREL CONTI and EVOREL SEQUI increases estradiol to early follicular levels, with a consequent significant decrease in hot flushes, improvement in Kupperman Index and beneficial changes in vaginal cytology.
However, there is substantial evidence that oestrogen replacement therapy is associated with an increase in endometrial cancer. There is also compelling evidence that adjunctive progestogen treatment protects against oestrogen-induced endometrial cancer. Therefore, women with a uterus should receive combination oestrogen-progestogen hormone replacement therapy.
Norethisterone acetate, used in EVOREL CONTI and EVOREL SEQUI, is rapidly hydrolysed to norethisterone, a synthetic 19-nortestosterone derivative of the 13-methyl gonane group, with potent progestational activity. Transdermal norethisterone acetate administration prevents oestrogen-related endometrial proliferation. Combined 17β-estradiol-norethisterone acetate therapy is effective in treating the deficits associated with menopause.
5.2 Pharmacokinetic Properties
Estradiol is readily absorbed from the gastro-intestinal tract but is extensively metabolised by the intestinal mucosa and the liver during the first hepatic passage. Transdermal delivery of estradiol is sufficient to cause a systemic effect.
Estradiol distributes widely in body tissues and is bound to albumin (~60-65%) and sex-hormone-binding globulin (~35-45%) in serum. Serum protein-binding fractions remain unaltered following transdermal delivery of estradiol. Estradiol is promptly eliminated from the systemic circulation. The elimination half
In a single and multiple application study in postmenopausal women, serum estradiol concentrations increased rapidly from pretreatment levels (~ 5 pg/ml) after application of an EVOREL CONTI TDS. At four hours after application, the mean serum estradiol concentration was ~19 pg/ml. A mean peak serum estradiol concentration of ~41 pg/ml above the pretreatment level was observed at about 23 hours following application. Serum estradiol concentrations remained elevated for the 3.5-day application period. Concentrations returned rapidly to pretreatment levels within 24 hours following removal of the TDS. A serum half-life of ~6.6 hours was determined following removal of the TDS, indicative of the skin depot effect. Multiple application of the EVOREL CONTI TDS resulted in little or no accumulation of estradiol in the systemic circulation. Higher circulating levels of estradiol were attained from EVOREL 50. Both formulations were shown to be effective in achieving serum estradiol concentration typically seen in premenopausal women.
Prior to treatment, the mean serum estradiol to estrone concentration ratio (E2/E1) was less than 0.3 in the postmenopausal women studied. During use of EVOREL CONTI TDS the E2/E1 ratios increased rapidly and were maintained at the physiological levels that approximated 1. The E2/E1 ratios returned to pretreatment levels within 24 hours after removal of the TDS. An average E2/E1 ratio that approximated 1 was also maintained over an entire 3.5-day application period following EVOREL 50 application.
Norethisterone acetate is rapidly hydrolysed to the active progestogen, norethisterone. After oral administration, norethisterone is subject to pronounced first-pass metabolism which reduces the bioavailability. Transdermal delivery of norethisterone acetate produces a sustained and effective level of norethisterone in the systemic circulation.
Norethisterone distributes widely in body tissues and is bound to albumin (~61%) and sex-hormone-binding globulin (~36%) in serum. The elimination half-life is ~6 to 12 hours following oral administration which is not altered following long-term therapy. Norethisterone is primarily metabolised in the liver by reduction of the α,β-unsaturated ketone structure in ring A of the molecule. Among the four possible stereoisomeric tetrahydrosteroids, the 5β-,3α-hydroxy-derivative appears to be the predominant metabolite. These compounds are primarily excreted in urine and faeces as sulphate and glucuronide conjugates.
In a single and multiple application study in postmenopausal women, serum norethisterone concentrations rose within 1 day after application of an EVOREL CONTI TDS to a mean steady-state level of ~199 pg/ml. Mean steady-state serum norethisterone concentrations ranging between ~141 to 224 pg/ml were maintained for the entire 3.5-day application period following multiple application. Mean concentrations declined rapidly to the lower limit of assay quantitation at 24 hours after removal of the TDS. A serum half-life of ~15 hours was determined following removal of the TDS, indicative of the skin depot effect. As expected from transdermal delivery of most drugs, only a transient and limited increase in serum norethisterone concentrations was observed following multiple application of the TDS.
5.3 Preclinical Safety Data
Estradiol is a naturally occurring hormone and norethisterone acetate is a synthetic derivative of 19-nortestosterone. The pharmacology and toxicology of estradiol and norethisterone acetate are well documented.
Additional toxicity studies which include local tolerance studies in rabbits and dermal sensitisation studies in guinea pigs have been conducted to support registration of EVOREL CONTI and EVOREL SEQUI. These studies indicate that the EVOREL CONTI TDS caused mild local skin irritation. It is recognised that test studies on rabbits over
6. Pharmaceutical Particulars
6.1 List Of Excipients
Adhesive: acrylate-vinylacetate copolymer (Duro-Tak 387-2287).
Guar gum.
Backing film: polyethylene terephthalate foil (Hostaphan MN19).
Release liner: siliconised polyethylene terephthalate foil, is removed before application.
6.2 Incompatibilities
No creams, lotions or powders should be applied to the skin area where the TDS is to be applied to prevent interference with the adhesive properties of EVOREL 50 TDS and EVOREL CONTI TDS.
6.3 Shelf Life
EVOREL CONTI and EVOREL SEQUI have a shelf
6.4 Special Precautions For Storage
Store at room temperature, at or below 25°C, within the original sachet and box.
Keep out of reach of children. This also applies to used and disposed TDSs.
6.5 Nature And Contents Of Container
EVOREL CONTI:
Each carton box has 8 or 24 TDSs in individual foil
− surlyn-ionomer film on the inside,
− then aluminium foil,
− then polyethylene film,
− with a layer of bleached reinforced paper on the outside.
Non-marketed pack sizes:
Cartons containing 2 TDSs in individual foil
EVOREL SEQUI:
Each carton box has 8 TDSs in individual foil
− surlyn-ionomer film on the inside,
− then aluminium foil,
− then polyethylene film,
− with a layer of bleached reinforced paper on the outside.
One EVOREL SEQUI box contains 4 EVOREL50 TDSs and 4 EVOREL CONTI TDSs.
6.6 Special Precautions For Disposal And Other Handling
The TDSs should be placed on a clean, dry area of skin on the trunk of the body below the waist. Creams, lotions or powders may interfere with the adhesive properties of the EVOREL CONTI and EVOREL SEQUI TDS. The TDS should not be applied on or near to the breasts. The area of application should be changed, with an interval of at least one week allowed between applications to a particular site. The skin area selected should not be damaged or irritated. The waistline should not be used because excessive rubbing of the TDS may occur.
The TDS should be used immediately after opening the sachet. Remove one part of the protecting foil. Apply the exposed part of adhesive to the application site from the edge to the middle; avoid wrinkling of the TDS. The second part of the protective foil should now be removed and the freshly exposed adhesive applied. Wrinkling should again be avoided and the palm of the hand used to press the TDS onto the skin and to bring the TDS to skin temperature at which the adhesive effect is optimised. Do not touch the adhesive part of the TDS.
When using EVORELSEQUI for the first two weeks, one of the EVOREL 50 TDSs should be applied and changed twice weekly. During the following two weeks of EVOREL SEQUI, one of the EVOREL CONTI TDSs should be applied, also to be changed twice weekly. The patient then starts again with a new box of EVOREL SEQUI.
To remove the EVOREL TDS, peel away an edge of the patch and pull smoothly away from the skin.
Any gum that remains on the skin after removal of EVOREL TDS may be removed by rubbing it off with the fingers, washing with soap and water or by using baby oil.
The EVOREL TDS should be disposed of in household waste (do not flush down the toilet).
7. Marketing Authorisation Holder
Janssen-Cilag Limited
Saunderton
High Wycombe
Buckinghamshire
HP14 4HJ
UK
8. Marketing Authorisation Number(S)
Evorel Conti: PL 0242/0319
Evorel Sequi: PL 0242/0320
9. Date Of First Authorisation/Renewal Of The Authorisation
Date of First Authorisation: 15 May 1997
10. Date Of Revision Of The Text
Evorel Conti: 4 December 2003
Evorel Sequi: 4 December 2003
Legal category POM
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