Evorel

1. NAME OF THE MEDICINAL PRODUCT

Evorel® 25 Patch, Evorel 50 Patch, Evorel 75 Patch and Evorel 100 Patch.

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Evorel 25: 1.6 mg estradiol/patch

Evorel 50: 3.2 mg estradiol/patch

Evorel 75: 4.8 mg estradiol/patch

Evorel 100: 6.4 mg estradiol/patch

3. PHARMACEUTICAL FORM

Evorel is a square shaped, transparent, self-adhesive transdermal delivery system (patch) of 0.2 mm thickness for application to the skin surface. It consists of a monolayered adhesive matrix throughout which 17 beta estradiol is uniformly distributed. The adhesive matrix is protected on the outside surface (from clothes etc) by a polyethylene teraphthalate backing foil, while the adhesive surface of the patch is covered by a polyester sheet (the release liner) which is removed before placing the patch on the body surface. This release liner has an S-shaped incision which facilitates easy removal from the patch.

Evorel is available in four sizes corresponding to four different concentrations:

Evorel 25 is marked 'CE25', has a surface area of 8 sq cm and contains 1.6 mg estradiol corresponding to a release rate of 25 micrograms of estradiol in 24 hours.
Evorel 50 is marked 'CE50', has a surface area of 16 sq cm and contains 3.2 mg estradiol corresponding to a release rate of 50 micrograms of estradiol in 24 hours.
Evorel 75 is marked 'CE75', has a surface area of 24 sq cm and contains 4.8 mg estradiol corresponding to a release rate of 75 micrograms of estradiol in 24 hours.
Evorel 100 is marked 'CE100', has a surface area of 32 sq cm and contains 6.4 mg estradiol corresponding to a release rate of 100 micrograms of estradiol in 24 hours.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Oestrogen replacement for the symptomatic relief of menopausal symptoms.

Evorel 50, 75 and 100 only:

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
Route of administration: transdermal.

Menopausal symptoms

Therapy should be started with one Evorel 50 patch (delivering 50 micrograms of estradiol/24 hours) and the dose adjusted after the first month if necessary depending on efficacy and signs of over-oestrogenisation (eg breast tenderness). For maintenance therapy the lowest effective dose should be used; a maximum dose of 100 micrograms of estradiol/24 hours should not be exceeded.

Evorel 50, 75 and 100 only:

Post menopausal osteoporosis

Evorel 50, 75 and 100 are recommended as an effective bone-sparing dose, with lower doses of estradiol slowing but not halting bone loss.

Evorel should be applied twice weekly on a continuous basis, each patch being renewed after 3 to 4 days and a fresh patch applied. Evorel should be applied to the skin as soon as it is removed from the wrapper. Recommended application sites are on clean, dry, healthy, intact skin and each application should be made to a slightly different area of skin on the trunk below waistline.Evorel should not be applied on or near the breasts. Evorel should remain in place during bathing and showering. Should it fall off during bathing or showering the patient should wait until cutaneous vasodilation ceases before applying a replacement patch to avoid potential excessive absorption. Should a patch fall off at other times it should be replaced immediately.

Patients can be advised to use baby oil to help remove any gum/glue which may remain on their skin after patch removal.

Unopposed oestrogen therapy is not recommended unless the patient has had hysterectomy. Where a progestogen is considered necessary, the appropriate dose should be administered for not less than 12 days each month.

Children:

Evorel is not indicated in children.

4.3 Contraindications

Known or suspected malignant tumours of the breast, genital tract or other oestrogen dependent neoplasia. Undiagnosed vaginal bleeding, known or suspected pregnancy and lactation, severe hepatic, renal or cardiac disease, Rotor syndrome or Dubin-Johnson syndrome, active thrombophlebitis, active deep venous thrombosis, thromboembolic disorders, or a history of confirmed venous thromboembolism, endometriosis, hypersensitivity to any of the excipients.

4.4 Special warnings and precautions for use

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.

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.

Administration of unopposed oestrogen therapy in patients with an intact uterus has been reported to increase the risk of endometrial hyperplasia. Repeated breakthrough bleeding should be investigated, including endometrial biopsy.

Close monitoring is recommended in patients with: epilepsy, diabetes or hypertension (as oestrogens may cause fluid retention), disturbances or impairment of liver function, mastopathy or a strong family history of breast cancer, fibrocystic disease, uterine fibromyomata, cholelithiasis, otosclerosis, multiple sclerosis, systemic lupus erythematosus, porphyria, melanoma, migraine and asthma, as these conditions may be worsened by oestrogen therapy.

Consideration should be given to discontinuing treatment at least four weeks prior to surgery or during periods of prolonged immobilisation. Also, if hypertension develops after initiating therapy, consider discontinuing Evorel while the cause is investigated.

Epidemiological studies have suggested that hormone replacement therapy (HRT) is associated with an increased relative risk of developing venous thromboembolism (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 thromboembolism develops after initiating therapy the drug should be discontinued.

Evorel is not to be used for contraception.

4.5 Interaction with other medicinal products and other forms of Interaction

Drugs which cause liver enzyme induction may alter oestrogen action. Examples of such drugs include barbiturates, hydantoins, carbamazepine, meprobamate, phenylbutazole and rifampicin. In transdermal administration of estradiol, a first pass effect via the liver is avoided.

There have been no reports of interaction with Evorel although the clinical exposure has been very limited.

4.6 Pregnancy and lactation

Evorel is contra-indicated in pregnancy and lactation.

4.7 Effects on ability to drive and use machines

In normal use, Evorel would not be expected to have any effect on the ability to drive or use machinery.

4.8 Undesirable effects

Although side effects are rare, minor effects which do not usually preclude continuation of therapy include headaches, nausea, breast tenderness and intermittent bleeding.

In clinical studies with Evorel (50 µg/24 hours) the following side effects were seen: breast tenderness (less than 2%), bleeding (less than 2%) and intermittent bleeding/spotting (less than 5%). None were serious, reflecting the known profile of oestrogen or oestrogen/progestogen therapy. Skin reactions were reported by less than 6% of patients over six treatment cycles. Rarely, dizziness, bloating, oedema, weight gain and leg cramps may occur.

4.9 Overdose

By virtue of the mode of administration of Evorel, overdosage is unlikely, but effects can if necessary be reversed by removal of the patch. The most commonly observed symptoms of overdose with oestrogen therapy are breast tenderness, nausea and breakthrough bleeding.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Estradiol is a naturally occurring oestrogenic hormone. It is formed in the ovarian follicles under the influence of the pituitary gland. In the female it stimulates the accessory reproductive organs and causes development of the secondary sexual changes in the endometrium during the first half of the menstrual cycle.

Estradiol is readily and completely absorbed from the gastro-intestinal tract and through the skin and mucous membranes. Metabolism is primarily in the liver. Excretion of the less active metabolites, primarily oestrone and oestriol is via the urine.

Evorel releases estradiol transdermally into the circulation in pre-menopausal physiological amounts.

In post-menopausal women, Evorel increased estradiol levels to early and mid-follicular phase levels. The transcutaneous route avoids the first pass hepatic effect seen with orally administered oestrogens.

In contrast with oral oestrogens, stimulation of hepatic protein synthesis is largely avoided with consequent lack of effect on circulating levels of renin substrate, thyroid binding globulin, sex hormone binding globulin and cortisol binding globulin. Similarly coagulation factors also appear to be unaffected (eg fibrinopeptide A etc). Transdermal estradiol does not affect circulating levels of renin.

Studies with Evorel have shown a significant decrease in hot flushes, improvement in Kupperman Index and vaginal cytology.

Local tolerance with Evorel has been very good. The adhesive matrix used has a low irritation index.

5.2 Pharmacokinetic properties

General characteristics: Oestrogens are in general readily absorbed from the gastro-intestinal tract, through the skin and mucous membranes. Absorption from the gastro-intestinal tract is prompt and complete. Transdermal absorption of oestrogens is sufficient to cause a systemic effect. Inactivation of oestrogens in the body is mainly in the liver and consequently the limited oral effectiveness of oestrogens is related to first pass hepatic metabolism and not to poor absorption. A certain proportion of oestrogen is excreted into the bile and then reabsorbed from the intestine. During the enterohepatic circulation, estradiol is readily oxidised to the less pharmacologically active oestrone which may in turn then be hydrated to form oestriol (also pharmacologically less than estradiol). Estradiol circulates in the blood in association with sex hormone-binding globulin and albumin.

Characteristics in patients: With Evorel, therapeutic serum estradiol levels are achieved approximately four hours after application to the skin. From 10 hours onwards, the serum levels remain stable and at early to mid-follicular levels throughout the duration of the application (3 to 4 days).

Twenty four hours following removal of the transdermal therapeutic system estradiol levels return to baseline.

5.3 Preclinical safety data

Not applicable.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipient(s)

Adhesive acrylic polymer (Duro-Tak 387-2287)

Guar gum (meyprogat 90)

Hostaphan MN19 (polyester film - removed before application)

6.2 Incompatibilities

None known.

6.3 Shelf-life

36 months for the product as packed for sale.

6.4 Special precautions for storage

Do not store above 25°C.

6.5 Nature and contents of container

Each Evorel patch size is presented in a sealed protective pouch. The pouches are packed in a cardboard carton.

6.6 Instructions for use and handling

None.

7. MARKETING AUTHORISATION HOLDER

Janssen-Cilag Ltd
Saunderton
High Wycombe
Buckinghamshire
HP14 4HJ
UK

8. MARKETING AUTHORISATION NUMBER(S)

Evorel 25 PL/0242/0293
Evorel 50 PL/0242/0223
Evorel 75 PL/0242/0294
Evorel 100 PL/0242/0295

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

1 November 1995

10. DATE OF REVISION OF THE TEXT

4 December 2003

Legal category POM


Home Forum Anti-Androgens Contraceptives Estrogens Progestins Testosterone Aerodiol Climaval Elleste Solo Estraderm TTS Estrofem Ethinylestradiol Hormonin Evorel Oestradiol Implant Oestrogel Premarin Progynova Zumenon	1. NAME OF THE MEDICINAL PRODUCT Evorel® 25 Patch, Evorel 50 Patch, Evorel 75 Patch and Evorel 100 Patch. 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Evorel 25: 1.6 mg estradiol/patch Evorel 50: 3.2 mg estradiol/patch Evorel 75: 4.8 mg estradiol/patch Evorel 100: 6.4 mg estradiol/patch 3. PHARMACEUTICAL FORM Evorel is a square shaped, transparent, self-adhesive transdermal delivery system (patch) of 0.2 mm thickness for application to the skin surface. It consists of a monolayered adhesive matrix throughout which 17 beta estradiol is uniformly distributed. The adhesive matrix is protected on the outside surface (from clothes etc) by a polyethylene teraphthalate backing foil, while the adhesive surface of the patch is covered by a polyester sheet (the release liner) which is removed before placing the patch on the body surface. This release liner has an S-shaped incision which facilitates easy removal from the patch. Evorel is available in four sizes corresponding to four different concentrations: Evorel 25 is marked 'CE25', has a surface area of 8 sq cm and contains 1.6 mg estradiol corresponding to a release rate of 25 micrograms of estradiol in 24 hours. Evorel 50 is marked 'CE50', has a surface area of 16 sq cm and contains 3.2 mg estradiol corresponding to a release rate of 50 micrograms of estradiol in 24 hours. Evorel 75 is marked 'CE75', has a surface area of 24 sq cm and contains 4.8 mg estradiol corresponding to a release rate of 75 micrograms of estradiol in 24 hours. Evorel 100 is marked 'CE100', has a surface area of 32 sq cm and contains 6.4 mg estradiol corresponding to a release rate of 100 micrograms of estradiol in 24 hours. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Oestrogen replacement for the symptomatic relief of menopausal symptoms. Evorel 50, 75 and 100 only: 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 Route of administration: transdermal. Menopausal symptoms Therapy should be started with one Evorel 50 patch (delivering 50 micrograms of estradiol/24 hours) and the dose adjusted after the first month if necessary depending on efficacy and signs of over-oestrogenisation (eg breast tenderness). For maintenance therapy the lowest effective dose should be used; a maximum dose of 100 micrograms of estradiol/24 hours should not be exceeded. Evorel 50, 75 and 100 only: Post menopausal osteoporosis Evorel 50, 75 and 100 are recommended as an effective bone-sparing dose, with lower doses of estradiol slowing but not halting bone loss. Evorel should be applied twice weekly on a continuous basis, each patch being renewed after 3 to 4 days and a fresh patch applied. Evorel should be applied to the skin as soon as it is removed from the wrapper. Recommended application sites are on clean, dry, healthy, intact skin and each application should be made to a slightly different area of skin on the trunk below waistline.Evorel should not be applied on or near the breasts. Evorel should remain in place during bathing and showering. Should it fall off during bathing or showering the patient should wait until cutaneous vasodilation ceases before applying a replacement patch to avoid potential excessive absorption. Should a patch fall off at other times it should be replaced immediately. Patients can be advised to use baby oil to help remove any gum/glue which may remain on their skin after patch removal. Unopposed oestrogen therapy is not recommended unless the patient has had hysterectomy. Where a progestogen is considered necessary, the appropriate dose should be administered for not less than 12 days each month. Children: Evorel is not indicated in children. 4.3 Contraindications Known or suspected malignant tumours of the breast, genital tract or other oestrogen dependent neoplasia. Undiagnosed vaginal bleeding, known or suspected pregnancy and lactation, severe hepatic, renal or cardiac disease, Rotor syndrome or Dubin-Johnson syndrome, active thrombophlebitis, active deep venous thrombosis, thromboembolic disorders, or a history of confirmed venous thromboembolism, endometriosis, hypersensitivity to any of the excipients. 4.4 Special warnings and precautions for use 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. 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. Administration of unopposed oestrogen therapy in patients with an intact uterus has been reported to increase the risk of endometrial hyperplasia. Repeated breakthrough bleeding should be investigated, including endometrial biopsy. Close monitoring is recommended in patients with: epilepsy, diabetes or hypertension (as oestrogens may cause fluid retention), disturbances or impairment of liver function, mastopathy or a strong family history of breast cancer, fibrocystic disease, uterine fibromyomata, cholelithiasis, otosclerosis, multiple sclerosis, systemic lupus erythematosus, porphyria, melanoma, migraine and asthma, as these conditions may be worsened by oestrogen therapy. Consideration should be given to discontinuing treatment at least four weeks prior to surgery or during periods of prolonged immobilisation. Also, if hypertension develops after initiating therapy, consider discontinuing Evorel while the cause is investigated. Epidemiological studies have suggested that hormone replacement therapy (HRT) is associated with an increased relative risk of developing venous thromboembolism (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 thromboembolism develops after initiating therapy the drug should be discontinued. Evorel is not to be used for contraception. 4.5 Interaction with other medicinal products and other forms of Interaction Drugs which cause liver enzyme induction may alter oestrogen action. Examples of such drugs include barbiturates, hydantoins, carbamazepine, meprobamate, phenylbutazole and rifampicin. In transdermal administration of estradiol, a first pass effect via the liver is avoided. There have been no reports of interaction with Evorel although the clinical exposure has been very limited. 4.6 Pregnancy and lactation Evorel is contra-indicated in pregnancy and lactation. 4.7 Effects on ability to drive and use machines In normal use, Evorel would not be expected to have any effect on the ability to drive or use machinery. 4.8 Undesirable effects Although side effects are rare, minor effects which do not usually preclude continuation of therapy include headaches, nausea, breast tenderness and intermittent bleeding. In clinical studies with Evorel (50 µg/24 hours) the following side effects were seen: breast tenderness (less than 2%), bleeding (less than 2%) and intermittent bleeding/spotting (less than 5%). None were serious, reflecting the known profile of oestrogen or oestrogen/progestogen therapy. Skin reactions were reported by less than 6% of patients over six treatment cycles. Rarely, dizziness, bloating, oedema, weight gain and leg cramps may occur. 4.9 Overdose By virtue of the mode of administration of Evorel, overdosage is unlikely, but effects can if necessary be reversed by removal of the patch. The most commonly observed symptoms of overdose with oestrogen therapy are breast tenderness, nausea and breakthrough bleeding. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Estradiol is a naturally occurring oestrogenic hormone. It is formed in the ovarian follicles under the influence of the pituitary gland. In the female it stimulates the accessory reproductive organs and causes development of the secondary sexual changes in the endometrium during the first half of the menstrual cycle. Estradiol is readily and completely absorbed from the gastro-intestinal tract and through the skin and mucous membranes. Metabolism is primarily in the liver. Excretion of the less active metabolites, primarily oestrone and oestriol is via the urine. Evorel releases estradiol transdermally into the circulation in pre-menopausal physiological amounts. In post-menopausal women, Evorel increased estradiol levels to early and mid-follicular phase levels. The transcutaneous route avoids the first pass hepatic effect seen with orally administered oestrogens. In contrast with oral oestrogens, stimulation of hepatic protein synthesis is largely avoided with consequent lack of effect on circulating levels of renin substrate, thyroid binding globulin, sex hormone binding globulin and cortisol binding globulin. Similarly coagulation factors also appear to be unaffected (eg fibrinopeptide A etc). Transdermal estradiol does not affect circulating levels of renin. Studies with Evorel have shown a significant decrease in hot flushes, improvement in Kupperman Index and vaginal cytology. Local tolerance with Evorel has been very good. The adhesive matrix used has a low irritation index. 5.2 Pharmacokinetic properties General characteristics: Oestrogens are in general readily absorbed from the gastro-intestinal tract, through the skin and mucous membranes. Absorption from the gastro-intestinal tract is prompt and complete. Transdermal absorption of oestrogens is sufficient to cause a systemic effect. Inactivation of oestrogens in the body is mainly in the liver and consequently the limited oral effectiveness of oestrogens is related to first pass hepatic metabolism and not to poor absorption. A certain proportion of oestrogen is excreted into the bile and then reabsorbed from the intestine. During the enterohepatic circulation, estradiol is readily oxidised to the less pharmacologically active oestrone which may in turn then be hydrated to form oestriol (also pharmacologically less than estradiol). Estradiol circulates in the blood in association with sex hormone-binding globulin and albumin. Characteristics in patients: With Evorel, therapeutic serum estradiol levels are achieved approximately four hours after application to the skin. From 10 hours onwards, the serum levels remain stable and at early to mid-follicular levels throughout the duration of the application (3 to 4 days). Twenty four hours following removal of the transdermal therapeutic system estradiol levels return to baseline. 5.3 Preclinical safety data Not applicable. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipient(s) Adhesive acrylic polymer (Duro-Tak 387-2287) Guar gum (meyprogat 90) Hostaphan MN19 (polyester film - removed before application) 6.2 Incompatibilities None known. 6.3 Shelf-life 36 months for the product as packed for sale. 6.4 Special precautions for storage Do not store above 25°C. 6.5 Nature and contents of container Each Evorel patch size is presented in a sealed protective pouch. The pouches are packed in a cardboard carton. 6.6 Instructions for use and handling None. 7. MARKETING AUTHORISATION HOLDER Janssen-Cilag Ltd Saunderton High Wycombe Buckinghamshire HP14 4HJ UK 8. MARKETING AUTHORISATION NUMBER(S) Evorel 25 PL/0242/0293 Evorel 50 PL/0242/0223 Evorel 75 PL/0242/0294 Evorel 100 PL/0242/0295 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 1 November 1995 10. DATE OF REVISION OF THE TEXT 4 December 2003 Legal category POM
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