Evorel Conti 3,1 mg/3,2 mg Transdermal patch

Hormone replacement therapy (HRT) for the relief of menopausal symptoms (vasomotor symptoms such as hot flushes and atrophic vaginitis/vulvitis) for women with an intact uterus.

Posology
ADULTS: EVOREL CONTI should be applied twice weekly, without interruption to the trunk below the waist. EVOREL CONTI should not be continued for longer than 5 years. Should a patch fall off, it should be replaced immediately with a new patch. However, the usual day of changing patches should be maintained.
Special populations
LIVER OR KIDNEY FUNCTION IMPAIRMENT: Insufficient data are available to guide dose adjustments for patients with severe liver or kidney function impairment.
ELDERLY: Data are insufficient in regard to the use of EVOREL CONTI in the elderly (> 65 years old).
Method of administration
Transdermal use. Directions for use/handling: The EVOREL CONTI should be placed on a clean, dry, healthy, intact area of skin, on the trunk of the body below the waist. Creams, lotions or powders may interfere with the adhesive properties of the patch. The patch should not be applied on or near 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 patch may occur. The patch 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 patch. 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 patch onto the skin and to bring the patch to skin temperature at which the adhesive effect is optimised. The patient should avoid contact between fingers and the adhesive part of the patch during application. Should a patch fall off, a new patch should be applied immediately. However, the usual day of changing patches should be maintained. It is not necessary to remove the patch during bathing or showering. It is recommended, however, that the patch be removed prior to a sauna bath, and that a new patch is applied immediately thereafter. If a patch change is missed, the missed patch should be applied as soon as remembered. However, the usual day of changing patches should be maintained. Forgetting a dose may increase the likelihood of break through bleeding and spotting. To remove the EVOREL CONTI patch, peel away an edge of the patch and pull smoothly away from the skin. The patches should be disposed of in household waste (do not flush down the toilet). Any adhesive that remains on the skin after removal of EVOREL CONTI patch may be removed washing with soap and water or by rubbing it off with the fingers.

• Known hypersensitivity to estradiol, norethisterone acetate or any other component of this product listed in section 6.1.
• Known current or past or suspected breast cancer.
• Family history of breast cancer.
• Known or suspected estrogen dependent malignant tumours (e.g. endometrial cancer) or pre-malignant tumours (e.g. untreated atypical endometrial hyperplasia).
• Undiagnosed genital bleeding.
• Pregnancy and lactation (see section 4.6).
• Active liver disease or a history of liver disease as long as liver function tests have failed to return to normal.
• Previous or current venous thromboembolism (deep venous thrombosis, pulmonary embolism).
• Known thrombophilic conditions.
• Inherited thrombophilia.
• Active or past arterial thromboembolic disease (e.g. cerebrovascular accident, myocardial infarction).
• Porphyria.
• Patients known with inherited genetic mutations: BRCA 1 and BRCA 2 genes.
• Early menstrual periods (before age 12 years).
• History of non-cancerous breast diseases (atypical hyperplasia or lobular carcinoma in situ).
• Previous treatment using radiation therapy to the chest or breast.
• Previous treatment with diethylstilboestrol (DES).
• Depression not well controlled with treatment.
• A history of depression with the use of estrogen and/or progesterone/progestogen containing medicines irrespective of the indication, dosage formulation and route of administration.

Prior to commencing, and periodically during therapy, it is recommended that the patient be given a thorough physical and gynaecological examination. A complete medical and family history of thrombophlebitis or thromboembolic disorders should be taken. Repeated breakthrough bleeding, unexplained vaginal bleeding, and changes noticed during breast examination require further evaluation. A careful appraisal of the risk/benefit ratio should be undertaken before the initiation of treatment.

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 EVOREL CONTI, in particular:

• Leiomyoma (uterine fibroids) or endometriosis
• Risk factors for thromboembolic disorders (see below)
• Risk factors for estrogen dependent tumours, e.g. first degree relative with breast cancer
• Hypertension
• Liver disorders
• Diabetes mellitus
• Cholelithiasis
• Migraine or severe headache
• Systemic lupus erythematosus
• A history of endometrial hyperplasia (see below)
• Epilepsy
• Mastopathy.

Conditions which require monitoring while on EVOREL CONTI therapy: Estrogens such as in EVOREL CONTI may cause fluid retention. Cardiac or renal dysfunction should be carefully observed. Disturbances of liver function. History of cholestatic jaundice. Pre-existing hypertriglyceridaemia. Cases of large increases of plasma triglycerides leading to pancreatitis have been reported in this condition.

Reasons for immediate withdrawal of therapy: Therapy should be discontinued in case a contraindication is discovered and in the following situations:

• Jaundice or deterioration in liver function
• Increase in blood pressure
• New onset of migraine-type headache
• Pregnancy.

Breast cancer: EVOREL CONTI contains estrogen only which, on prolonged use, may increase the risk of developing breast cancer. A meta-analysis of prospective epidemiological studies from 1992 to 2018 reported a significant increase in the risk of developing breast cancer in 55 575 women 40 u2013 59 years of age who used menopausal hormone therapy (MHT). The risk increased steadily with duration of use and was slightly greater for estrogen-progestogen than estrogen only preparations, and the risk persisted for more than 10 years after stopping the treatment. The relative risk (RR) to develop breast cancer for estrogen-progestogen preparations was 1,60 at 1 u2013 4 years and RR = 2,08 at 5 u2013 14 years, while that for estrogen only preparations was 1,17 at 1 u2013 4 years and 1,33 at 5 u2013 14 years. There was no risk to develop breast cancer in women who started MHT at 60 years of age. All women on EVOREL CONTI should receive yearly breast examinations by a healthcare provider and perform monthly breast self-examinations. Mammography evaluations should be done on patient age, risk factors and prior mammogram results.

Combined estrogen progestogen therapy: The randomised placebo-controlled trial the Womenu2019s Health Initiative study (WHI), and epidemiological studies are consistent in finding an increased risk of breast cancer in women taking combined estrogen progestogen for HRT that becomes apparent after about 3 years.

Estrogen-only therapy: The WHI trial found no increase in the risk of breast cancer in hysterectomised women using estrogen-only HRT. 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 progestogen combined treatment, increases the density of mammographic images which may adversely affect the radiological detection of breast cancer.

Ovarian Cancer: Long term (at least 5 years) use of estrogen only HRT products in hysterectomised women has been associated with an increased risk of ovarian cancer in some epidemiological studies. Some studies including the WHI trial suggest that the long-term use of combined HRTs such as in EVOREL CONTI may also confer an increased risk.

Venous thromboembolism: Hormone replacement therapy (HRT) is associated with a higher relative risk of developing venous thromboembolism (VTE), such as deep vein thrombosis or pulmonary embolism. One randomised controlled trial and epidemiological studies found a two to threefold higher risk for users compared with non-users. Personal or a strong family history of recurrent thromboembolism or recurrent spontaneous abortions should be investigated in order to exclude a thrombophilic predisposition. Until a thorough evaluation of thrombophilic factors has been made or anticoagulant treatment is initiated, the use of EVOREL CONTI in such patients should be viewed as contraindicated. Those women already on anticoagulant treatment require careful consideration of the benefit risk of use of EVOREL CONTI. The risk of VTE may be temporarily increased with prolonged immobilisation, major trauma surgery. Scrupulous attention should be given to prophylactic measures to prevent VTE following surgery. Where prolonged immobilisation is liable to follow elective surgery EVOREL CONTI treatment should be discontinued four to six weeks, and earlier if possible ahead of surgery. Treatment should not be restarted until after the woman is completely mobilised. If VTE develops after initiating therapy, EVOREL CONTI should be discontinued. Patients should be told to contact their doctors immediately when they become aware of a potential thromboembolic symptom (e.g., painful swelling of a leg, sudden pain in the chest, dyspnoea).

Coronary artery disease (CAD): Estrogen only: Randomised controlled studies found no protective effect for the risk of CAD in hysterectomised women using estrogen only therapy for the risk of CAD. Combined estrogen progestogen therapy such as EVOREL CONTI: The relative risk of CAD during use of combined estrogen progestogen HRT is increased.

Stroke: There is an increased risk of stroke in healthy women during treatment with HRT. Combined estrogen progestogen and estrogen only therapy are associated with an increased risk of ischaemic stroke.

Dementia: HRT use does not improve cognitive function. There is evidence of increased risk of dementia in women using continuous combined such as EVOREL CONTI or estrogen-only HRT.

Depressed mood, depression and the risk of suicidality: Mood changes and depression are side effects reported with the use of hormonal containing products including EVOREL CONTI. There is some evidence that use of estrogen and/or progesterone/progestogen containing medicines may be associated with severe depression and a higher risk of suicidal thoughts/behavior (e.g. talking about suicide, withdrawing from social contact, having mood swings, being preoccupied with death or violence, feeling hopeless about a situation, increasing use of alcohol/drugs, doing self-destructive things, personality changes) and suicide. Prescribers should inform their patients to contact their doctor for advice if they experience mood changes and depression whilst on treatment with EVOREL CONTI.

EVOREL CONTI is not to be used as contraception. The EVOREL CONTI should be kept away from children.

Medicines which induce microsomal liver enzyme activity may alter estrogen and progestogen metabolism and reduce the therapeutic effect of EVOREL CONTI. Examples of such medicines are barbiturates, hydantoins, carbamazepine, meprobamate, phenylbutazone, rifampicin, rifabutin, bosentan and certain non nucleoside reverse transcriptase inhibitors (e.g. nevirapine and efavirenz) used in the treatment of HIV/AIDS infections. Ritonavir and nelfinavir, although known as strong inhibitors of the cytochrome P450 isoenzymes, by contrast exhibit inducing properties when used concomitantly with steroid hormones. Metabolism may be affected by St. Johnu2019s wort preparations (Hypericum perforatum), which induce certain cytochrome P450 isoenzymes in the liver (e.g. CYP 3A4) as well as P glycoprotein. The induction of the P450 isoenzymes may reduce plasma concentrations of the estrogen component of EVOREL CONTI possibly resulting in a decrease in therapeutic effects and increased vaginal bleeding. The induction of these same isoenzymes may also reduce circulating concentrations of the progestin component of EVOREL CONTI, which could result in a diminished protective effect against estrogen induced endometrial hyperplasia. Estrogen-containing oral contraceptives have been shown to significantly decrease plasma concentrations of lamotrigine when co administered due to induction of lamotrigine glucuronidation. This may reduce seizure control. Although the potential interaction between EVOREL CONTI therapy and lamotrigine has not been studied, it is expected that a similar interaction exists, which may lead to a reduction in seizure control among women taking both medicines together. Therefore, dosage adjustment of lamotrigine may be necessary.

Pregnancy
The use of EVOREL CONTI is contraindicated in pregnancy (see section 4.3). If pregnancy occurs during medication with EVOREL CONTI, treatment should be withdrawn immediately.
Breastfeeding
The use of EVOREL CONTI is contraindicated during lactation (see section 4.3).

No information available.

Tabulated summary of adverse reactions Clinical Trial Data The safety of EVOREL CONTI was evaluated in 196 subjects in 3 clinical trials (including 2 active-controlled trials and 1 single arm trial). Adverse drug reactions (ADRs) reported for u2265 1 % of EVOREL CONTI treated subjects are shown in Table 1.

Table 1. Adverse Drug Reactions Reported by u2265 1 % of EVOREL CONTI-treated Subjects in 3 Clinical Trials of EVOREL CONTI

ADRs reported by < 1 % of treated subjects (N=196) in the above clinical trial dataset are shown in Table 2.

Table 2. Adverse Drug Reactions Reported by < 1 % of treated Subjects in 3 Clinical Trials with an estradiol and norethisterone patch

Additional ADRs reported in clinical trials with an estradiol patch alone in postmenopausal women are shown in Table 3.

Table 3. Adverse Drug Reactions Reported by EVOREL treated Subjects in 15 Clinical Trials (N = 2 584) of EVOREL

* Solicited signs/symptoms (recorded as yes/no) in 8 clinical trials of EVOREL (N = 1 739).

Post marketing Data Table 4. Adverse Drug Reactions Identified During Post Marketing Experience with EVOREL CONTI

Infections and Infestations Candidiasis Neoplasms Benign, Malignant and Unspecified (Incl. Cysts and Polyps) Breast neoplasms, endometrial cancer Psychiatric Disorders Mood swings Severe depression with a higher risk of suicidal thoughts/behavior and suicide Nervous System Disorders Cerebrovascular accident, dizziness, migraine Vascular Disorders Deep vein thrombosis Respiratory, Thoracic and Mediastinal Disorders Pulmonary embolism Gastrointestinal Disorders Abdominal distension Hepatobiliary Disorders Cholelithiasis Skin and Subcutaneous Tissue Disorders Stevens-Johnson Syndrome Reproductive System and Breast Disorders Breast enlargement General Disorders and Administration Site Conditions Application site erythema, Application site pruritus, Application site rash Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Health care providers are asked to report any suspected adverse reactions to SAHPRA via the u201c6.04 Adverse Drug Reaction Reporting Formu201d, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8.

Symptoms of overdose of EVOREL CONTI therapy may include nausea, break-through bleeding, breast tenderness, abdominal cramps and/or bloating. These symptoms can be reversed by removing the EVOREL CONTI.