EVOREL CONTI Patch Ref.[50563] Active ingredients: Estradiol Norethisterone

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 40-59 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 1-4 years and RR = 2,08 at 5-14 years, while that for estrogen only preparations was 1,17 at 1-4 years and 1,33 at 5-14 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 Women’s 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. John’s 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 activecontrolled trials and 1 single arm trial). Adverse drug reactions (ADRs) reported for ≥1% of EVOREL CONTI treated subjects are shown in Table 1.

Table 1. Adverse Drug Reactions Reported by ≥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:

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 “6.04 Adverse Drug Reaction Reporting Form”, found online under SAHPRA’s publications: https://www.sahpra.org.za/Publications/Index/8.

No data available.