CLIMARA® - 50 & CLIMARA® - 100
Oestradiol transdermal systems
Presentation
A transdermal delivery system comprising a patch containing oestradiol in an acrylate adhesive matrix. The transdermal delivery from a patch is maintained over 7 days.
The active component of the system is oestradiol. The remaining components of the system are pharmacologically inactive.
Climara-50: 12.5 cm² patch containing 3.8 mg of oestradiol (equivalent to 3.9 mg oestradiol hemihydrate)
Climara-100: 25.0 cm² patch containing 7.6 mg of oestradiol (equivalent to 7.8 mg oestradiol hemihydrate)
Uses
Actions
The loss of the ovarian function, accompanied by a depletion of oestrogen production, leads to the menopausal syndrome, characterised by vasomotoric-vegetative and organic symptoms. Hormone replacement therapy has the aim to eliminate these complaints. Of all physiological oestrogens, oestradiol is the most potent one with the highest affinity to the oestrogen receptor. In the oestrogen sensitive target organs, in particular uterus, hypothalamus, pituitary, vagina, urethra, breast, bones (osteoclasts) oestradiol exerts its effects, as other steroid hormones, by regulating the transcription of a limited number of genes. After diffusion through the cell membrane, oestradiol binds with high affinity to the oestrogen receptor. After activation by the oestradiol ligand the hormone receptor complex is translocated into the nucleus, where it binds to specific DNA sequences (hormone response elements) that enhance the transcription of adjacent genes. The full number of proteins that is induced by oestrogen is not known but is estimated to be 50 to 100.
After the menopause the production of oestradiol in the female organism is substantially reduced. The remaining oestradiol is mainly synthesised from precursors produced in the adrenal cortex, by aromatisation from androstenedione and to a lesser extent from testosterone by the enzyme aromatase thus forming oestrone and oestradiol, respectively. Oestrone is converted into oestradiol via the enzyme 17-hydroxysteroid-dehydrogenase. Both enzymes have been found in the liver and in fat and muscle tissue. The oestradiol/oestrone ratio in postmenopausal women is approximately 0.2 compared to a ratio of >1 in premenopausal women.
Climacteric disturbances can be treated by oestrogen replacement therapy with mean transdermal doses between 50 and 100 mcg oestradiol per day.
Independent of the route of administration, oestrogen doses, which are necessary for improvement of menopausal complaints, exert a dose dependent stimulating effect on mitosis and proliferation of the endometrium. Oestrogen monotherapy increases the frequency of endometrial hyperplasia and thus the risk of endometrial carcinoma. In order to avoid endometrial hyperplasia the sequential administration of a progestin for 10 - 12 days is recommended in non-hysterectomised postmenopausal women.
Pharmacokinetics
The once-a-week application regimen of Climara patches is comparable to a continuous low dose intravenous infusion aiming at smooth, stable, plateau-like oestradiol serum levels similar to those during the early/mid follicular phase during the reproductive life span. Transdermal administration avoids highly fluctuating oestradiol and metabolite levels in the serum seen after oral oestradiol substitution and avoids also an inundation of the liver with large amounts of oestradiol and its metabolites due to a high presystemic metabolisation of the compound ("first-pass effect") after oral intake. Thus, after transdermal administration of oestradiol, no effects on liver protein synthesis have been observed.
During a once-a-week application regimen of Climara patches, smooth and consistent oestradiol and oestrone serum level profiles within the desired range are achieved. No accumulation of either substance is observed following multiple 1-week patch applications. The absolute height of the oestradiol serum level profile is directly proportional to the area of the patch with mean steady state oestradiol serum levels in the range of 35 pg/ml after application of the 12.5 cm² patch, and approximately 70 pg/ml after application of the 25 cm² patch.
Nominal average absorption rates of 50 mcg/day and 100 mcg/day were calculated for Climara-50 and Climara-100, respectively.
After transdermal administration, the metabolisation of oestradiol to oestrone and conjugates remains within the physiological range as seen during the early follicular phase in the reproductive life period, indicated by an oestradiol/oestrone serum level ratio of approximately 1. Unphysiological high oestrone levels as a result of the intensive "first pass" metabolisation during oral oestradiol hormone replacement therapy, reflected in oestradiol/oestrone ratios as low as 0.1 are avoided.
The biotransformation and the excretion of the transdermally administered oestradiol is the same as that of the endogenous hormone: Oestradiol is eliminated from the body with a total serum clearance of approximately 15 - 30 ml/min/kg by biotransformation mainly in the liver but also extrahepatically e.g. in gut, kidney, skeletal muscles and target organs. These processes involve the formation of oestrone, oestriol, catecholestrogens and sulphate and glucuronide conjugates of these compounds, which are all distinctly less oestrogenic or even nonoestrogenic. A certain proportion of oestradiol metabolites are excreted in the bile and undergo a so-called enterohepatic circulation. Ultimately oestradiol metabolites are mainly excreted as sulphates and glucuronides with the urine.
Indications
Oestrogen replacement therapy for patients with disorders due to natural menopause or surgically induced menopause (only if due to noncarcinomatous diseases) e.g. vasomotor symptoms (hot flushes, sweating), sleep disturbances, atrophic conditions caused by deficient endogenous oestrogen production.
Prevention of postmenopausal osteoporosis.
Dosage and Administration
Treatment to control postmenopausal symptoms should be initiated with Climara-50 patch. If considered necessary, a higher dose should be used. Once treatment is established the lowest effective dose necessary for the relief of symptoms should be used.
The treatment can be given without interruption or it can be interrupted for 1 week after every 3 weeks.
For prevention of osteoporosis: Treatment with Climara patches to prevent postmenopausal bone loss should be initiated as soon as possible after the menopause. Treatment should be based on individual considerations.
Unopposed oestrogen therapy should not be used unless the patient has had a hysterectomy. In all other cases the appropriate dose of a progestogen should normally be administered for 10 - 12 days in every month.
If a continuous treatment regimen has been chosen, the administration of a progestogen may be initiated at an arbitrarily selected time (e.g. at the beginning or at the end of a month) and should be repeated at regular intervals of about 4 weeks.
If a cyclical (3-week) treatment regimen has been chosen, the progestogen should be administered during the last 10 - 12 days of the cycle.
A menstruation-like bleeding normally occurs 2 - 3 days after the end of the period of progestogen administration.
Mode of application
Following removal of the protective liner the adhesive side of Climara patches should be placed on a clean, dry area of the skin of the trunk. Climara patches should not be applied to the breasts. The sites of application should be rotated, with an interval of at least one week between applications to a particular site. The area selected should not be oily, damaged, or irritated. The waistline should be avoided since tight clothing may rub the patch off. The patch should be applied immediately after opening the pouch and removing the protective liner. The patch should be pressed firmly in place with the palm of the hand for about 10 seconds, making sure there is good contact, especially around the edges.
The patch should be changed once weekly.
If the patch is applied correctly, the patient can bath or shower as usual. The patch might, however, become detached from the skin in very hot bath water or in the sauna.
In the event that a patch falls off, a new patch should be applied for the remainder of the 7-day dosing interval.
Contraindications
- pregnancy
- lactation
- suspected or existing tumour of the uterus, breast or ovaries
- endometriosis
- severe disturbances of liver function
- previous or existing liver tumours
- active deep venous thrombosis, thromboembolic disorders, or a documented history of these conditions
- severe diabetes with vascular changes
- sickle cell anaemia; disturbances of lipometabolism
- a history of herpes of pregnancy
- osteosclerosis with deterioration during pregnancy
- jaundice or persistent itching during a previous pregnancy.
Reasons for immediate discontinuation
- occurrence for the first time of migrainous headaches or more frequent occurrence of unusually severe headaches, sudden perceptual disorders (e.g. disturbances of vision or hearing)
- first signs of thrombophlebitis or thromboembolic symptoms (for example, unusual pains in or swelling of the legs, stabbing pains on breathing or coughing for no apparent reason)
- a feeling of pain and tightness in the chest
- onset of jaundice
- onset of hepatitis
- itching of the whole body
- increase in epileptic seizures
- significant rise in blood pressure
- pregnancy
Warnings and Precautions
Before starting Climara patches, a thorough general medical and gynaecological examination (including the breasts and a PAP SMEAR) should be carried out and pregnancy excluded. As a precaution, control examinations should be conducted at intervals of about 6 months during treatment.
Where applicable, contraception should be practised with non-hormonal methods (with the exception of the rhythm and temperature methods).
If irregular bleeding occurs repeatedly during the use of Climara patches or if the bleeding in the treatment-free weeks is unusually profuse, thorough differential-diagnostic clarification is essential.
If there are, repeatedly, persistent skin irritations (e.g. persistent erythema or pruritus at the application site) even if the application site is changed according to the directions one should consider cessation of transdermal treatment.
Epidemiological studies have suggested that hormone replacement therapy (HRT) may be associated with an increased relative risk of developing venous thromboembolism (VTE), i.e. deep venous thrombosis or pulmonary embolism. Risk/benefit should therefore be carefully weighed in consultation with the patient when prescribing HRT to women with a risk factor for VTE.
Generally recognised risk factors for VTE include a personal history, a family history (the occurrence of VTE in a direct relative at a relatively early age may indicate genetic disposition), and severe obesity. The risk of VTE also increases with age. There is no consensus about the possible role of varicose veins in VTE.
The risk of VTE may be temporarily increased with prolonged immobilisation, major elective or post-traumatic surgery, or major trauma. Depending on the nature of the event and the duration of the immobilisation, consideration should be given to a temporary discontinuation of HRT.
The benefit of treatment with oestrogen-containing preparations is undisputed. The prolonged use of oestrogens alone in the climacteric can induce hyperplasia of the endometrium and, in this connection, increase the risk of endometrial cancer. This risk can best be minimised by the additional administration of a progestogen (normally for 10 - 12 days per month). This generally leads to secretory conversion and shedding of the uterine lining and, as a result, to menstruation-like bleeding after the end of the period of progestogen treatment.
Close medical supervision is necessary in patients with diabetes, hypertension, varicose veins, otosclerosis, multiple sclerosis, epilepsy, porphyria, tetany, chorea minor, heart failure, and disturbances of kidney or liver function, migraine. Patients with fibrocystic disease of the breasts and patients with first-degree relatives who have had breast cancer also require close supervision. The same applies to patients with benign tumours of the uterine smooth muscles, since the size of such tumours can increase under oestrogen therapy.
A meta-analysis from 51 epidemiological studies reported that there is a modest increase in the risk of having breast cancer diagnosed in women who have use HRT for more than five years. The findings may be due to an earlier diagnosis, the biological effects of HRT, or a combination of both. The relative risk increases with duration of treatment (by 2.3% per year of use). This is comparable to the increased risk of breast cancer observed in women with every year of delay of natural menopause. The increased risk gradually disappears during the course of the first five years after cessation of HRT. Breast cancers found in women using HRT are more likely to localised to the breast than those found in non-users.
Regular breast examinations and, where appropriate, mammography should be carried out in women on HRT. Breast status should also be closely monitored in women with a history of, or known breast nodules or fibrocystic breast disease.
In rare cases, benign and in even rarer cases, malignant liver tumours leading in isolated cases to life-threatening intraabdominal haemorrhage have been observed after the use of hormonal substances such as the one contained in Climara patches. If severe upper abdominal complaints, liver enlargement or signs of intraabdominal haemorrhage occur, a liver tumour should be included in the differential-diagnostic considerations.
Pregnancy and Lactation
Climara patches are contraindicated during pregnancy and lactation.
Adverse Effects
The most commonly reported side effect was skin irritation at the application site.
The following additional side effects are possible:
- Genitourinary system - changes in uterine bleeding pattern, breakthrough bleeding and spotting, increase in size of uterine leiomyomata, alterations in the amount of cervical secretion
- Breasts - tenderness, enlargement
- Gastrointestinal - nausea, abdominal pain, bloating, cholestatic jaundice
- Skin - chloasma or melasma which may be persistent. In individual cases an allergic contact dermatitis, a post-inflammatory pruritus and a generalised exanthema may occur
- Central nervous system - headache, migraine, dizziness
- Miscellaneous - alteration in body weight, worsening of porphyria, edema, and changes in libido
Interactions
Drug interaction studies have been performed neither with the Climara patches nor with other oestradiol transdermal systems. It may be anticipated, as for other steroid hormones, that drugs, which induce microsomal liver enzymes such as antiepileptics or antibiotics, could reduce the systemic bioavailability of transdermal oestradiol. However, it is probable that the systemic bioavailability of transdermally applied oestradiol is less affected by such an interaction than that of orally applied oestrogens. The requirement for oral antidiabetics or insulin can change.
Overdosage
Overdosage is unlikely with this type of application. Overdosage may cause nausea and vomiting and withdrawal bleeding may occur in some women. There is no specific antidote. Treatment should be symptomatic and the patch should be removed.
Pharmaceutical Precautions
Shelf life: 3 years.
Special conditions for storage
Store below 30°C (86°F). Do not store unpouched. Apply immediately upon removal from the protective pouch.
Package Quantities
Packs containing 4 patches.
Further Information
In primary dermal irritation studies, application of Climara patches resulted in mild irritation related to mechanical trauma at removal. In sensitization studies, Climara patches had no dermal sensitizing potential.
The components of the adhesive matrix of Climara patches (monomer and polymer) have been studied extensively and, at many multiple of the projected human exposure present a low risk. Additional excipients used in the adhesive matrix are either generally regarded as safe for use in food components or considered acceptable as an inactive ingredient for prescription and topical transdermal products.
The adhesive backing and release liner of Climara patches were tested in biological test methods and were considered to be compatible with biologic systems.
Description: A protective pouch containing a Climara-50 patch with a surface area of 12.5 cm² or a Climara-100 patch with a surface area of 25 cm². The patches comprise two layers. From the visible surface to the surface attached to the skin these are: a translucent polyethylene film; a drug reservoir of oestradiol in an acrylate adhesive matrix; a protective liner of release-coated polyester film is attached to the adhesive surface and must be removed prior to use. The protective pouch contains a desiccant.
List of excipients
Ethyl oleate, isopropyl myristate, glycerol monolaurate.
Incompatibilities
None so far known.
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