AERODIOL 150 micrograms/dose, nasal spray solution.

Qualitative and Quantitative Composition

Each spray delivers 0.07 ml of solution which contains estradiol equivalent to 150 micrograms of estradiol hemihydrate.

Pharmaceutical Form

Nasal spray, solution.

Clinical Particulars

Therapeutic indications

Replacement therapy for oestrogen deficiency symptoms in post menopausal women. The experience of treating women older than 65 years is limited.

Posology and method of administration

Nasal Route

The usual recommended dose for the initiation of treatment is 300 µg (2 sprays) per 24 hours as a single dose, i.e. 1 spray in each nostril.

Dosing should preferably take place at the same time every day.

After 2 or 3 cycles the dosage may be adjusted in response to clinical symptoms:

• If symptoms of oestrogen deficiency persist: vasomotor disorders (hot flushes, night sweats), urogenital atrophy (vaginal dryness, dyspareunia, vulvovaginal atrophy) or central nervous system disorders (deep disorders, fatigue, depressive tendencies), the number of sprays may be increased to 3 or 4 per day (450 µg or 600 µg), in divided doses, morning and evening.
• In the event of signs of hyperoestrogenism such as breast tenderness, abdominal bloating, anxiety, nervousness or aggressiveness, the dosage should be reduced to 1 spray (150µg) daily.

In all cases, treatment should be continued at the lowest effective dosage.

AERODIOL may be administered as cyclical or continuous treatment.

Cyclical treatment

AERODIOL is used cyclically for a duration of 21 to 28 days, followed by a 2- to 7-day treatment-free period.

Continuous treatment

AERODIOL is administered daily without a break in treatment. Continuous (non-cyclical) treatment may be indicated in hysterectomised women and in cases where oestrogen deficiency symptoms occur during the treatment-free period.

Progestogen treatment must be combined with AERODIOL for non-hysterectomised women and cover at least 12 days per cycle to avoid oestrogen-induced endometrial hyperplasia.

Sequential progestogen treatment should be administered as follows:

• if AERODIOL is administered cyclically, a progestogen will be added to estradiol for at least the last 12 days of treatment. Thus, no hormones will be administered during the treatment-free period of the cycle.
• if AERODIOL is administered continuously, it is recommended to take a progestogen for at least 12 days each month.

In either case, withdrawal bleeding will usually occur when the progestogen is discontinued.

The risk/benefit ratio should be re-evaluated regularly (every 6 months) to adjust the treatment if needed:

• for the duration of treatment with AERODIOL
• when changing from another hormonal treatment to AERODIOL

Priming

Before it is first used, the bottle must be primed by firmly activating the pump 3 times.

The bottle should be held vertically during administration. The head is bent slightly forward and the nozzle introduced into each nostril in turn. Pressure is then exerted on the pump. The patient must not breathe in during spraying nor blow the nose immediately afterwards.

In the event of a severely blocked nose, AERODIOL may be administered temporarily via the oromucosal route by administration via the upper gingival sulcus. In such circumstances, the usual dosage should be doubled.

Patients with a runny nose should blow their nose before administration of AERODIOL.

3 Contra-indications
This medicinal product should not be prescribed in cases of

4.4 Special warnings and special precautions for use
Before initiating or reinstituting HRT, a complete medical and gynaecological examination (including family history) should be performed, taking into account contraindications and warnings for use. During treatment, periodic check-ups are recommended of a frequency and nature adapted to the individual woman. Follow up examination of the breasts and/or mammography should be carried out in accordance with current accepted practices for well women, modified according to the clinical needs of the individual.

A reanalysis 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 hormone replacement therapy (HRT). The findings may be due to earlier diagnosis, an actual effect of HRT or a combination of both. The probability of diagnosing breast cancer increased with duration of treatment and returned to normal in the course of five years after stopping HRT. Breast cancers diagnosed in current or recent users of HRT are less likely to have spread outside the breast than those found in non-users.

Between the ages of 50 and 70, about 45 women in every 1,000 not using HRT will have breast cancer diagnosed, the rate increasing with age. It is estimated that among those who use HRT for 5 to 15 years, depending on age of starting and duration of treatment, the number of additional cases of breast cancer diagnosed will be of the order of 2 to 12 cases per 1,000 women.

Epidemiological studies have suggested that HRT is associated with a higher relative risk of developing venous thromboembolism (VTE) i.e. deep vein thrombosis or pulmonary embolism. The studies find a 2-3 fold higher risk for users compared with non-users which for healthy women amounts to one to two additional cases of VTE in 10,000 patient-years of treatment with HRT. The occurrence of such an event is more likely in the first year of HRT than later.

Generally recognised risk factors for VTE include a personal or family history, severe obesity (Body Mass Index > 30kg/m2) and systemic lupus erythematosus (SLE). There is no consensus about the rote of varicose veins in VTE.

Use of HRT in patients with a history of recurrent VTE or known thrombophilic states already on anticoagulant treatment requires careful consideration of the benefit-risk of use of HRT. (see also "Contra-indications")

The presence of a personal or strong family history of recurrent thromboembolism or recurrent spontaneous abortion should be investigated in order to exclude a thrombophilic predisposition. Until a definitive diagnosis has been made or anticoagulant treatment initiated, use of HRT in such patients should be viewed as contra-indicated.

The risk of VTE may be temporarily increased with prolonged immobilisation; major trauma or major surgery. As in all post-operative patients, 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 four to six weeks earlier, if possible.

If venous thromboembolism develops or is suspected alter initiating therapy, the drug should be discontinued.

Patients should be told to contact their doctors immediately if they are aware of a potential thromboembolic symptom (e.g. painful swelling of a leg, sudden pain in the chest, dyspnoea).

The risk of endometrial cancer is increased when oestrogens are administered atone for prolonged periods. It is therefore essential to combine a progestogen for at least 12 days per cycle in non-hysterectomised women. When the higher doses of Aerodiol (450 or 600 micrograms/day) are used, a higher dose and/or a longer duration/cycle of the gestagen should be considered for endometrial protection.

If any of the following conditions are present, have occurred previously and/or have been aggravated during pregnancy or previous hormone treatment, the benefits of treatment should be weighed against the possible risks. In these cases the patient should be closely supervised. It should be taken into account that these conditions may, in rare cases, recur or be aggravated during treatment with AERODIOL.

A history of estrogen-dependent tumours

Changes in glucose tolerance have been observed in some patients on oestrogen/progestogen therapy. AERODIOL may improve insulin sensitivity and elimination. For good glycaemic control of diabetic patients, they should be monitored during the first months of therapy.

Oestrogens may cause fluid retention and, therefore, patients with cardiac or renal dysfunction should be carefully observed.

The use of oestrogen may influence the results of certain endocrine and liver function tests.

The indications for immediate withdrawal of therapy are:

4.5 Interactions with other medicinal products and other forms of interaction
Combinations requiring precautions for use:
Enzyme inducers:
Anticonvulsants (carbamazepine, felbamate, oxcarbazepine, phenobarbital, phenytoin, primidone, topiramate), barbiturates, griseofulvin, rifabutin, rifampicin: risk of lowered oestrogen efficacy.
Clinical monitoring and possible adjustment of oestrogen dosage should be made during and after treatment with the inducer.

Nasal corticosteroids and nasally administered vasoconstricting agents:
The effect of concomitant administration of nasal corticosteroids or nasal vasoconstricting agents has not been studied.
Aerodiol should not be administered immediately after nasal corticosteroids or nasal vasoconstricting agents.

4.6 Pregnancy and lactation
Pregnancy:
This medicinal product is not indicated during pregnancy.
Clinically, the results of many epidemiological studies to date rule out a risk of malformations due to oestrogens administered atone or in combination at the beginning of pregnancy.
If a woman discovers that she is pregnant whilst taking Aerodiol she should stop the medication immediately.

Lactation:
Not applicable.

4.7 Effects on the ability to drive and use machines
No effects on ability to drive and use machines have been observed.

4.8 Undesirable effects
The most frequently reported undesirable effects(>10%) during treatment with AERODIOL are symptoms at the application site: prickling-tingling sensation, sneezing and rhinorrhoea.
Other undesirable effects reported in users of AERODIOL or other non-oral estradiol preparations are listed in the table.

Exceptional cases of chloasma, erythema multiforme, erythema nodosum and hepatic adenoma have been reported in women using estrogens.
Venous thromboembolic disorders, i.e. deep leg or pelvic venous thrombosis and pulmonary embolism, is more frequent among HRT users than among non-users. For further information see sections 4.3 "Contra-indications" and 4.4 "Special warnings and special precautions for use".

4.9 Overdose
The route of administration makes significant acute overdose unlikely. The effects of overdose are generally breast tenderness, abdominal/pelvic bloating, nausea and aggressiveness.

5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties

ATC Classification: G03CA03
OESTROGENS (Genitourinary system and sex hormones)
The oestrogen component of Aerodiol is 17B-estradiol, identical to the endogenous human 17B-estradiol and classified as a natural oestrogen. 17B-estradiol substitutes for the deficiency of oestrogen production in menopausal women, alleviates menopausal symptoms and normalises the vaginal milieu. AERODIOL constitutes pulsed oestrogen therapy that provides a hormone exposure similar to that found during the early to mid follicular phases of the menstrual cycle.
Following application with AERODIOL via the nasal route, 17B-estradiol rapidly penetrates the tells and activates oestrogen specific receptors in the tell nucleus. Once activated, receptors bind to specific DNA sites inducing a cascade of reactions and protein synthesis over several hours (3 to 7 hours for the fast processes, 12 to 24 hours for the slow processes).
During treatment, due to the mechanism of action, the minimum FSH values are observed 6 to 8 hours post-dosing and a decrease is still present immediately before the next dose.
AERODIOL avoids intestinal and liver first pass effects in contrast to orally administered oestrogens. In a controlled study of 6 months duration, AERODIOL was shown not to induce an increase in triglycerides and had no effect on circulating angiotensinogen levels; a decrease in total cholesterol, lipoprotein (a), apolipoprotein B has been observed, with no change in HDL cholesterol.

5.2 Pharmacokinetic properties
When administered at a dose of 300 µg AERODIOL achieves peak serum estradiol levels around 1000 pg/mL,10 to 30 minutes post-dosing. 17B-estradiol (EZ) is rapidly distributed. Return to values close to baseline occurs within 12 hours of dosing.
The absolute bioavailability of estradiol when administered by the nasal route is around 25% and is higher than that following oral administration because AERODIOL avoids intestinal and liver first pass effects in contrast to orally administered oestrogens.
Hormone exposure, as expressed by the area under the curve of plasma estradiol concentration against time (AUC24h) is proportional to the dose. Following nasal administration of 300 µg, the AUC24h is similar to that obtained using other administration routes (patch delivering 50 µg/d, 2-mg tablet) but with a different kinetic profile (pulse).
In clinical trials, no case of non-absorption was observed.
E1 (Estrone)/E2 ratios are around 1. A 20% decrease in bioavailability of estradiol has been observed in heavy smokers (1 pack/day).
Cigarette smoking immediately before AERODIOL administration does not modify the nasal absorption of estradiol.

5.3 Preclinical safety data
Local tolerability studies in animals have shown that nasal administration of estradiol does not damage the nasal mucosa.

6. PHARMACEUTICAL PARTICULARS
6.1 List of Excipients
Methyl B-cyclodextrin (RAMER), sodium chloride, sodium hydroxide or hydrochloric
acid, purified water.

6.2 Incompatibilities
Not applicable.

6.3 Shelf Life
2 years.

6.4 Special precautions for storage
No special precautions for storage.

6.5 Nature and contents of container
4.2 ml (60 sprays) in a bottle (Type-1 glass) with a metering pump (polypropylene) and a nasal applicator (polypropylene); packs of 1 and 3 bottles.

6.6 Instructions for use/handling
No special requirements.

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