Premarin 0.3mg Coated Tablets

Premarin 0.625mg Coated Tablets

Premarin 1.25mg Coated Tablets

Tablets containing 0.3mg, 0.625mg or 1.25mg Conjugated Estrogens USP.

Coated Tablet

Premarin 0.3mg tablets are green oval biconvex, sugar-coated tablets marked with “0.3” in white ink.

Premarin 0.625mg tablets are maroon oval biconvex sugar-coated tablets marked with “ 0.625” in white ink.

Premarin 1.25mg tablets are yellow oval biconvex sugar-coated tablets marked with “1.25” in black ink.

Premarin 0.3mg, 0.625mg and 1.25mg:

- Hormone replacement therapy for estrogen deficiency symptoms in postmenopausal women.

Premarin 0.625mg and 1.25mg:

- 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.

Adults:

Premarin is an estrogen only HRT.

Treatment of Postmenopausal Symptoms

Premarin 0.3-1.25mg daily is the usual starting dose for women without a uterus. Continuous administration is recommended.

For initiation and continuation of treatment of postmenopausal symptoms, the lowest effective dose for the shortest duration (see also Section 4.4 Special warnings and precautions for use) should be used. Treatment to control menopausal symptoms should be initiated with Premarin 0.3mg. If symptoms are not adequately controlled, higher doses of Premarin may be prescribed. Once treatment is established the lowest effective dose necessary for the relief of symptoms should be used. Patients should be re-evaluated periodically to determine if treatment for symptoms is still necessary.

Treatment of osteoporosis

The minimum effective dose is 0.625mg daily for most patients. (See section 5.1 Pharmacodynamic properties).

Starting or Changing Treatment

In women who are not taking hormone replacement therapy or women who switch from a continuous combined hormone replacement therapy product, treatment may be started on any convenient day. In women transferring from a sequential hormone replacement therapy regimen, treatment should begin the day following completion of the prior regimen.

Concomitant progestogen use for women with a uterus

In women with a uterus, where the addition of a progestogen is necessary it should be added for at least 12-14 days every 28 day cycle to reduce the risk to the endometrium.

Unless there is a previous diagnosis of endometriosis, it is not recommended to add a progestogen in hysterectomised women.

The benefits of the lower risk of endometrial hyperplasia and endometrial cancer due to adding progestogen should be weighed against the increased risk of breast cancer (see sections 4.4 Special warnings and precautions for use and 4.8 Undesirable effects).

Forgotten tablet: If a tablet is forgotten, it should be taken as soon as the patient remembers, therapy should then be continued as before. If more than one tablet has been forgotten only the most recent tablet should be taken, the patient should not take double the usual dose to make up for missed tablets.

Missed pills may cause breakthrough bleeding in women with a uterus.

Elderly

There are no special dosage requirements for elderly patients, but as with all medicines, the lowest effective dose should be used.

Children

Not recommended.

1. Known, past or suspected breast cancer

2. Known or suspected estrogen-dependent malignant tumours (e.g. endometrial cancer)

3. Undiagnosed genital bleeding

4. Untreated endometrial hyperplasia

5. Previous or current venous thromboembolism (e.g. deep vein thrombosis, pulmonary embolism)

6. Known thrombophilic disorders (e.g. protein C, protein S, or antithrombin deficiency, see section 4.4)

7. Active or recent arterial thromboembolic disease (e.g. angina, myocardial infarction)

8. Acute liver disease or history of liver disease where the liver function tests have failed to return to normal

9. Known hypersensitivity to the active substances or to any of the excipients of Premarin tablets

10. Porphyria

For the treatment of postmenopausal symptoms, HRT should only be initiated for symptoms that adversely affect quality of life. In all cases, a careful appraisal of the risks and benefits should be undertaken at least annually and HRT should only be continued as long as the benefit outweighs the risk.

Evidence regarding the risks associated with HRT in the treatment of premature menopause is limited. Due to the low level of absolute risk in younger women, however, the balance of benefits and risks for these women may be more favourable than in older women.

1. Medical examination/Follow up

Before initiating or reinstituting HRT, a complete personal and family medical history should be taken. Physical (including pelvic and breast) examination should be guided by this and by the contraindications and warnings for use. During treatment, periodic check-ups are recommended of a frequency and nature adapted to the individual women. Women should be advised what changes in their breasts should be reported to their doctor or nurse (see 'Breast Cancer' below). Investigations, including appropriate imaging tools, e.g. mammography, should be carried out in accordance with currently accepted screening practices, modified to the clinical needs of the individual.

2. Conditions that 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 Premarin, in particular:

− Leiomyoma (uterine fibroids) or endometriosis

− Risk factors for thromboembolic disorders (see below)

− Risk factors for estrogen dependent tumours (e.g. first degree heredity for breast cancer)

− Hypertension

− Liver disorders (e.g. liver adenoma)

− Diabetes mellitus with or without vascular involvement

− Cholelithiasis

− Migraine or (severe) headaches

− Systemic lupus erythematosus (SLE)

− A history of endometrial hyperplasia (see below)

− Epilepsy

− Asthma

− Otosclerosis

3. Reasons for immediate withdrawal of therapy

Therapy should be discontinued if a contra-indication is discovered and in the following situations:

− Jaundice or deterioration in liver function

− Significant increase in blood pressure

− New onset of migraine-type headache

− Pregnancy

4. Endometrial Hyperplasia and Carcinoma

In women with an intact uterus the risk of endometrial hyperplasia and carcinoma is increased when estrogens are administered alone for prolonged periods. The reported increase in endometrial cancer risk among estrogen-only users varies from 2-to 12-fold greater compared with non-users, depending on the duration of treatment and estrogen dose (see section 4.8). After stopping treatment risk may remain elevated for at least 10 years.

The addition of a progestogen for at least 12 days per month/28 day cycle or continuous combined estrogen-progestagen therapy in non-hysterectomised women prevents the excess risk associated with estrogen-only HRT.

For oral doses of conjugated equine estrogens >0.625 mg the endometrial safety of added progestagens has not been demonstrated. The reduction in risk to the endometrium should be weighed against the increase in the risk of breast cancer of added progestogen (see 'Breast Cancer' below and section 4.8 Undesirable effects).

Breakthrough bleeding and spotting may occur during the first months of treatment. If breakthrough bleeding or spotting appears after some time on therapy, or continues after treatment has been discontinued, the reason should be investigated, which may include endometrial biopsy to exclude endometrial malignancy.

Unopposed estrogen stimulation may lead to pre-malignant or malignant transformation in the residual foci of endometriosis. Therefore, the addition of progestogens to estrogen replacement therapy should be considered in women who have undergone hysterectomy because of endometriosis, if they are known to have residual endometriosis (but see above).

5. Breast Cancer

The overall evidence suggests an increased risk of breast cancer in women taking combined estrogen-progestagen and possibly also estrogen-only HRT, that is dependent on the duration of taking HRT.

A randomised placebo-controlled trial, The Women's Health Initiative Study (WHI) found no increase in the risk of breast cancer in hysterectomised women using estrogen-only HRT. Observational studies have mostly reported a small increase in risk of having breast cancer diagnosed that is substantially lower than that found in users of estrogen-progestagen combinations (see Section 4.8 Undesirable effects).

For all HRT, an excess risk becomes apparent within a few years of use and increases with the duration of intake 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.

6. Ovarian Cancer

Ovarian cancer is much rarer than breast cancer. Long-term (at least 5-10 years) use of estrogen-only HRT products has been associated with an increased risk of ovarian cancer (see section 4.8). Some studies including the WHI trial suggest that the long-term use of combined HRTs may confer a similar, or slightly smaller, risk (see section 4.8).

7. Venous thromboembolism

Hormone replacement therapy (HRT) is associated with a 1.3-3 fold risk of developing venous thromboembolism (VTE) i.e. deep vein thrombosis or pulmonary embolism. The occurrence of such an event is more likely in the first year of HRT than later (see section 4.8).

Patients with a history of VTE or known thrombophilic states have an increased risk of VTE. HRT may add to this risk. HRT is therefore contraindicated in these patients (see section 4.3). Personal or strong family history of thromboembolism or recurrent spontaneous abortion should be investigated in order to exclude a thrombophilic predisposition.

Generally recognised risk factors for VTE include, use of estrogens, older age, major surgery, prolonged immobilisation, obesity (Body Mass Index >30kg/m²), pregnancy/postpartum period, systemic lupus erythematosus (SLE) and cancer. There is no consensus about the possible role of varicose veins in VTE.

As in all postoperative patients scrupulous attention should be given to prophylactic measures to prevent VTE following surgery. If prolonged immobilisation is liable to follow elective surgery, particularly abdominal or orthopaedic surgery to the lower limbs temporarily stopping HRT 4 to 6 weeks earlier is recommended. Treatment should not be restarted until the woman is completely mobilised.

In women with no personal history of VTE but with a first degree relative with a history of thrombosis at young age, screening may be offered after careful counselling regarding its limitations (only a proportion of thrombophilic defects are identified by screening). If a thrombophilic defect is identified which segregates with thrombosis in family members or if the defect is 'severe' (e.g, antithrombin, protein S, or protein C deficiencies or a combination of defects) HRT is contraindicated.

Women already on chronic anticoagulant treatment require careful consideration of the benefit-risk of use of HRT.

If VTE develops after initiating therapy, the drug should be discontinued. Patients should be told to contact their doctors immediately when they are aware of potential thromboembolic symptoms (e.g. painful swelling of a leg, sudden pain in the chest, dyspnoea).

8. Coronary Artery Disease (CAD)

There is no evidence from randomised controlled trials of protection against myocardial infarction in women with or without existing CAD who received combined estrogen-progestagen or estrogen-only HRT. Randomised controlled data found no increased risk of CAD in hysterectomised women using estrogen-only therapy.

9. Ischaemic Stroke

Combined estrogen-progestagen and estrogen-only therapy are associated with an up to 1.5-fold increase in risk of ischaemic stroke. The relative risk does not change with age or time since menopause. However, as the baseline risk of stroke is strongly age-dependent, the overall risk of stroke in women who use HRT will increase with age (see section 4.8).

Other Conditions

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

11. The use of estrogen may influence the laboratory results of certain endocrine tests and liver enzymes.

Estrogens increase thyroid binding globulin (TBG), leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI), T4 levels (by column or by radio-immunoassay) or T3 levels (by radio-immunoassay). T3 resin uptake is decreased, reflecting the elevated TBG. Free T4 and free T3 concentrations are unaltered.

Other binding proteins may be elevated in serum, i.e. corticoid binding globulin (CBG), sex-hormone-binding globulin (SHBG) leading to increased circulating corticosteroids and sex steroids, respectively. Free or biologically active hormone concentrations are unchanged. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-I-antitrypsin, ceruloplasmin).

Some patients dependent on thyroid hormone replacement therapy may require increased doses in order to maintain their free thyroid hormone levels in an acceptable range. Therefore, patients should have their thyroid function monitored more frequently when commencing concurrent treatment in order to maintain their free thyroid hormone levels in an acceptable range.

12. A worsening of glucose tolerance may occur in patients taking estrogens and therefore diabetic patients should be carefully observed while receiving hormone replacement therapy.

This product contains lactose and sucrose. Patients with rare hereditary problems of galactose intolerance, fructose intolerance, the Lapp lactase deficiency, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

13. There is an increase in the risk of gallbladder disease in women receiving HRT (see conditions that need supervision).

14. Women with pre-existing hypertriglyceridemia should be followed closely during estrogen replacement or hormone replacement therapy, since rare cases of large increases of plasma triglycerides leading to pancreatitis have been reported with estrogen therapy in this condition.

15. Estrogens should be used with caution in individuals with severe hypocalcaemia.

16. HRT use does not improve cognitive function. There is some evidence from the WHI trial of increased risk of probable dementia in women who start using continuous combined or estrogen-only HRT after the age of 65.

17. Exogenous estrogens may induce or exacerbate symptoms of angioedema, particularly in women with hereditary angioedema.

The metabolism of estrogens may be increased by concomitant use of substances known to induce drug-metabolising enzymes, specifically cytochrome P450 enzymes, such as anticonvulsants (e.g. phenobarbital, phenytoin, carbamazepine) and anti-infectives (e.g. rifampicin, rifabutin, nevirapine, efavirenz).

Ritonavir and nelfinavir, although known as strong inhibitors, by contrast exhibit inducing properties when used concomitantly with steroid hormones.

Herbal preparations containing St John's wort (Hypericum perforatum) may induce the metabolism of estrogens.

Clinically, an increased metabolism of estrogens and progestogens may lead to decreased effect and changes in the uterine bleeding profile.

The response to metyrapone may be reduced.

Premarin is not indicated during pregnancy.

For women with a uterus

If pregnancy occurs during medication with Premarin treatment should be withdrawn immediately. The results of most epidemiological studies to date relevant to inadvertent foetal exposure to estrogens indicate no teratogenic or foetotoxic effects.

Lactation:

Premarin is not indicated during lactation.

None known.

See also Section 4.4 Special warnings and special precautions for use.

Adverse drug reactions (ADRs)

The adverse reactions listed in the table are based on post-marketing spontaneous (reporting rate), clinical trials and class-effects.

Breast Cancer

• An up to 2-fold increased risk of having breast cancer diagnosed is reported in women taking combined estrogen-progestagen therapy for more than 5 years.

• Any increased risk in users of estrogen-only therapy is substantially lower than that seen in users of estrogen-progestagen combinations.

• The level of risk is dependent on the duration of use (see section 4.4).

• Results of the largest randomised placebo-controlled trial (WHI-study) and largest epidemiological study (MWS) are presented.

Million Women study– Estimated additional risk of breast cancer after 5 years' use

US WHI studies – additional risk of breast cancer after 5 years' use

‡When the analysis was restricted to women who had not used HRT prior to the study there was no increased risk apparent during the first 5 years of treatment: after 5 years the risk was higher than in non-users.

*Taken from baseline incidence rates in developed countries

**WHI study in women with no uterus, which did not show an increase in risk of breast cancer

Endometrial Cancer

Postmenopausal women with a uterus

The endometrial cancer risk is about 5 in every 1000 women with a uterus not using HRT.

In women with a uterus, use of estrogen-only HRT is not recommended because it increases the risk of endometrial cancer (see section 4.4).

Depending on the duration of estrogen-only use and estrogen dose, the increase in risk of endometrial cancer in epidemiology studies varied from between 5 and 55 extra cases diagnosed in every 1000 women between the ages of 50 and 65.

Adding a progestagen to estrogen-only therapy for at least 12 days per cycle can prevent this increased risk. In the Million Women Study the use of five years of combined (sequential or continuous) HRT did not increase risk of endometrial cancer (RR of 1.0 (0.8-1.2)).

Ovarian cancer

Long-term use of estrogen-only and combined estrogen-progestagen HRT has been associated with a slightly increased risk of ovarian cancer. In the Million Women Study 5 years of HRT resulted in 1 extra case per 2500 users.

Risk of venous thromboembolism

HRT is associated with a 1.3-3-fold increased relative risk of developing venous thromboembolism (VTE), i.e. deep vein thrombosis or pulmonary embolism. The occurrence of such an event is more likely in the first year of using HT (see section 4.4). Results of the WHI studies are presented:

WHI studies – Additional risk of VTE over 5 years' use

*Study in women with no uterus

Risk of coronary artery disease

• The risk of coronary artery disease is slightly increased in users of combined estrogen-progestagen HRT over the age of 60 (see section 4.4).

Risk of ischaemic stroke

• The use of estrogen-only and estrogen + progestagen therapy is associated with an up to 1.5 fold increased relative risk of ischaemic stroke. The risk of haemorrhagic stroke is not increased during use of HRT.

• This relative risk is not dependent on age or on duration of use, but as the baseline risk is strongly age-dependent, the overall risk of stroke in women who use HRT will increase with age, see section 4.4.

WHI studies combined - Additional risk of ischaemic stroke* over 5 years' use

*no differentiation was made between ischaemic and haemorrhagic stroke.

Other adverse reactions reported in association with estrogen/progestogen treatment including Premarin:

• Estrogen-dependent neoplasms benign and malignant, e.g. endometrial hyperplasia, endometrial cancer

• Venous thromboembolism, i.e. deep leg or pelvic venous thrombosis and pulmonary embolism, is more frequent among hormone replacement therapy users than among non-users. For further information, see section 4.3 Contraindications and 4.4 Special warnings and special precautions for use.

• Myocardial infarction

• Gallbladder disease

• Skin and subcutaneous disorders: erythema multiforme, erythema nodosum, vascular purpura

• Probable dementia (see section 4.4 Special warnings and special precautions for use)

• Exacerbation of otosclerosis

• Gynecomastia in males

Symptoms of overdosage of estrogen-containing products in adults and children may include nausea, vomiting, breast tenderness, dizziness, abdominal pain, drowsiness/ fatigue and withdrawal bleeding may occur in females. There is no specific antidote, and further treatment should be symptomatic.

ATC Code: G03C A57

Conjugated Estrogens

The active ingredients are primarily the sulphate esters of estrone, equilin sulphates, 17α-estradiol and 17β-estradiol. These substitute for the loss of estrogen production in menopausal women, and alleviate menopausal symptoms. Estrogens prevent bone loss following menopause or ovariectomy.

Relief of estrogen-deficiency symptoms

In a 1-year clinical trial (n=2,805), vasomotor symptoms were assessed for efficacy during the first 12 weeks of treatment in a subset of symptomatic women (n=241, 0.625mg n=27, 0.3mg n=30) who had at least 7 moderate or severe hot flushes daily or 50 moderate to severe hot flushes during the week before randomisation. Premarin 0.3mg and 0.625mg tablets were shown to be statistically better than placebo at weeks 4, 8 and 12 for relief of both frequency and severity of moderate to severe vasomotor symptoms.

The incidence of endometrial hyperplasia with Premarin, ie unopposed estrogen, at cycle 13 for 0.625mg (n=249) and 0.3mg (n=269) was assessed. The number of patients with hyperplasia was 20 (8.03%) for 0.625mg and 1 (0.37%) for 0.3mg.

Prevention of osteoporosis

At present there is no established screening programme for determining women at risk of developing osteoporotic fracture. Epidemiological studies suggest a number of individual risk factors which contribute to the development of postmenopausal osteoporosis. These include: early menopause; family history of osteoporosis; thin, small frame; cigarette use; recent prolonged systemic corticosteroid use.

Estrogen deficiency at menopause is associated with an increasing bone turnover and decline in bone mass. The effect of estrogens on the bone mineral density is dose-dependent. Protection appears to be effective for as long as treatment is continued. After discontinuation of HRT, bone mass is lost at a rate similar to that in untreated women.

Evidence from the WHI trial and meta-analysed trials shows that current use of HRT, alone or in combination with a progestogen – given to predominantly healthy women – reduces the risk of hip, vertebral and other osteoporotic fractures. HRT may also help prevent fractures in women with low bone density and/or established osteoporosis, but the evidence for that is limited.

In the HOPE study, prevention of bone loss was assessed by measurement of bone mineral density (BMD), at the final on-therapy evaluation (cycle 26 or the last available evaluation for those who discontinued early), primarily at the anteroposterior lumbar spine (L₂ to L₄ BMD). Secondarily, BMD measurements of the total body, femoral neck and trochanter were analysed.

The mean increase in anteroposterior lumbar spine bone mineral density (L₂ to L₄ BMD) after 2 years treatment was 2.46% ± 0.37 with Premarin 0.625mg.

Premarin also has an effect of the other BMD parameters. The mean increase in total femoral neck BMD was 1.82% ± 0.45 with Premarin 0.625mg. The mean increase in femoral trochanter BMD was 3.82% ± 0.58 with Premarin 0.625mg.

Absorption

Conjugated estrogens are soluble in water and are well absorbed from the gastrointestinal tract after release from the drug formulation. The Premarin tablets release conjugated estrogens slowly over several hours. The pharmacodynamic profile of unconjugated and conjugated estrogens following doses of 3 x 0.3mg and 2 x 0.625mg are provided in Table 1.

Distribution

The distribution of exogenous estrogen is similar to that of endogenous estrogens. Estrogens are widely distributed in the body and are generally found in higher concentrations in the sex hormone target organs. Estrogens circulate in the blood largely bound to sex hormone binding globulin (SHBG) and albumin.

Metabolism

Exogenous estrogens are metabolised in the same manner as endogenous estrogens. Circulating estrogens exist in dynamic equilibrium of metabolic interconversions. These transformations take place mainly in the liver. Estradiol is converted reversibly to estrone, and both can be converted to estriol, which is the major urinary metabolite. Estrogens also undergo enterohepatic recirculation via sulphate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the gut following reabsorption. In post-menopausal women a significant proportion of the circulating estrogens exists as sulphate conjugates, especially estrone sulphate, which serves as a circulating reservoir for the formation of more active estrogens.

Excretion

Estriol, estrone and estradiol are excreted in the urine along with glucuronide and sulphate conjugates.

Table 1 – Pharmacokinetic parameters for Premarin

Pharmacokinetic profile for unconjugated estrogens following a dose of 3 x 0.3mg or 2 x 0.625mg

Pharmacokinetic profile for conjugated estrogens following a dose of 3 x 0.3mg or 2 x 0.625mg

* t_1/2 = terminal-phase disposition half-life (0.693/γ)

Long-term continuous administration of natural and synthetic estrogens in certain animal species increases the frequency of carcinomas of the breast, cervix, vagina and liver.

Premarin 0.3mg:

Calcium sulphate anhydrous

Carnauba wax

Microcrystalline cellulose

Glyceryl mono-oleates

Lactose monohydrate

Magnesium stearate

Methylcellulose

Macrogol

Shellac solution (pharmaceutical glaze)

Sucrose

Titanium dioxide (E171)

Stearic acid

Edible ink (Opacode S-828905)†

Opalux Green AS-R-11501‡

†contains titanium dioxide (E171), purified water, shellac, ethanol, N-butly alcohol, propylene glycol, ammonia solution and ethyl acetate.

‡ contains sucrose, yellow iron oxide (172), indigo carmine aluminium lake (E172), titanium dioxide, polyvinyl pyrrolidone, sodium benzoate, methyl p-hydroxybenzoate, propyl p-hydroxybenzoate and purified water.

Premarin 0.625mg:

Calcium sulphate anhydrous

Carnauba wax

Microcrystalline cellulose

Glyceryl mono-oleates

Lactose monohydrate

Magnesium stearate

Methylcellulose

Macrogol

Shellac solution (pharmaceutical glaze)

Sucrose

Titanium dioxide (E171)

Opalux maroon colour AS-R-3910^†

Stearic acid

Edible ink (Opacode S-8-28905)^††

† Opalux maroon colour contains sucrose, purified water, erythrosine (E127), titanium dioxide (E171), sunset yellow (E110), indigo carmine (E132), polyvinylpyrrolidone and sodium benzoate.

^†† Edible ink (Opacode S-8-28905) contains titanium dioxide (E171), shellac (E904), purified water, ethanol, N-butyl alcohol, propylene glycol (E1520), ammonia solution and ethyl acetate.

Premarin 1.25mg:

Calcium sulphate

Carnauba wax

Microcrystalline cellulose

Glyceryl mono-oleates

Lactose

Magnesium stearate

Methylcellulose

Macrogol 20000

Shellac solution (Pharmaceutical glaze)

Sucrose

Titanium dioxide (E171)

Steraric acid

Edible ink (Opacode S-8-27741) ^††

Colours

Sunset yellow (E110)

Quinoline yellow aluminium lake (E104)

^††Edible ink (Opacode S-8-27741) Iron oxide black, shellac, purified water, ethanol, N-butyl alcohol, propylene glycol, ammonium solution, and ethyl acetate.

Not applicable.

Three years.

Do not store above 25°C.

Polyvinylchloride (PVC)/Aluminium foil blisters containing 28 tablets. One carton pack contains 3 blisters.

Securitainers containing 100 tablets

PVC/Aluminium foil blisters containing 21 tablets

Not applicable.

Pfizer Limited

Ramsgate Road

Sandwich

Kent

CT13 9NJ

United Kingdom

21 July 2011

May 2012

Ref: PA 5_1 UK