Prempak-C 0.625mg/0.15 mg Coated Tablets

Prempak-C 1.25mg/0.15 mg Coated Tablets

Prempak-C 0.625mg consists of 28 tablets containing 0.625mg conjugated estrogens USP, and 12 tablets containing 0.15mg norgestrel.

Prempak-C 1.25mg consists of 28 tablets containing 1.25mg conjugated estrogens USP, and 12 tablets containing 0.15mg norgestrel.

For a full list of excipients, see section 6.1.

Prempak-C 0.625mg coated tablets

Maroon oval biconvex sugar-coated tablet marked with '0.625' in white ink.

Round light brown sugar coated tablets containing norgestrel 0.15mg.

Prempak-C 1.25mg coated tablets

Yellow oval biconvex sugar coated tablet marked with “1.25” in black ink.

Round light brown sugar coated tablets containing norgestrel 0.15mg.

• Hormone replacement therapy for estrogen deficiency symptoms in menopausal and postmenopausal women

• 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:

Prempak-C is available for oral use in a sequential regimen for treatment of women with a uterus. The recommended starting dose is 0.625mg-1.25mg conjugated estrogens daily. One norgestrel tablet should be taken daily from day 17 to day 28 of estrogen therapy. Continuous estrogen administration is recommended. For maintenance, the lowest effective dose should be used.

For treatment of postmenopausal symptoms:

0.625-1.25mg conjugated estrogens daily depending on the response of the individual. One norgestrel tablet should be taken daily from day 17 to day 28 of estrogen therapy.

Prophylaxis of osteoporosis:

The minimum effective dose is 0.625mg daily for most patients. One norgestrel tablet should be taken daily from day 17 to day 28 of estrogen therapy. (See section 5.1 Pharmacological properties)

For most postmenopausal women therapy may be commenced at any convenient time although if the patient is still menstruating, commencement on first day of bleeding is recommended. In women transferring from another sequential hormone replacement therapy regimen, treatment should begin the day following completion of the prior regimen. Withdrawal bleeding usually occurs within three to seven days after the last norgestrel tablet.

Maintenance/Continuation/Extended treatment:

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 special precautions for use) should be used. Patients should be re-evaluated periodically to determine if treatment for symptoms is still necessary.

The benefits of the lower risk of endometrial hyperplasia and endometrial cancer due to adding a progestogen should be weighed against the increased risk of breast cancer (see sections 4.4 Special warnings and special 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 the missed tablet.

Missed pills may cause breakthrough bleeding.

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 cancer of the breast

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

3. Undiagnosed abnormal 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 Prempak-C 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.

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 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 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 Prempak-C, in particular:

− Leiomyoma (uterine fibroids) or endometriosis

− A family history of, or other 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. hepatic adenoma, hepatic hemangiomas)

− 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

The risk of endometrial hyperplasia and carcinoma is increased when estrogens are administered alone for prolonged periods (see section 4.8). The addition of a progestogen for at least 12 days of the cycle in non-hysterectomised women greatly reduces this risk. Unless there is a previous diagnosis of endometriosis it is not recommended to add a progestogen in hysterectomised women.

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).

Break-through bleeding and spotting may occur during the first months of treatment. If break-through 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.

5. Breast Cancer

A randomised placebo-controlled trial, the Women's Health Initiative study (WHI), and epidemiological studies, including the Million Women Study (MWS), have reported an increased risk of breast cancer in women taking estrogens, estrogen-progestogen combinations or tibolone for HRT for several years (see Section 4.8). 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.

In the MWS, the relative risk of breast cancer with conjugated equine estrogens (CEE) or estradiol (E2) was greater when a progestogen was added, either sequentially or continuously, and regardless of type of progestogen. There was no evidence of a difference in risk between the different routes of administration.

In the WHI study, the continuous combined conjugated equine estrogen and medroxyprogesterone acetate (CEE + MPA) product used was associated with breast cancers that were slightly larger in size and more frequently had local lymph node metastases compared to placebo.

HRT, especially estrogen-progestogen combined treatment, increases the density of mammographic images which may adversely affect the radiological detection of breast cancer.

6. Venous thromboembolism

Hormone replacement therapy (HRT) is associated with a higher relative risk of developing venous thromboembolism (VTE) i.e. 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. For non- users it is estimated that the number of cases of VTE that will occur over a 5-year period is about 3 per 1000 women aged 50-59 years and 8 per 1000 women aged between 60-69 years. It is estimated that in healthy women who use HRT for 5 years, the number of additional cases of VTE over a 5year period will be between 2 and 6 (best estimate = 4) per 1000 women aged 50-59 years and between 5 and 15 (best estimate = 9) per 1000 women aged 60-69 years. 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 and severe obesity (Body Mass Index>30kg/m²) and systemic lupus erythematosus (SLE). There is no consensus about the possible role of varicose veins in VTE.

Patients with a history of VTE or known thrombophilic states have an increased risk of VTE. HRT may add to this risk. Personal or strong family history of thromboembolism or recurrent spontaneous abortion should be investigated in order to exclude a thrombophilic predisposition. Until a thorough evaluation of thrombophilic factors has been made or anticoagulant treatment initiated, use of HRT in such patients should be viewed as contraindicated. Those women already on anticoagulant treatment require careful consideration of the benefit-risk of use of HRT.

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 4-6 weeks earlier, if this is possible. Treatment should not be restarted until the woman is completely mobilised.

If venous thromboembolism 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).

7. Coronary Artery Disease (CAD)

There is no evidence from randomised controlled trials of cardiovascular benefit with continuous combined conjugated estrogens and MPA. Two large clinical trials (WHI and HERS i.e. Heart and Estrogen/progestin Replacement Study) showed a possible increased risk of cardiovascular morbidity in the first year of use and no overall benefit. For other HRT products, there are only limited data from randomised controlled trials examining effects in cardiovascular morbidity or mortality. Therefore, it is uncertain whether these findings also extend to other HRT products.

8. Stroke

One large randomised clinical trial (WHI-trial) found, as a secondary outcome, an increased risk of ischaemic stroke in healthy women during treatment with continuous combined conjugated estrogens and MPA. For women who do not use HRT, it is estimated that the number of cases of stroke that will occur over a 5 year period is about 3 per 1000 women aged 50-59 years and 11 per 1000 women aged 60-69 years. It is estimated that for women who use conjugated estrogens and MPA for 5 years, the number of additional cases will be between 0 and 3 (best estimate =1) per 1000 users aged 50-59 years and between 1 and 9 (best estimate = 4) per 1000 users aged 60-69 years. It is unknown whether the increased risk also extends to other HRT products.

9. Ovarian Cancer

Long term (at least 5-10 years) use of estrogen-only HRT products in hysterectomised women has been associated with an increased risk of ovarian cancer in some epidemiological studies. It is uncertain whether long-term use of combined HRT confers different risk than estrogen-only products.

Other Conditions

10. Estrogens/progestogens may cause fluid retention and therefore patients with cardiac or renal dysfunction should be carefully observed. Patients with terminal renal insufficiency should be closely observed, since it is expected that the level of circulating active ingredients in Prempak-C is increased.

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. Changed estrogen levels may affect certain endocrine and liver function tests.

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

14. 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.

15. 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.

16. Estrogens should be used with caution in individuals with disease that can predispose to severe hypocalcaemia (e.g. hypoparathyroidism).

17. There is no conclusive evidence for improvement of cognitive function. There is some evidence from the WHI trial of increased risk of probable dementia in women who start using continuous combined CEE and MPA after the age of 65. It is unknown whether the findings apply to younger post-menopausal women or other HRT products.

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

The metabolism of estrogens and progestogens 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 and progestogens.

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.

Pregnancy:

Prempak-C is not indicated during pregnancy. If pregnancy occurs during medication with Prempak-C treatment should be withdrawn immediately.

Clinically, data on a limited number of exposed pregnancies indicate no adverse effects of MPA on the foetus.

The results of most epidemiological studies to date relevant to inadvertent foetal exposure to combinations of estrogens and progestogens indicate no teratogenic or foetotoxic effect.

Lactation:

Prempak-C is not indicated during lactation.

None known.

See also Section 4.4.

Adverse drug reactions (ADRs)

Undesirable effects reported in post-marketing spontaneous (reporting rate), clinical trials and class-effects are listed in the following table per body system and per frequency and this is for all age groups. The frequency is defined as follows: very common: 1/10, common: 1/100 and < 1/10, uncommon: 1/1,000 and < 1/100, rare: 1/10,000 and < 1/1,000, very rare: 1/10,000.

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Breast cancer

According to evidence from a large number of epidemiological studies and one randomised placebo-controlled trial, the Women's Health Initiative (WHI), the overall risk of breast cancer increases with increasing duration of HRT use in current or recent HRT users.

For estrogen-only HRT, estimates of relative risk (RR) from a reanalysis of original data from 51 epidemiological studies (in which >80% of HRT use was estrogen-only HRT) and from the epidemiological Million Women Study (MWS) are similar at 1.35 (95%CI 1.21 – 1.49) and 1.30 (95%CI 1.21 – 1.40), respectively.

For estrogen plus progestogen combined HRT, several epidemiological studies have reported an overall higher risk for breast cancer than with estrogens alone.

The MWS reported that, compared to never users, the use of various types of estrogen-progestogen combined HRT was associated with a higher risk of breast cancer (RR = 2.00, 95%CI: 1.88 – 2.12) than use of estrogens alone (RR = 1.30, 95%CI: 1.21 – 1.40) or use of tibolone (RR=1.45; 95%CI 1.25-1.68).

The WHI trial reported a risk estimate of 1.24 (95%CI 1.01 – 1.54) after 5.6 years of use of estrogen-progestogen combined HRT (CEE + MPA) in all users compared with placebo.

The absolute risks calculated from the MWS and the WHI trial are presented below:

The MWS has estimated, from the known average incidence of breast cancer in developed countries, that:

The WHI trial estimated that after 5.6 years of follow-up of women between the ages of 50 and 79 years, an additional 8 cases of invasive breast cancer would be due to estrogen-progestogen combined HRT (CEE + MPA) per 10,000 women years.

According to calculations from the trial data, it is estimated that:

The number of additional cases of breast cancer in women who use HRT is broadly similar for women who start HRT irrespective of age at start of use (between the ages of 45-65) (see section 4.4).

Endometrial Cancer

In women with an intact uterus, the risk of endometrial hyperplasia and endometrial cancer increases with increasing duration of use of unopposed estrogens. According to data from epidemiological studies, the best estimate of the risk is that for women not using HRT about 5 in every 1000 are expected to have endometrial cancer diagnosed between the ages of 50 and 65. Depending on the duration of treatment and estrogen dose, the reported increase in endometrial cancer risk among unopposed estrogen users varies from 2-to 12-fold greater compared with non-users. Adding a progestogen to estrogen-only therapy greatly reduces this increased risk.

Other adverse reactions reported in association with estrogen/progestogen treatment including Prempak-C:

• 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 and 4.4.

• Myocardial infarction

• Stroke

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

• Probable dementia (see section 4.4)

• Exacerbation of otosclerosis

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: G03F A10

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.

Progestogen:

As estrogens promote the growth of the endometrium, unopposed estrogens increase the risk of endometrial hyperplasia and cancer. The addition of a progestogen reduces but does not eliminate the estrogen-induced risk of endometrial hyperplasia in non-hysterectomised women.

The following data are from studies done with a different progestogen to that in Prempak-C. However, since the effect is due to the conjugated estrogens, these results can be extrapolated to other conjugated estrogen plus progestogen combination products.

Relief of estrogen-deficiency symptoms

In a 1-year clinical trial (n=2,808), vasomotor symptoms were assessed for efficacy during the first 12 weeks of treatment in a subset of symptomatic women (n=241) who had at least 7 moderate or severe hot flushes daily or 50 moderate to severe hot flushes during the week before randomisation. Premique 0.625 mg/2.5 mg(conjugated estrogens/medroxyprogesterone acetate) was 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.

Prevention of osteoporosis

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.

After 3 years of treatment with Premique 0.625 mg/2.5 mg, the increase in lumbar spine bone mineral density (BMD) was 4.87% ± 0.66. The percentage of women who maintained (less than 1% BMD loss per year) or gained BMD in lumbar zone during treatment was 92%.

Premique 0.625 mg/2.5 mg also had an effect on hip BMD. The increase after 3 years was 1.94% ± 0.44 at total hip. The percentage of women who maintained (less than 1% BMD loss per year) or gained BMD in hip zone during treatment was 88%.

Conjugated Estrogens

Absorption

Conjugated estrogens are soluble in water and are well absorbed from the gastrointestinal tract after release from the drug formulation. Premarin tablets (conjugated estrogens only) release conjugated estrogens slowly over several hours. The pharmacodynamic profile of unconjugated and conjugated estrogens following a dose of 2 x 0.625mg is 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 2 x 0.625mg

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

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

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

Norgestrel

The biologically active isomer, levonorgestrel, is rapidly and almost completely absorbed after administration by mouth, and undergoes little first pass hepatic metabolism. It is highly bound to plasma proteins; 42 to 68% to sex hormone binding globulin and 30 to 56% to albumin. Levonorgestrel and norgestrel are metabolised in the liver to sulphate and glucuronide conjugates, which are excreted in the urine and to a lesser extent in the faeces.

The pharmacokinetic profile of levonorgestrel following an oral dose of 150 micrograms and repeat dosing performed until a steady state was achieved is provided in Table 1.

The proportion of levonorgestrel bound to sex hormone binding globulin is higher when it is given with an estrogen. This indicates that the pharmacokinetic parameters for each active substance will differ when used in combination.

Table 1 – Pharmacokinetic parameters for Levonorgestrel following a dose of 150 microgram and repeat dosing until steady state achieved

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

Prempak-C 0.625 Conjugated estrogen tablets:

Calcium sulphate anhydrous

Carnauba wax

Microcrystalline cellulose

Glyceryl mono-oleates

Lactose monohydrate

Magnesium stearate

Methylcellulose

Marcrogol

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 AS-R-3910 contains sucrose, purified water, erythrosine (E127), titanium dioxide (E171), sunset yellow (E110), indigo carmine (E132), povidone (E1201) and sodium benzoate (E211).

^††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.

Prempak-C 1.25mg Conjugated estrogen tablets:

Calcium sulphate anhydrous

Carnauba wax

Microcrystalline cellulose

Glyceryl mono-oleates

Lactose

Magnesium stearate

Methylcellulose

Macrogol 20000

Shellac solution (Pharmaceutical glaze)

Sucrose

Titanium dioxide (E171)

Stearic acid

Colours

Sunset yellow (E110)

Quinoline yellow aluminium lake (E104)

Edible ink (Opacode S-8-27741) containing;

Iron oxide black

Shellac

Purified water

Ethanol

N-butyl alcohol

Propylene glycol

Ammonium solution

Ethyl acetate.

Norgestrel tablets:

Bleached wax

Calcium carbonate

Carnauba wax

Lactose

Magnesium stearate

Macrogol,

Polyvinyl pyrrolidone

starch

Sucrose

Talc

Titanium dioxide (E171)

Colour E172.

Not applicable.

Three years.

Do not store above 25^oC.

Polyvinylchloride (PVC)/Aluminium foil blisters containing 28 conjugated estrogen and 12 norgestrel tablets. One carton pack contains 3 blisters.

Not applicable.

Pfizer Limited

Ramsgate Road

Sandwich

Kent

CT13 9NJ

United Kingdom

11^th August 2011

August 2011

Ref: PC 2_1