SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Co-cyprindiol 2 mg / 0.035 mg coated tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

One coated tablet contains:

Cyproterone acetate 2 mg Ethinylestradiol 0.035 mg

For a full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Coated tablet

Each tablet is round and beige.

4    CLINICAL PARTICULARS

4.1 Therapeutic indications

Co-cyprindiol is recommended for use in women only for the treatment of: -a) severe acne, refractory to prolonged oral antibiotic therapy.

-b) moderately severe hirsutism.

Although Co-cyprindiol also acts as an oral contraceptive, it should only be used in patients requiring hormone treatment for the above conditions (see section 4.4. For duration of treatment, see section 4.2.)

The medicinal product is not recommended to be used for contraception only.

4.2 Posology and method of administration

Co-cyprindiol inhibits ovulation and thereby prevents conception. Patients who are using Co-cyprindiol should not therefore use an additional hormonal contraceptive, as this will expose the patient to an excessive dose of hormones and is not necessary for effective contraception.

The first period of treatment is started on the first day of the menstrual cycle then one tablet daily for 21 days. Each subsequent course is started after 7 tablet-free days following which menstruation should occur.

Withdrawal bleeding usually occurs by 2-4 days after the last tablet. If this does not occur, it may be necessary to exclude pregnancy.

Starting tablets

No previous hormonal contraception (during the preceding month): Tablets should be started on day 1 of the natural menstrual cycle (first day of bleeding). Tablet-taking may also be started during bleeding days 2-5, but in that case an additional non-hormonal contraceptive method is recommended for the first seven days of the first cycle.

Switch from another combined oral contraceptive, patch or vaginal ring: Tablets should preferably be started on the day following the intake of the last active tablet of the previous combined oral contraceptive, but at the latest following the usual tablet-free or placebo-tablet interval of the previous combined oral contraceptive, or after removal of the patch or the vaginal ring.

Switch from progestagen -only contraceptives (minipills, injections, implants or IUS): The switch from minipills can be made at all times (the switch from implants or IUS on the day of its removal and from injections on the next scheduled day of injection), but the user should be advised to use an additional non-hormonal contraceptive method for the first seven days of tablet-taking.

After abortion during the first trimester: Tablet-taking can be started immediately. In this case no other contraceptive method is needed.

After childbirth or abortion during the second trimester: Breast feeding mothers: see section 4.6. The use of the tablets should be started 21 to 28 days after childbirth or abortion during the second trimester. If tablet-taking is started later than this, an additional non-hormonal contraceptive method should be used for the first seven days of tablet-taking. However, if intercourse has already occurred, pregnancy should be excluded or the woman should wait for her first natural period before starting the next tablet.

Missing tablets: If the patient forgets a single tablet, it should be taken within 12 hours of the correct time to maintain contraceptive protection. With larger errors, additional contraception (barrier method, such as a condom) is needed. Handling of missed tablets may be managed by the following two basic rules:

• Tablet-taking must never be discontinued for longer than 7 days.

•    Adequate suppression of the hypothalamic-pituitary-ovarian axis requires 7 days of uninterrupted tablet-taking.

Accordingly, the following advice can be given for daily practice:

Week 1

The woman should take the last missed tablet as soon as she remembers, even if this means taking two tablets at the same time. She then continues to take the next tablets at her usual time. In addition, a barrier method such as a condom should be used for the next 7 days. If the woman has had sexual intercourse in the 7 days before missing the tablet, the possibility of a pregnancy must be considered. The more tablets have been missed and the closer they are to the regular tablet-free break, the higher the risk of pregnancy.

Week 2

The woman should take the last missed tablet as soon as she remembers, even if this means taking two tablets at the same time. She then continues to take the next tablets at her usual time. Provided that the woman has taken her tablets correctly in the 7 days preceding the first missed tablet, there is no need to use extra contraceptive precautions. If she has not taken the tablets correctly or has missed more than one tablet, she should be advised to use extra contraceptive precautions for the next 7 days.

Week 3

The risk of reduced contraceptive reliability is imminent because of the forthcoming tablet-free break of 7 days. However, reduced contraceptive protection can still be prevented by adjusting the dosage. By adhering to the following advice, there is no need to use extra contraceptive precautions, provided that all the tablets have been taken correctly in the 7 days preceding the first missed tablet.

If this is not the case, the woman should follow the first of these two options and use extra contraceptive precautions for the next 7 days as well.

•    The woman should take the last missed tablet as soon as she remembers, even if this means taking two tablets at the same time. She then continues to take the next tablets at her usual time. The next pack is started as soon as the current pack is finished, i.e. there is no tablet-free break. There will probably be no withdrawal bleed until the end of the second pack, but the woman may experience spotting or breakthrough bleeding on tablet-taking days.

•    It is also possible to stop taking tablets from the current pack. The woman must then have a tablet-free break of 7 days, including the days she missed tablets, and then continue with the next pack.

If the woman misses several tablets and has no withdrawal bleed during the first normal tablet-free break, the possibility of a pregnancy must be considered.

Vomiting or diarrhoea: If vomiting or diarrhoea occurs tablets should be taken at regular time periods. In addition, a supplemental non-hormonal contraceptive method should be used for the next 7 days.

The duration of treatment depends upon the severity of the disease and the patient’s clinical status. Therapy usually lasts for several months. It is recommended that intake of Co-cyprindiol be continued for at least 3-4 cycles after symptoms have subsided, and that Co-cyprindiol is not continued solely to provide oral contraception. Repeat courses may be given if the androgen-dependent condition(s) recur.

4.3 Contraindications

•    Pregnancy is an absolute contra-indication for treatment with Co-cyprindiol and must be excluded before such treatment is begun (see section 4.6 and section 4.4).

•    Lactation

•    Severe disturbances of liver function, jaundice or persistent itching during a previous pregnancy, Dubin-Johnson syndrome, Rotor syndrome, previous or existing liver tumours.

•    Personal or family history of confirmed, idiopathic venous thromboembolism (VTE) (where a family history refers to VTE in a sibling or parent at a relatively early age.).

•    Current venous thrombotic or embolic processes.

•    Existing or previous arterial thrombotic or embolic processes.

•    The presence of a severe or multiple risk factor(s) for venous or arterial thrombosis may also constitute a contraindication (see section 4.4.)

•    Sickle-cell anaemia.

•    Mammary or endometrial carcinoma, or a history of these conditions.

•    Severe diabetes mellitus with vascular changes.

•    Abnormal vaginal bleeding of unknown cause.

•    Disorders of lipid metabolism.

•    History of herpes gestationis.

•    Deterioration of otosclerosis during pregnancy.

•    Migraine with focal neurological symptoms.

•    Hypersensitivity to cyproterone acetate, ethinylestradiol or any of the excipients of the medicinal product.

4.4 Special warnings and precautions for use

Prior to the initiation or reinstitution of treatment a complete medical history (including family history) should be taken and pregnancy should be ruled out. Blood pressure should be measured and a physical examination should be performed guided by the contra-indications (section 4.3 Contra-indications) and warnings (section 4.4 Special warnings and precautions for use). The frequency and nature of examinations should be based on established practice guidelines and be adapted to the individual woman. The woman should also be instructed to carefully read the user leaflet and to adhere to the advice given.

Warnings:

Like many other steroids, Co-cyprindiol, when given in very high doses and for the majority of the animal’s life span, has been found to cause an increase in the incidence of tumours, including carcinoma, in the liver of rats. The relevance of this finding to humans is unknown.

In rare cases benign and in even rarer cases malignant liver tumours leading in isolated cases to life-threatening intra-abdominal haemorrhage have been observed after the use of hormonal substances such as those contained in Co-cyprindiol. If severe upper abdominal complaints, liver enlargement or signs of intra-abdominal haemorrhage occur, a liver tumour should be included in the differential diagnosis.

Pregnancy is an absolute contra-indication for treatment with Co-cyprindiol and must be excluded before such treatment is begun (see section 4.6 ‘Pregnancy and Lactation’ and section 4.3 ‘Contraindications’).

Co-cyprindiol is composed of the progestogen cyproterone acetate and the oestrogen ethinylestradiol and is administered for 21 days of the monthly cycle. It therefore has a similar composition to that of a combined oral contraceptive (COC). The use of any COC or ‘Co-cyprindiol carries an increased risk for venous thromboembolism (VTE), including deep venous thrombosis and pulmonary embolism, compared with no use. The excess risk of VTE is highest during the first year a woman ever uses a COC. This increased risk is less than the risk of VTE associated with pregnancy, which is estimated as 60 per 100,000 pregnancies.

Full recovery from such disorders does not always occur; VTE is fatal in 1-2% of cases.

Epidemiological studies have shown that the incidence of VTE in users of oral contraceptives with low oestrogen content (< 50pg ethinylestradiol) is up to 40 cases per 100,0000 women-years. This compares with 5-10 cases per 100,000 women-years for non-users.

Certain factors may increase the risk of venous thrombosis e.g. severe obesity (body mass index >30 kg/m2), increasing age, a genetic predisposition to clotting or a personal or family history of confirmed, idiopathic VTE (where family history refers to VTE in a sibling or parent at a relatively early age, see contraindications section 4.3). In addition, the risk of VTE may be temporarily increased by prolonged immobilisation, major surgery, any surgery to the legs, or major trauma (see “Reasons for stopping Co-cyprindiol immediately”.

There is some epidemiological evidence that the incidence of VTE is higher in users of Co-cyprindiol when compared to users of COCs with low oestrogen content (<50pg).

The user group of Co-cyprindiol as a treatment for severe acne or moderately severe hirsutism is likely to include patients that may have an inherently increased cardiovascular risk such as that associated with polycystic ovarian syndrome.

Epidemiological studies have also associated the use of COCs with an increased risk for arterial (myocardial infarction, transient ischaemic attack) thromboembolism. Certain factors such as smoking, obesity, cardiovascular disease, hypertension, diabetes and migraine may increase the risk of arterial thromboembolism. The risk of arterial thrombosis associated with oral contraceptives increases with age, and this risk is aggravated by cigarette smoking.

An increased risk of cervical cancer in long-term users of combined oral contraceptives has been reported in some studies, but there continues to be controversy about the extent to which this is attributable to the confounding effects of sexual behaviour and other factors.

The possibility cannot be ruled out that certain chronic diseases may occasionally deteriorate during the use of the medicinal product (see ‘Precautions’ ).

A meta-analysis from 54 epidemiological studies reported that there is a slightly increased relative risk (RR= 1.24) of having breast cancer diagnosed in women who are currently using combined oral contraceptives (COCs). The excess risk gradually disappears during the course of the 10 years after cessation of COC use. Because breast cancer is rare in women under 40 years of age, the excess number of breast cancer diagnoses in current and recent COC users is small in relation to the overall risk of breast cancer. The observed pattern of increased risk may be due to an earlier diagnosis of breast cancer in COC users, the biological effects of COCs or a combination of both. The breast cancers diagnosed in ever-users tend to be less advanced clinically than the cancers diagnosed in never-users.

Use with caution in women with a family history of breast cancer. Women on this therapy, particularly with fibrocystic disease of the breast, or with a family history of breast cancer (first degree relatives) should have regular breast examinations, including mammography.

The medicinal product contains lactose monohydrate/sucrose.

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicinal product.

Herbal preparations containing St John’s wort (Hypericum perforatum) should not be used while taking Co-cyprindiol due to the risk of decreased plasma concentrations and reduced clinical effects of Co-cyprindiol (see section 4.5).

Reasons for stopping Co-cyprindiol immediately:

•    Occurrence for the first time, or exacerbation, of migrainous headaches or unusually frequent or unusually severe headaches.

•    Sudden disturbances of vision, or hearing or other perceptual disorders.

•    First signs of thrombophlebitis or thromboembolic symptoms (e.g. unusual pains in or swelling of the leg(s), stabbing pains on breathing or coughing for no apparent reason). Feeling of pain and tightness in the chest.

•    Six weeks before an elective major operation (e.g. abdominal, orthopaedic), any surgery to the legs, medical treatment for varicose veins or prolonged immobilisation, e.g. after accidents or surgery. Treatment should not be restarted until 2 weeks after full ambulation.

In case of emergency surgery, thombotic prophylaxis is usually indicated e.g. subcutaneous heparin.

•    Onset of jaundice, hepatitis, itching of the whole body.

•    Increase in epileptic seizures.

•    Significant rise in blood pressure.

•    Onset of severe depression.

•    Severe upper abdominal pain or liver enlargement.

•    Clear worsening of conditions known to deteriorate during use of hormonal contraception or during pregnancy.

•    Pregnancy is a reason for stopping immediately because it has been suggested by some investigations that oral contraceptives taken early in pregnancy may slightly increase the risk of foetal malformations. Other investigations have failed to support these findings. The possibility therefore cannot be excluded, but it is certain that if a risk exists at all, it is small.

Precautions:

The following conditions require careful observation during medicinal product- a deterioration or first appearance of any of these conditions may indicate that use of Co-cyprindiol should be discontinued: a history of severe depressive states, varicose veins, diabetes, hypertension, epilepsy, otosclerosis, multiple sclerosis, porphyria, tetany, disturbed liver function, gall-stones, cardiovascular diseases, renal diseases, chloasma, uterine fibroids, asthma, intolerance to contact lenses, history of phlebitis, Sydenham’s chorea, family history of clotting disorders, obesity, SLE (systemic lupus erythematosus) and migraine or any disease that is prone to worsen during pregnancy. Some women may experience amenorrhoea or oligomenorrhoea after discontinuation of Co-cyprindiol, especially when these conditions existed prior to use.

Women should be informed of this possibility.

It should be borne in mind that the use of ultraviolet lamps for the treatment of acne, or prolonged exposure to sunlight, increases the risk of the deterioration of chloasma.

4.5 Interaction with other medicinal products and other forms of interaction

Some medicinal products taken concurrently accelerate the metabolism of the hormones and may reduce the contraceptive reliability of the medicinal product and include barbiturates, anti-epileptics such as primidone, phenobarbitone, phenytoin and carbamazepine, phenylbutazone, rifampicin, ampicillin, griseofulvin, Oxcarbazepin, Topiramat, Felbamat, Ritonavir and other antibiotics. Oral tetracyclines, if used in conjunction with the medicinal product, may have such an effect, although it has not been shown. When medicinal products of these classes are being taken, it is, therefore, advisable to use additional methods of contraception (excluding oral contraceptives and other hormonal methods) since an extremely high degree of protection must be provided when the medicinal product is being taken. With rifampicin additional contraceptive precautions should be continued for 4 weeks after treatment stops. The requirement for oral antidiabetics or insulin can change. MAO (Monoamine-oxidase) inhibitors inhibit the metabolism of oestrogen which may cause oestrogen induced undesirable effects.

The herbal preparation St John’s wort (Hypericum perforatum) should not be taken concomitantly with this medicine as this could potentially lead to a loss of contraceptive effect. Break through bleeding and unintended pregnancies have been reported. This is due to induction of medicinal product metabolising enzymes by St John’s wort. The inducing effect may persist for at least two weeks after cessation of treatment with St John’s wort.

For women taking rifampicin, additional contraceptive precautions should be continued for 4 weeks after treatment stops, even if only a short course was administered.

4.6 Pregnancy and lactation

Studies in animals have shown effects on embryonal/foetal development, the potential risk for humans is unknown (see section 5.3).

Co-cyprindiol is contraindicated in pregnancy (see section 4.3).

Pregnancy should be excluded before treatment is begun.

If pregnancy occurs during use of Co-cyprindiol the therapy should be discontinued immediately.

Cyproterone Acetate and Ethinylestradiol are excreted in breast milk (0.2% and 0.02% respectively).

Co-cyprindiol is contraindicated during lactation (see section 4.3).

4.7 Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed.

4.8 Undesirable effects

Undesirable effects which have been seen in connection with the use of combined oral contraceptive pill have also been experienced when taking Co-cyprindiol.

Around 10-30% of women can expect some undesirable effects during the first few cycles of treatment. These include tension in the breast, nausea, vomiting, headaches, changed body weight or libido and depressive moods. These initial undesirable effects are often mild and usually disappear within 2-4 months of treatment.

The use of combined oral contraceptives (COCs) is associated with an increased risk for venous (deep venous thrombosis, pulmonary embolism) and arterial (myocardial infarction, transient ischaemic attack) thromboembolism (For more information concerning VTE and other possible severe adverse events see Section 4.4).

Reduction of menstrual flow may occur. This is not abnormal and it is to be expected in some patients.

If withdrawal bleeding does not occur, pregnancy must be excluded by a pregnancy test after a suitable interval before a new course of tablets is started.

Very light ‘spotting’ or heavier breakthrough bleeding may occur during tablettaking, especially in the first few cycles. It appears to be generally of no significance except where it indicates errors of tablet-taking, or where the possibility of interaction with other medicinal products exists. However, if irregular bleeding is persistent, an organic cause should be considered.

Transient liver function changes may occur; occasionally there may also be an increased risk of thromboembolic processes and raised blood-pressure in women who are predisposed to this. In some cases there has been a reduced tolerance to contact lens wear. If lens tolerance changes, an ophthalmologist should be consulted.

The radio-iodine uptake shows that thyroid function is unchanged. There is a rise in serum protein-bound iodine, similar to that in pregnancy and during the administration of oestrogens. This is due to the increased capacity of the plasma proteins for binding thyroid hormones, rather than to any change in glandular function. In women taking the medicinal product, the content of protein-bound iodine in blood serum should, therefore, not be used for the evaluation of thyroid function.

The medicinal product may accelerate erythrocyte sedimentation in the absence of any disease. This effect is due to change in the proportion of the plasma protein fractions. Increases in plasma copper, iron and alkaline phosphatase have also been recorded.

System organ class	Common >1/100, <1/10	Uncommon >1/1,000, <1/100	Rare >1/10000, <1/1000
Blood and lymphatic -system disorders		• Elevation of blood pressure	•    Venous thromboembolism (deep venous thrombosis, pulmonary embolism) •    Arterial thromboembolism (myocardial infarction, ischaemic attack). •    Blood sedimentation rate increase •    Increase of serum copper, serum ferrum & alkaline phosphatase
Endocrine disorders	• Breast tension		•    Decreased glucose tolerance •    Elevated blood sugar •    Increased insulin need •    Pancreatitis
Nervous system disorders	•    Depressive moods •    Change in libido
Eye disorders			•    Decreased epiphora •    There have been isolated reports of poor tolerance of contact lenses in association with oral contraceptives.
Gastrointestinal disorders	•    Nausea •    Vomiting
Hepatobiliary disorders			•    Reversible elevation of transaminase levels •    Hepatitis •    Intrahepatic cholestasis •    Gallstones •    Benign liver adenoma •    Focal nodular hyperplasia •    Disorder of the metabolism of folic acid or tryptophane can occur •    Cholelithiasis •    Cholestasis (including cholestatic jaundice) •    Liver tumours (following long-term use
Skin and subcutaneous tissue disorders	•    Hypersensitivity reactions •    Oedema •    Skin rashes		•    In predisposed women, Co-cyprindiol may cause chloasma, which may be exacerbated by exposure to sunlight •    Pruritus •    Alopecia
Reproductive system and breast disorders	•    Intermenstrual Bleeding •    Dysmenorrhoea •    Breast tenderness •    Breast pain	• Reduction of menstrual flow	• Increased tendency to vaginal candidiasis, nonspecific discharge

	•    Galactorrhoea •    Breast enlargement
General disorders and administration site conditions	•    Change in body-weight •    Headache •    Migraine	• Fluid retention

4.9 Overdose

There have been no reports concerning overdose, but, on general principles from a knowledge of the pharmacological actions of the constituents of the medicinal product, it would seem unnecessary to treat. There are no specific antidotes and treatment should be symptomatic.

Symptoms of overdose are nausea, vomiting and withdrawal bleeding.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antiandrogens and estrogens, Cyproterone and estrogen ATC code: G03HB01

Cyproterone Acetate possesses anti-androgenic and progestational activity. It blocks androgen-receptors; it also reduces androgen synthesis by a negative feedback effect on the hypothalamo-pituitary-ovarian systems. Sex hormone-binding globulin (SHBG) levels are increased by the oestrogen component of the medicinal product, thus reducing the free, circulating plasma levels of androgens. Unlike some other progestogens, cyproterone acetate has no tendency to reduce SHBG levels. The oestrogen component also acts as an oral contraceptive, with a mode of action similar to those for oestrogens in general.

The results from epidemiological investigations have shown that the use of high dosed combined oral contraceptives (50pg ethinylestradiol) lowers the risk of endometrial and ovarian cancer. However, it has yet to be established whether the beneficial effects also apply to the lower dose oral contraceptives.

5.2 Pharmacokinetic properties

Cyproterone Acetate

After oral administration of 2mg Cyproterone Acetate sugar-coated tablets, CPA is completely absorbed. It is rapidly metabolised and slowly excreted in the faeces and urine. Its terminal t'A after a single oral 50mg dose to healthy volunteers has been reported to be between 38h (radioimmunoassay) and 39h (total radioactivity) although a terminal half-life in healthy volunteers of up to 100 hours has also been reported.

Cyproterone Acetate is metabolised first by hydrolysis to free cyproterone, then by 15 P-hydroxylation to 15-hydroxycyproterone. This metabolite has 10% of the progestational activity of Cyproterone Acetate but has similar anti-androgenic activity. Excretion is effected slowly via the kidneys and faeces.

Ethinylestradiol

Ethinylestradiol is rapidly and almost completely absorbed from the gastro-intestinal tract, but is to a certain degree subject to a first-past metabolism in the intestine wall. Bioavailability amounts to approximately 40%. Maximum plasma concentrations are achieved 1-2 hours after oral application. Ethinylestradiol accumulates in the body fat and endometrium. The reported (half-life t'A) varies from 6 to 30 hours. In comparison to other oestrogens it is only metabolised slowly in the liver. It is conjugated with glucuronic acid and sulphate. Ethinylestradiol is subject to a clear enterohepatic cycle. 60% of excretion is effected via the kidneys and 40% via faeces.

5.3 Preclinical safety data

In laboratory animals, most of the effects of cyproterone acetate following repeated administration are related to the anti-androgenic and progestagenic actions of the medicinal product. In rat and mouse studies, cyproterone acetate produced an induction of liver enzymes and liver hypertrophy.

The potentially sensitising effect of ethinylestradiol and cyproterone acetate has not been studied in animals.

Acknowledged first-line genotoxicity tests, carried out with cyproterone acetate, usually showed negative results. Other tests, however, showed that cyproterone acetate is able to produce DNA-adducts (and to increase the DNA-recovery activity) in liver cells of rats and monkeys, as well as in freshly isolated humane hepatocytes. This DNA-adduct formation was found in exposures expected to occur in the recommended dosages for cyproterone acetate. An in vivo consequence of cyproterone acetate treatment in the rat was the increased incidence of focal, possibly preneoplastic liver impairments, in which cellular enzymes in female rats were changed.

The clinical significance of these findings is uncertain at the moment. So far no indications exist that the incidence of liver tumours in man is increased.

In long-term studies in mice and rats cyproterone acetate enhanced the incidences of tumours of the pituitary, liver and/or mammary gland. Long-term treatment with ethinyl estradiol can also enhance the incidences of certain neoplasms in laboratory animals. The clinical relevance with respect to low-dose treatment with cyproterone acetate and ethinyl estradiol is, however, questionable.

Animal studies have revealed that feminisation of male foetuses may occur if cyproterone acetate is administered during the phase of embryogenesis at which

differentiation of the external genitalia occurs. Although the results of these tests are not necessarily relevant to man, the possibility must be considered that administration of Co-cyprindiol to women after the 45th day of pregnancy could cause feminisation of male foetuses. It follows from this that pregnancy is an absolute contra-indication for treatment with the Co-cyprindiol, and must be excluded before such treatment is begun (for further information see Sections 4.3 and 4.4).

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Tablet Core

Lactose monohydrate Maize starch Povidone K25 Talc

Magnesium stearate

Tablet Coating Sucrose

Povidone 700 000 Macrogol 6000 Calcium carbonate Glycerol 85%

Titanium dioxide (E171)

Iron oxide yellow (E172)

Montanglycol wax

6.2 Incompatibilities

Not applicable

6.3 Shelf life

3 years.

6.4 Special precautions for storage

Do not store above 25°C. Keep blister in the outer carton.

6.5 Nature and contents of container

Blisters

Polyvinylchloride blisters sealed onto aluminium foil.

Pack sizes

21 and 63 (3x21) tablets. Calendar pack. Not all pack sizes may be marketed

6.6 Special precautions for disposal

No special requirements.

7    MARKETING AUTHORISATION HOLDER

Generics (UK) Limited Station Close, Potters Bar Hertfordshire EN6 1TL United Kingdom

8    MARKETING AUTHORISATION NUMBER(S)

PL 04569/0486

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION

05/07/2001 / 04/07/2006

10 DATE OF REVISION OF THE TEXT

28/02/2007