Organon Laboratories Limited

Cerazette 75 microgram film-coated tablet

Each tablet contains 75 microgram desogestrel.

Excipient: lactose <65 mg

For a full list of excipients, see section 6.1

Film-coated tablet.

The tablet is white, round, biconvex and 5 mm in diameter. On one side it is coded KV above 2 and on the reverse side Organon _*.

Contraception.

How to take Cerazette

Tablets must be taken every day at about the same time so that the interval between two tablets always is 24 hours. The first tablet should be taken on the first day of menstrual bleeding. Thereafter one tablet each day is to be taken continuously, without taking any notice on possible bleedings. A new blister is started directly the day after the previous one.

How to start Cerazette

•No preceding hormonal contraceptive use [in the past month]

Tablet taking has to start on day 1 of the woman's natural cycle (day 1 is the first day of her menstrual bleeding). Starting on days 2-5 is allowed, but during the first cycle a barrier method is recommended for the first 7 days of tablet-taking.

•Following first-trimester abortion

After first-trimester abortion it is recommended to start immediately. In that case there is no need to use an additional method of contraception.

•Following delivery or second-trimester abortion

Contraceptive treatment with Cerazette after delivery can be initiated before the menstruations have returned. If more than 21 days have elapsed pregnancy ought to be ruled out and an additional method of contraception should be used for the first week. For additional information for breastfeeding women see Section 4.6.

How to start Cerazette when changing from other contraceptive methods

•Changing from a combined hormonal contraceptive (combined oral contraceptive (COC), vaginal ring, or transdermal patch).

The woman should start Cerazette preferably on the day after the last active tablet (the last tablet containing the active substances) of her previous COC or on the day of removal of her vaginal ring or transdermal patch. In these cases, the use of an additional contraceptive is not necessary. Not all contraceptive methods may be available in all EU countries.

The woman may also start at the latest on the day following the usual tablet-free, patch-free, ring-free, or placebo tablet interval of her previous combined hormonal contraceptive, but during the first 7 days of tablet-taking an additional barrier method is recommended.

•Changing from a progestogen-only-method (minipill, injection, implant, or from a progestogen-releasing intrauterine system [IUS])

The woman may switch any day from the minipill (from an implant or the IUS on the day of its removal, from an injectable when the next injection would be due.

Management of missed tablets

Contraceptive protection may be reduced if more than 36 hours have elapsed between two tablets. If the user is less than 12 hours late in taking any tablet, the missed tablet should be taken as soon as it is remembered and the next tablet should be taken at the usual time. If she is more than 12 hours late, she should use an additional method of contraception for the next 7 days. If tablets were missed in the first week and intercourse took place in the week before the tablets were missed, the possibility of a pregnancy should be considered.

Advice in case of gastrointestinal disturbances

In case of severe gastro-intestinal disturbance, absorption may not be complete and additional contraceptive measures should be taken.

If vomiting occurs within 3-4 hours after tablet-taking, absorption may not be complete. In such an event, the advice concerning missed tablets, as given in Section 4.2 is applicable.

Treatment surveillance

Before prescription, a thorough case history should be taken and a thorough gynaecological examination is recommended to exclude pregnancy. Bleeding disturbances, such as oligomenorrhoea and amenorrhoea should be investigated before prescription. The interval between check-ups depends on the circumstances in each individual case. If the prescribed product may conceivably influence latent or manifest disease (see Section 4.4), the control examinations should be timed accordingly.

Despite the fact that Cerazette is taken regularly, bleeding disturbances may occur. If the bleedings are very frequent and irregular, another contraceptive method should be considered. If the symptoms persist, an organic cause should be ruled out.

Management of amenorrhoea during treatment depends on whether or not the tablets have been taken in accordance with the instructions and may include a pregnancy test.

The treatment should be stopped if a pregnancy occurs.

Women should be advised that Cerazette does not protect against HIV (AIDS) and other sexually transmitted diseases.

• Hypersensitivity to the active substance or to any of the excipients.

• Known or suspected pregnancy.

• Active venous thromboembolic disorder.

• Presence or history of severe hepatic disease as long as liver function values have not returned to normal.

• Known or suspected sex-steroid sensitive malignancies.

• Undiagnosed vaginal bleeding.

If any of the conditions/risk factors mentioned below is present, the benefits of progestogen use should be weighed against the possible risks for each individual woman and discussed with the woman before she decides to start with Cerazette. In the event of aggravation, exacerbation, or first appearance of any of these conditions, the woman should contact her physician. The physician should then decide on whether the use of Cerazette should be discontinued.

The risk for breast cancer increases in general with increasing age. During the use of combined oral contraceptives (COCs) the risk for having breast cancer diagnosed is slightly increased. This increased risk disappears gradually within 10 years after discontinuation of OC use and is not related to the duration of use, but to the age of the woman when using the COC. The expected number of cases diagnosed per 10 000 women who use COCs (up to 10 years after stopping) relative to never users over the same period have been calculated for the respective age groups and is presented in the table below.

The risk in users of progestogen-only contraceptives (POCs), such as Cerazette, is possibly of similar magnitude as that associated with COCs. However, for POCs the evidence is less conclusive. Compared to the risk of getting breast cancer ever in life, the increased risk associated with COCs is low. The cases of breast cancer diagnosed in COC users tend to be less advanced than in those who have not used COCs.

The increased risk in COC users may be due to an earlier diagnosis, biological effects of the pill or a combination of both.

Since a biological effect of progestogens on liver cancer cannot be excluded an individual benefit/risk assessment should be made in women with liver cancer.

When acute or chronic disturbances of liver function occur, the woman should be referred to a specialist for examination and advice.

Epidemiological investigations have associated the use of COCs with an increased incidence of venous thromboembolism (VTE, deep venous thrombosis and pulmonary embolism). Although the clinical relevance of this finding for desogestrel used as a contraceptive in the absence of an oestrogenic component is unknown, Cerazette should be discontinued in the event of a thrombosis. Discontinuation of Cerazette should also be considered in case of long-term immobilisation due to surgery or illness. Women with a history of thrombo-embolic disorders should be made aware of the possibility of a recurrence.

Although progestogens may have an effect on peripheral insulin resistance and glucose tolerance, there is no evidence for a need to alter the therapeutic regimen in diabetics using progestogen-only pills. However, diabetic patients should be carefully observed during the first months of use.

If a sustained hypertension develops during the use of Cerazette, or if a significant increase in blood pressure does not adequately respond to antihypertensive therapy, the discontinuation of Cerazette should be considered.

Treatment with Cerazette leads to decreased estradiol serum levels, to a level corresponding with the early follicular phase. It is as yet unknown whether the decrease has any clinically relevant effect on bone mineral density.

The protection with traditional progestogen-only pills against ectopic pregnancies is not as good as with combined oral contraceptives, which has been associated with the frequent occurrence of ovulations during the use of progestogen-only pills. Despite the fact that Cerazette consistently inhibits ovulation, ectopic pregnancy should be taken into account in the differential diagnosis if the woman gets amenorrhoea or abdominal pain.

Chloasma may occasionally occur, especially in women with a history of chloasma gravidarum. Women with a tendency to chloasma should avoid exposure to the sun or ultraviolet radiation whilst taking Cerazette.

The following conditions have been reported both during pregnancy and during sex steroid use, but an association with the use of progestogens has not been established: jaundice and/or pruritus related to cholestasis; gallstone formation; porphyria; systemic lupus erythematosus; haemolytic uraemic syndrome; Sydenham's chorea; herpes gestationis; otosclerosis-related hearing loss; (hereditary) angioedema.

Cerazette contains less than 65mg lactose and therefore should not be administered to patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption.

Interactions

Interactions between hormonal contraceptives and other medicinal products may lead to breakthrough bleeding and/or contraceptive failure. The following interactions have been reported in the literature (mainly with combined contraceptives but occasionally also with progestogen-only contraceptives).

Hepatic metabolism: Interactions can occur with medicinal products that induce microsomal enzymes, which can result in increased clearance of sex hormones (such as, hydantoins, (e.g. phenytoin), barbiturates (e.g. phenobarbital), primidone, carbamazepine, rifampicin, and possibly also for oxcarbazepine, topiramate, rifabutin, felbamate, ritonavir,nelfinavir, griseofulvin and products containing St. John's wort (Hypericum perforatum)).

Maximal enzyme induction is not seen for 2-3 weeks, but may then be sustained for at least 4 weeks after the cessation of drug therapy.

Women on treatment with any of these medicinal products should temporarily use a barrier method in addition to Cerazette. With microsomal enzyme-inducing drugs, the barrier method should be used during the time of concomitant drug administration and for 28 days after their discontinuation. For women on long-term treatment with hepatic enzyme inducers a non-hormonal method of contraception should be considered.

During treatment with medical charcoal, the absorption of the steroid in the tablet may be reduced and thereby the contraceptive efficacy. Under these circumstances the advice as given for missed tablets in Section 4.2. is applicable.

Hormonal contraceptives may interfere with the metabolism of other drugs. Accordingly, plasma and tissue concentrations may either increase (e.g. cyclosporin) or decrease.

Note: The prescribing information of concomitant medications should be consulted to identify potential interactions.

Laboratory tests

Data obtained with COCs have shown that contraceptive steroids may influence the results of certain laboratory tests, including biochemical parameters of liver, thyroid, adrenal and renal function, serum levels of (carrier) proteins, e.g. corticosteroid binding globulin and lipid/lipoprotein fractions, parameters of carbohydrate metabolism and parameters of coagulation and fibrinolysis. The changes generally remain within the normal range. To what extent this also applies to progestogen-only contraceptives is not known..

Animal studies have shown that very high doses of progestagenic substances may cause masculinisation of female foetuses.

Extensive epidemiological studies have revealed neither an increased risk of birth defects in children born to women who used COCs prior to pregnancy, nor a teratogenic effect when COCs were taken inadvertently during early pregnancy. Pharmacovigilance data collected with various desogestrel-containing COCs also do not indicate an increased risk.

Cerazette does not influence the production or the quality (protein, lactose, or fat concentrations) of breast milk. However, small amounts of etonogestrel are excreted in the breast milk. As a result, 0.01 - 0.05 microgram etonogestrel per kg body weight per day may be ingested by the child (based on an estimated milk ingestion of 150 ml/kg/day).

Limited long-term follow-up data are available on children, whose mothers started using Cerazette during the 4^th to 8^th week post-partum. They were breast-fed for 7 months and followed up to 1.5 years (n=32) or to 2.5 years (n=14) of age. Evaluation of growth and physical and psychomotor development did not indicate any differences compared to nursing infants, whose mother used a copper IUD. Based on the available data Cerazette may be used during lactation. The development and growth of a nursing infant, whose mother uses Cerazette, should however, be carefully observed.

Cerazette has no or negligible influence on the ability to drive and use machines.

The most commonly reported undesirable effect in the clinical trials is bleeding irregularity.Some kind of bleeding irregularity has been reported in up to 50% of women using Cerazette. Since Cerazette causes ovulation inhibition close to 100%, in contrast to other progestogen-only pills, irregular bleeding is more common than with other progestogen-only pills. In 20 - 30% of the women, bleeding may become more frequent, whereas in another 20% bleeding may become less frequent or totally absent. Vaginal bleeding may also be of longer duration. After a couple of months of treatment, bleedings tend to become less frequent. Information, counselling and a bleeding diary can improve the woman's acceptance of the bleeding pattern.

The most commonly reported side effects in the clinical trials with Cerazette (>2.5%) were acne, mood changes, breast pain, nausea and weight increase. The side effects mentioned below have been judged by the investigators as having an established, probable or possible link to the treatment.

MedDRA version 9.0

Breast discharge may occur during use of Cerazette. On rare occasions, ectopic pregnancies have been reported (see Section 4.4 ).

In women using (combined) oral contraceptives a number of (serious) undesirable effects have been reported. These include venous thromboembolic disorders, arterial thromboembolic disorders, hormone-dependent tumours (e.g. liver tumours, breast cancer) and chloasma, some of which are discussed in more detail in Section 4.4 .

There have been no reports of serious deleterious effects from overdose. Symptoms that may occur in this case are: nausea, vomiting and, in young girls, slight vaginal bleeding. There are no antidotes and further treatment should be symptomatic.

Pharmacotherapeutic group: hormonal contraceptives for systemic use,

ATC code: G03A C09.

Cerazette^®is a progestagen-only pill, which contains the progestogen desogestrel . Like other progestogen-only pills, Cerazette is best suited for use during breast feeding and for women who may not or do not want to use oestrogens. In contrast to traditional progestogen-only pills, the contraceptive effect of Cerazette^® is achieved primarily by inhibition of ovulation. Other effects include increased viscosity of the cervical mucus.

When studied for 2 cycles, using a definition of ovulation as a progesterone level greater than 16nmol/L for 5 consecutive days, the ovulation incidence was found to be 1% (1/103) with a 95% confidence interval of 0.02%-5.29% in the ITT group (user and method failures). Ovulation inhibition was achieved from the first cycle of use. In this study, when Cerazette was discontinued after 2 cycles (56 continuous days), ovulation occurred on average after 17 days (range 7-30 days).

In a comparative efficacy trial (which allowed a maximum time of 3 hours for missed pills) the overall ITT Pearl-Index found for Cerazette^® was 0.4 (95% confidence interval 0.09-1.20), compared to 1.6 (95% confidence interval 0.42-3.96) for 30 μg levonorgestrel.

The Pearl-Index for Cerazette is comparable to the one historically found for COCs in the general COC-using population.

Treatment with Cerazette leads to decreased estradiol levels, to a level corresponding to the early follicular phase. No clinically relevant effects on carbohydrate metabolism, lipid metabolism, and haemostasis have been observed.

ABSORPTION

After oral dosing of Cerazette^® desogestrel (DSG) is rapidly absorbed and converted into etonogestrel (ENG). Under steady-state conditions, peak serum levels are reached 1.8 hours after tablet-intake and the absolute bioavailability of ENG is approximately 70%.

DISTRIBUTION

ENG is 95.5-99% bound to serum proteins, predominantly to albumin and to a lesser extent to SHBG.

METABOLISM

DSG is metabolised via hydroxylation and dehydrogenation to the active metabolite ENG. ENG is metabolised via sulphate and glucuronide conjugation.

ELIMINATION

ENG is eliminated with a mean half-life of approximately 30 hours, with no difference between single and multiple dosing. Steady-state levels in plasma are reached after 4-5 days. The serum clearance after i.v. administration of ENG is approximately 10 l per hour. Excretion of ENG and its metabolites either as free steroid or as conjugates, is with urine and faeces (ratio 1.5:1). In lactating women, ENG is excreted in breast milk with a milk/serum ratio of 0.37-0.55. Based on these data and an estimated milk intake of 150 ml/kg/day, 0.01 - 0.05 microgram etonogestrel maybe ingested by the infant.

Toxicological studies did not reveal any effects other than those which can be explained from the hormonal properties of desogestrel.

TABLET CORE

Silica, colloidal anhydrous; all-rac-α-tocopherol; lactose monohydrate; maize starch; povidone; stearic acid.

FILM COATING

Hypromellose; macrogol 400; talc; titanium dioxide (E 171).

Not applicable

3 years.

This medicinal product does not require any special storage conditions.

PVC/Aluminium blister. Each blister contains 28 tablets. Each carton contains 1, 3 or 6 blisters packed separately in an aluminium laminated sachet. Not all pack sizes may be marketed.

No special requirements.

Organon (Ireland) Ltd, P O Box 2857, Drynam Road, Swords, Co Dublin, Ireland

61/27/1

August 14, 1998/ 12 December 2007

Feb 2008