CERAZETTE Film-coated tablet Ref.[8043] Active ingredients: Desogestrel

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 use of combined oral contraceptives (COCs) the risk of having breast cancer diagnosed is slightly increased. This increased risk disappears gradually within 10 years after discontinuation of COC 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 has 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.

Depressed mood and depression are well-known undesirable effects of hormonal contraceptive use (see section 4.8). Depression can be serious and is a well-known risk factor for suicidal behaviour and suicide. Women should be advised to contact their physician in case of mood changes and depressive symptoms, including shortly after initiating the treatment.

The efficacy of Cerazette may be reduced in the event of missed tablets (Section 4.2), gastro-intestinal disturbances (Section 4.2), or concomitant medications that decrease the plasma concentration of etonogestrel, the active metabolite of desogestrel (Section 4.5).

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

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.

Interactions

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

Effect of other medicinal products on Cerazette

Interactions can occur with medicinal products that induce microsomal enzymes, which can result in increased clearance of sex hormones and may lead to breakthrough bleeding and/or contraceptive failure.

Management

Enzyme induction can occur after a few days of treatment. Maximum enzyme induction is generally observed within a few weeks. After drug therapy is discontinued, enzyme induction can last for about 4 weeks.

Short-term treatment

Women on treatment with hepatic enzyme-inducing medicinal or herbal products should be advised that the efficacy of Cerazette may be reduced. A barrier contraceptive method should be used in addition to Cerazette. The barrier method must be used during the whole time of concomitant drug therapy and for 28 days after discontinuation of the hepatic enzyme-inducing medicinal product.

Long-term treatment

For women on long-term therapy with enzyme-inducing medicinal products, an alternative method of contraception unaffected by enzyme-inducing medicinal products should be considered.

Substances increasing the clearance of contraceptive hormones (diminished contraceptive efficacy by enzyme induction) e.g.:

Barbiturates, bosentan, carbamazepine, phenytoin, primidone, rifampicin, efavirenz and possibly also felbamate, griseofulvin, oxcarbazepine, topiramate, rifabutin and products containing the herbal remedy St. John’s Wort (hypericum perforatum).

Substances with variable effects on the clearance of contraceptive hormones:

When co-administered with hormonal contraceptives, many combinations of HIV protease inhibitors (e.g. ritonavir, nelfinavir) and non-nucleoside reverse transcriptase inhibitors (e.g. nevirapine) and/or combinations with Hepatitis C virus (HCV) medicinal products (e.g. boceprevir, telaprevir), can increase or decrease plasma concentrations of progestins. The net effect of these changes may be clinically relevant in some cases.

Therefore, the prescribing information of concomitant HIV/HCV medications should be consulted to identify potential interactions and any related recommendations. In case of any doubt, an additional barrier contraceptive method should be used by women on protease inhibitor or non-nucleoside reverse transcriptase inhibitor therapy.

Substances decreasing the clearance of contraceptive hormones (enzyme inhibitors):

Concomitant administration of strong (e.g. ketoconazole, itraconazole, clarithromycin) or moderate (e.g. fluconazole, diltiazem, erythromycin) CYP3A4 inhibitors may increase the serum concentrations of progestins, including etonogestrel, the active metabolite of desogestrel.

Effects of Cerazette on other medicinal products:

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

Pregnancy

Cerazette is not indicated during pregnancy. If pregnancy occurs during treatment with Cerazette, further intake should be stopped.

Animal studies have shown that very high doses of progestogenic 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.

Breastfeeding

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 in comparison 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.

Fertility

Cerazette is indicated for the prevention of pregnancy. For information on return to fertility (ovulation), see section 5.1.

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 other undesirable effects in the clinical trials with Cerazette (>2.5%) were acne, mood changes, breast pain, nausea and weight increase. The undesirable effects are mentioned in the table below.

All undesirable effects are listed by system organ class and frequency; common (≥1/100), uncommon (1/1,000 to <1/100) and rare (<1/1,000).

Infections and infestations

Uncommon: Vaginal infection

Psychiatric disorders

Common: Mood altered, Depressed mood, Libido decreased

Nervous system disorders

Common: Headache

Eye disorders

Uncommon: ontact lens intolerance

Gastrointestinal disorders

Common: Nausea

Uncommon: Vomiting

Skin and subcutaneous tissue disorders

Common: Acne

Uncommon: Alopecia

Rare: Rash, Urticaria, Erythema nodosum

Reproductive system and breast disorders

Common: Breast pain, Menstruation irregular, Amenorrhoea

Uncommon: Dysmenorrhoea, Ovarian cyst

General disorders and administration site condition

Uncommon: Fatigue

Investigations

Common: Weight increased

* 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 addition, (aggravation of) angioedema and/or aggravation of hereditary angioedema may occur (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.

Breakthrough bleeding and/or contraceptive failure may result from interactions of other drugs (enzyme inducers) with hormonal contraceptives (see section 4.5).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard.

Not applicable.