SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Azalia 75 microgram film-coated tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

One film-coated tablet contains 75 microgram desogestrel.

Excipient with known effect: 52.34 mg lactose (as lactose monohydrate). For the full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Film-coated tablet.

White or almost white, round, biconvex film-coated tablets of about 5,5 mm in diameter, with a sign “D” on one side and “75” on the other side.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Contraception

4.2    Posology and method of administration

Posology

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 bleeding. A new blister is started directly the day after the previous one.

How to start Azalia

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 Azalia 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 Azalia 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 Azalia 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 tablet

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 subsection “Management of missed tablet” 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 Azalia is taken regularly, bleeding disturbances may occur. If bleeding is 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 Azalia does not protect against HIV (AIDS) and other sexually transmitted diseases.

Paediatric population

The safety and efficacy of desogestrel in adolescents below 18 years has not yet been established. No data are available.

Method of administration For oral administration.

4.3    Contraindications

•    Hypersensitivity to the active substance or to    any of the excipients listed in section 6.1

•    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.

4.4    Special warnings and precautions for use

If any of the conditions/risk factors mentioned below is present, the benefits of progesterone use should be weighed against the possible risks for each individual woman and discussed with the woman before she decides to start with {(Invented) name}. 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 {(Invented) name} should be discontinued.

The risk for breast cancer increases in general with increasing age. During the 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 have been calculated for the respective age groups and is presented in the table below.

Age category	Expected cases COC-users	Expected cases nonusers
16-19 years	4.5	4
20-24 years	17.5	16
25-29 years	48.7	44
30-34 years	110	100
35-39 years	180	160
40-44 years	260	230

The risk in progestogen-only contraceptives (POCs), such as {(Invented) name} 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 cannot be excluded, an individual benefit/risk assessment should be made in women with pre-existing breast cancer and in women in whom breast cancer is diagnosed while using desogestrel-only pill.

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, {(Invented) name} should be discontinued in the event of a thrombosis. Discontinuation of {(Invented) name} should also be considered in case of long-term immobilisation due to surgery or illness. Women with a history of thromboembolic disorders should be 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 {(Invented) name}, or if a significant increase in blood pressure does not adequately respond to antihypertensive therapy, discontinuation with the use of {(Invented) name} should be considered.

Treatment with {(Invented) name} 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 {(Invented) name} 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 {(Invented) name}.

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.

Medical examination/consultation

Prior to the initiation or reinstitution of {(Invented) name} a complete medical history (including family history) should be taken and pregnancy must be ruled out. Blood pressure should be measured and a physical examination should be performed, guided by the contraindications (see section 4.3) and warnings (see section 4.4). The woman should also be instructed to carefully read the user leaflet and to adhere to the advice given. The frequency and nature of examinations should be based on established practice guidelines and be adapted to the individual woman.

Women should be advised that {(Invented) name} does not protect against HIV infections (AIDS) and other sexually transmitted diseases.

Reduced efficacy

The efficacy of {(Invented) name}” may be reduced in the event of e.g. missed hormone-containing tablets (see section 4.2), gastro-intestinal disturbances during hormone-containing tablet taking (see section 4.2) or concomitant medication (see section 4.5).

Changes in vaginal bleeding pattern

During the use of a progestogen-only contraceptive, vaginal bleeding may become more frequent or of longer duration in some women, whereas in others bleeding may become incidental or be totally absent. These changes are often a reason for the woman to reject the method or to be non-compliant. Acceptance of bleeding pattern can be improved by offering women who have chosen to use {(Invented) name} careful counselling on this point. Evaluation of vaginal bleeding should be done on an ad hoc basis and may include examination to exclude malignancy or pregnancy.

{(Invented) name} film-coated tablets contain 52.34 mg lactose (as lactose monohydrate). Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

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 Azalia.

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 therapy 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. cyclosporine) 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.

4.6 Fertility, pregnancy and lactation

Pregnancy

Azalia is not indicated during pregnancy. If pregnancy occurs during treatment with Azalia, 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 OCs were taken inadvertently during early pregnancy. Pharmacovigilance data collected with various desogestrel-containing COCs also do not indicate an increased risk.

Breast-feeding

Desogestrel does not influence the production or the quality (protein, lactose, or fat concentrations) of breast milk. However, small amounts of etonogestrel, (the metabolite of desogestrel) 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 Azalia 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, Azalia may be used during lactation. The development and growth of a nursing infant, whose mother uses Azalia, should, however, be carefully observed.

4.7 Effects on ability to drive and use machines

Desogestrel has no or neglible influence on the ability to drive and use machines.

4.8 Undesirable effects

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 desogestrel. Since desogestrel 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 desogestrel >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 to <1/10), uncommon (>1/1,000 to <1/100) and rare (>1/10,000 to <1/1,000).

System Organ Class (MedDRA)*	Frequency of adverse reactions
	Common > 1/100 to <1/10	Uncommon > 1/1,000 to < 1/100	Rare >1/10,000 to <1/1,000
Infections and infestations		Vaginal infection
Psychiatric disorders	Mood altered, Libido decreased, Depressed mood
Nervous system disorders	Headache
Eye disorders		Contact lens intolerance
Gastrointestinal disorders	Nausea	Vomiting
Skin and subcutaneous tissue disorders	Acne	Alopecia	Rash, Urticaria, Erythema nodosum
Reproductive system and breast disorders	Breast pain, Menstruation irregular, Amenorrhoea	Dysmenorrhoea, Ovarian cyst
General disorders and administration site condition		Fatigue
Investigations	Weight increased

*MedDRA version 16.1

Breast discharge may occur during use of Azalia. 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.

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 "www.mhra.gov.uk/yellowcard".

4.9 Overdose

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.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Hormonal contraceptives for systemic use, Progestogens, ATC code: G03AC09

Azalia film-coated tablet is a progestogen-only pill, which contains the progestogen desogestrel.

Mechanism of action

Like other progestogen-only pills, Azalia 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 Azalia 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 16 nmol/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 intention-to-treat group (user and method failures). Ovulation inhibition was achieved from the first cycle of use. In this study, when desogestrel 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 intention-to-treat Pearl-Index found for desogestrel was 0.4 (95% confidence interval 0.09-1.20), compared to 1.6 (95% confidence interval 0.42-3.96) for 30 pg levonorgestrel.

The Pearl-Index for desogestrel is comparable to the one historically found for combined OCs in the general OC-using population.

Treatment with desogestrel 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.

Paediatric population

No clinical data on efficacy and safety are available in adolescents below 18 years.

5.2 Pharmacokinetic properties

Absorption

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

Distribution

Etonogestrel is 95.5-99% bound to serum proteins, predominantly to albumin and to a lesser extent to sex hormone binding globuline (SHGB).

Biotransformation

Desogestrel is metabolised via hydroxylation and dehydrogenation to the active metabolite etonogestrel. Etonogestrel is metabolised via sulphate and glucuronide conjugation.

Elimination

Etonogestrel 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 etonogestrel is approximately 10 l per hour. Excretion of etonogestrel and its metabolites either as free steroid or as conjugates, is with urine and faeces (ratio 1.5:1). In lactating women, etonogestrel 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.

5.3 Preclinical safety data

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

6 PHARMACEUTICAL PARTICULARS

List of excipients

Tablet core:

Lactose monohydrate, Potato starch,

Povidone K-30,

Silica, colloidal anhydrous, Stearic acid, all-rac-a-Tocopherol

Tablet coat:

Poly[vinyl alcohol]; Titanium dioxide, E171; Macrogol 3000;

Talc

6.2 Incompatibilities

Not applicable.

6.3    Shelf life

Two years.

6.4    Special precautions for storage

Store in the original package in order to protect from light and moisture.

This medicinal product does not require any special temperature storage conditions.

6.5 Nature and contents of container

Azalia film-coated tablets are packaged in a blister made of transparent, hard PVC/PVDC-Aluminium foil. Each blister is placed in a laminated aluminium sachet. The blisters in the sachets are packed into a folded carton box with a patient leaflet and etui storing bag.

Pack sizes: 1x28, 3x28, 6x28, 13x28 film-coated tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

Any unused medicinal product or waste material should be disposed of in accordance with local requirements

7 MARKETING AUTHORISATION HOLDER

Gedeon Richter Plc.

Gyomroi ut 19-21 1103, Budapest Hungary

8    MARKETING AUTHORISATION NUMBER(S)

PL 04854/0089

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION

Date of first authorisation: 18/06/2010

10 DATE OF REVISION OF THE TEXT

15/02/2015