Azalia

Desogestrel.

Each film-coated tablet contains 75 microgram desogestrel.
Excipient with known effect: 52.34 mg lactose (as lactose monohydrate).
Excipients/Inactive Ingredients: Tablet core: Lactose monohydrate, Potato starch, Povidone K-30, Colloidal anhydrous silica, Stearic acid, all-rac-α-Tocopherol.
Tablet coat: Poly[vinyl alcohol]; Titanium dioxide, E171; Macrogol 3000; Talc.

Pharmacotherapeutic group: Hormonal contraceptives for systemic use, Progestogens. ATC code: G03AC09.
Pharnacology: Pharmacodynamics: Mechanism of action: Azalia is a progestogen-only pill, which contains the progestogen desogestrel. 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.
The Pearl-Index for desogestrel is comparable to the one historically found for COCs in the general COC-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.
Pharmacokinetics: Absorption: After oral dosing of Azalia desogestrel (DSG) 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 (SHBG).
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 may be ingested by the infant.
Special populations: Effect of renal impairment: No studies were performed to evaluate the effect of renal disease on the pharmacokinetics of DSG.
Effect of hepatic impairment: No studies were conducted to evaluate the effect of hepatic disease on the pharmacokinetics of DSG. However, steroid hormones may be poorly metabolized in women with impaired liver function.
Ethnic groups: No studies were performed to assess pharmacokinetics in ethnic groups.
Toxicology: Preclinical safety data: No effects are expected other than those, which can be explained from the hormonal properties of desogestrel.

Contraception.

Recommended Dosage: Posology: To achieve contraceptive effectiveness, Azalia must be used as directed (see "How to take Azalia" and "How to start Azalia").
Special populations: Renal impairment: No clinical studies have been performed in patients with renal impairment.
Hepatic impairment: No clinical studies have been performed in patients with hepatic insufficiency. Since the metabolism of steroid hormones might be impaired in patients with severe hepatic disease, the use of Azalia in these women is not indicated as long as liver function values have not returned to normal.
Paediatric population: The safety and efficacy of Azalia in adolescents below 18 years has not been established. No data are available.
Method of administration: Oral use.
How to take Azalia: The tablets must be taken in the order directed on the package every day at about the same time of the day with some liquid as needed. One tablet is to be taken daily for 28 consecutive days. Each subsequent pack is started immediately after finishing the previous pack.
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.
Changing from a combined hormonal contraceptive (combined oral contraceptive (COC), vaginal ring, or transdermal patch): The woman should start with 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.
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); an additional contraceptive method is not necessary.
Following first-trimester abortion: After first-trimester abortion it is recommended to start immediately; an additional contraceptive method is not necessary.
Following delivery or second-trimester abortion: The woman should be advised to start at day 21 to 28 after delivery or second-trimester abortion.
When starting later, she should be advised to additionally use a barrier method for the first 7 days of tablet-taking. However, if intercourse has already occurred, pregnancy should be excluded before the actual start of Azalia use or the women has to wait for her first menstrual period.
For breastfeeding women: see "Statement on usage during pregnancy and lactation" under Use in Pregnancy & Lactation.
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 follow the same advice but also use an additional method of contraception for the next 7 days.
If tablets were missed in the very first week of use 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 gastrointestinal 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 previously mentioned "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, 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.
Route of Administration: Oral use.

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.

Hypersensitivity to the active substance or to any of the excipients listed in Description.
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 as follows 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 Azalia. 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 Azalia 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 risk in users of progestogen-only contraceptives (POCs), such as Azalia 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.
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, Azalia should be discontinued in the event of a thrombosis.
Discontinuation of Azalia should also be considered in case of long-term immobilisation due to surgery or illness.
Women with a history of thromboembolic 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 Azalia, or if a significant increase in blood pressure does not adequately respond to antihypertensive therapy, the discontinuation of Azalia should be considered.
Treatment with Azalia 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 Azalia 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 Azalia.
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.
Azalia film-coated tablets contain 52.34 mg lactose (as lactose monohydrate) and therefore should not be administered to patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption.
Effects on ability to drive and use machines: Desogestrel has no or negligible influence on the ability to drive and use machines.

Pregnancy: Azalia is not indicated during pregnancy. If pregnancy occurs during treatment with Azalia, further intake should be stopped.
According to animal data 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.
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).
According to limited long-term follow-up data on children, whose mothers started using Azalia during the 4th to 8th weeks post-partum, 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.
Fertility: Azalia is indicated for the prevention of pregnancy. For information on return to fertility (ovulation).

The most commonly reported undesirable effects were bleeding irregularity, acne, mood changes, breast pain, nausea and weight increase. The undesirable effects are mentioned in the table as follows. (See table.)

Click on icon to see table/diagram/image

Breast discharge may occur during use of Azalia. On rare occasions, ectopic pregnancies may occur (see "Precautions"). In addition, (aggravation of) angioedema and/or aggravation of hereditary angioedema may occur (see "Precautions").
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 "Precautions".
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 national reporting.

Interactions: Note: The prescribing information of concomitant medications should be consulted to identify potential interactions.
Effect of other medicinal products on Azalia: 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 Azalia may be reduced. A barrier contraceptive method should be used in addition to Azalia. 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 Azalia 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. ciclosporin) or decrease (e.g. lamotrigine).
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.

Store below 30°C in the original package in order to protect from light and moisture.

Oral Contraceptives

G03AC09 - desogestrel ; Belongs to the class of progestogens. Used as systemic contraceptives.

C