1 Name of Medicine
Drospirenone.
2 Qualitative and Quantitative Composition
White active film-coated tablets: Each tablet contains 4 mg of drospirenone.
Green placebo film-coated tablets: The tablet does not contain active substances.
Excipient(s) with known effect.
Each white active film-coated tablet contains 17.5 mg of lactose.
Each green placebo film-coated tablet contains 55.5 mg of lactose monohydrate.
For the full list of excipients, see Section 6.1 List of Excipients.3 Pharmaceutical Form
Film-coated tablet.
The active tablet is a round, white tablet with the letters "E" and "D" debossed on opposite sides, with a diameter of 5 mm.
The placebo tablet is a round, green tablet with the letter "E" and the number "4" debossed on opposite sides, with a diameter of 5 mm.
4.1 Therapeutic Indications
Contraception.
4.2 Dose and Method of Administration
Dose.
How to take Slinda.
One tablet is to be taken daily for 28 consecutive days; one white active tablet daily during the first 24 days and one green inactive tablet daily during the 4 following days. Tablets must be taken every day, at about the same time of the day, so that the interval between two tablets is always 24 hours. Tablets should be taken in the order shown on the blister. Stickers marked with the 7 days of the week are provided. The patient should choose the sticker that starts with the day they begin taking the tablets and stick it on the blister.
The first tablet of the treatment should be taken on the first day of menstrual bleeding. Thereafter tablet taking is continuous. A subsequent pack is started immediately after finishing the previous pack, without a break in daily tablet intake.
How to start Slinda.
No preceding hormonal contraceptive use (in the past month).
Tablet-taking has to start on day 1 of the patient's natural cycle (first day of her menstrual bleeding). When doing so, no additional contraceptive measures are necessary.
Starting on days 2-5 is allowed, but during the first pill pack a barrier method should be used until the patient has completed 7 days of uninterrupted white tablet-taking.
Following first-trimester abortion.
After first-trimester abortion it is recommended to start Slinda immediately after abortion took place. In that case there is no need to use an additional contraceptive method.
Following delivery or second-trimester abortion.
Contraceptive treatment with Slinda is recommended to start between 21 and 28 days after delivery or second trimester abortion. If contraceptive treatment with Slinda is initiated later but before the menstruations have returned, pregnancy must be ruled out and an additional method of contraception should be used for the first week.
For breast-feeding patients, see Section 4.6 Fertility, Pregnancy and Lactation.
Changing from a combined hormonal contraceptive (combined oral contraceptive (COC), vaginal ring or transdermal patch).
The patient should start Slinda preferably on the day after the last active tablet (the last tablet containing the active substances) of their previous COC or on the day of removal of their vaginal ring or transdermal patch. In these cases, the use of an additional contraceptive is not necessary.
The patient may also start Slinda at the latest on the day following the usual tablet-free, ring-free, patch-free or placebo tablet interval of their 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 (progestogen-only pill (POP), injection, implant) or from a progestogen-releasing intrauterine system (IUS).
The patient may switch any day from another POP and should start Slinda the day after, within 24 hours of discontinuing the previous POP. A patient may switch from an implant or following IUS removal on the same day that the implant or IUS is removed. A patient may switch from using an injectable contraceptive and should start Slinda on the day the next injection was due to occur. In all of these cases, the use of an additional contraceptive is not necessary.
Management of missed tablets.
The management of missed tablets can be guided by the following two basic rules:
1. Seven days of uninterrupted taking of active tablets is required to attain adequate suppression of the hypothalamic-pituitary-ovarian-axis. Active tablet-taking must never be discontinued for longer than 7 days.
2. The greater the number of white active tablets that are missed, and the closer they are to the green placebo tablets, the higher the risk of a pregnancy.
If the patient is less than 24 hours late in taking any white active tablet, contraceptive protection is not reduced. The patient should take the tablet as soon as they remember and should take further tablets at the usual time.
If the patient is more than 24 hours late in taking any white active tablet, contraceptive protection may be reduced.
The following advice can be given if a white active tablet is missed during:
Day 1-7.
The patient should take the last missed white active tablet as soon as they remember, even if this means taking two tablets at the same time. The patient should then continue to take tablets at the usual time.
In addition, a barrier method such as a condom should be used until they have completed 7 days of uninterrupted white active table-taking.
If intercourse took place in the preceding 7 days, the possibility of a pregnancy should be considered.
Days 8-17.
The patient should take the last missed tablet as soon as they remember, even if this means taking two tablets at the same time. The patient should then continue to take tablets at the usual time.
Provided that the patient has taken the active tablets correctly in the 7 days preceding the first missed tablet, there is no need to use extra contraceptive precautions. However, if they have missed more than 1 tablet, they should be advised to use extra precautions until they have completed 7 days of uninterrupted white active tablet-taking.
Days 18-24.
Contraceptive reliability is reduced.
Contraceptive protection can still be provided, by adhering to either of the following two options:
a. The patient should take the last missed tablet as soon as they remember, even if this means taking two tablets at the same time. They then continue to take tablets at the usual time until the white active tablets are used up. The 4 green placebo tablets from the last row should be discarded, and the next blister pack started straight away. The patient is unlikely to have a withdrawal bleed until the end of the active tablets section of the second pack, but they may experience spotting or breakthrough bleeding on active tablet-taking days.
b. Alternatively, the patient may be advised to discontinue active tablet-taking from the current blister pack. They should immediately commence taking the green placebo tablets for a maximum of 3 days, such that the total number of green placebo tablets plus missed active white tablets is not more than 4. The patient should subsequently commence taking active white tablets from a new blister pack.
Provided that in the 7 days preceding the first missed tablet the patient has taken all tablets correctly, there is no need to use extra contraceptive precautions.
If the patient has missed a tablet during the preceding 7 days, then the patient should use extra contraceptive precautions for the next 7 days and follow option a) above.
If the patient missed tablets and subsequently has no withdrawal bleed in the placebo tablet interval, the possibility of a pregnancy should be considered.
Please note: If the patient is not sure about the number or colour of tablets missed and what advice to follow, a barrier method should be used until they have completed 7 days of uninterrupted white active tablet-taking.
Green placebo tablets missed.
Contraceptive protection is not reduced. Green tablets from the last (4th) row of the blister can be disregarded. However, the missed tablets should be discarded to avoid unintentionally prolonging the placebo tablet phase.
Advice in case of gastrointestinal disturbances.
In case of severe gastrointestinal disturbances (e.g. vomiting or diarrhoea), absorption may not be complete and additional contraceptive measures should be taken.
If vomiting or diarrhoea occurs within 3-4 hours after tablet-taking, a new (replacement) tablet should be taken as soon as possible. The new tablet should be taken within 12 hours of the usual time of tablet-taking if possible. If more than 12 hours elapse, the advice concerning missed tablets, as given in Dose and Method of Administration, "Management of missed tablets", is applicable. If the patient does not want to change their normal tablet-taking schedule, they have to take the extra tablet(s) from another blister pack.
Paediatric population.
Safety and efficacy of Slinda have been established in patients of reproductive age. Safety and efficacy are expected to be the same for post pubertal adolescents under the age of 18 and patients 18 years and older. Use of this product before menarche is not indicated.
Method of administration.
For oral use.4.3 Contraindications
Progestogen-only contraceptives (POCs) like Slinda should not be used in the presence of any of the conditions listed below. Should any of the conditions appear for the first time during Slinda use, the medicinal product should be discontinued immediately.
Active venous thromboembolic disorder.
Presence or history of severe hepatic disease as long as liver function values have not returned to normal.
Severe renal insufficiency or acute renal failure.
Known or suspected sex-steroid sensitive malignancies.
Undiagnosed vaginal bleeding.
Known or suspected pregnancy.
Hypersensitivity to the active substance or to any of the excipients listed in Section 6.1 List of Excipients.
4.4 Special Warnings and Precautions for Use
If any of the conditions/risk factors mentioned below are present, the benefits of Slinda should be weighed against the possible risks for each individual patient and discussed with the patient before they decide to start using Slinda. In the event of aggravation, exacerbation or first appearance of any of these conditions, the patient should contact their physician. The physician should then decide whether Slinda use should be discontinued.
Hyperkalaemia.
Drospirenone is an aldosterone antagonist with potassium sparing properties. In most cases, no increase of potassium levels is to be expected. However, it's recommended to check serum potassium levels during the first treatment cycle in patients presenting with renal insufficiency and pre-treatment serum potassium in the upper reference range, and during concomitant use of potassium sparing medicinal products (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Circulatory disorders.
From epidemiological studies there is little evidence for an association between progestogen-only preparations and an increased risk of myocardial infarction or cerebral thromboembolism. Rather, the risk of cardiovascular and cerebral events is related to increasing age, hypertension, and smoking. In patients with hypertension the risk of stroke may be slightly enhanced by progestogen-only preparations.
Although not statistically significant, some studies indicate that there may be a slightly increased risk of venous thromboembolism (deep venous thrombosis, pulmonary embolism) associated with the use of progestogen-only preparations. Generally recognised risk factors for venous thromboembolism (VTE) include a positive personal or family history (VTE in a sibling or a parent at a relatively early age), age, obesity, prolonged immobilisation, major surgery or major trauma.
Treatment should be stopped at once if there are symptoms of an arterial or venous thrombotic event or suspicion thereof and discontinuation of Slinda should be considered in case of prolonged immobilisation due to surgery or illness.
Bone metabolism.
Treatment with Slinda leads to decreased estradiol serum levels, to a level corresponding with the early follicular phase. It is currently unknown whether the decrease in estradiol serum levels may have a clinically relevant effect on bone mineral density. Loss of bone mineral density is of particular concern during adolescence and early adulthood, a critical period of bone accretion. It is unknown if bone mineral density decrease in this population will reduce peak bone mass and increase the risk for fracture in later life.
Breast cancer.
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 patients who are currently using oral contraceptives (OCs), mainly using estrogen-progestogen preparations. The excess risk gradually disappears during the course of the 10 years after cessation of combined OC (COC) use. Because breast cancer is rare in patients under 40 years of age, the excess number of breast cancer diagnoses in current and recent COC patients is small in relation to the overall risk of breast cancer. These studies do not provide evidence for causation. The observed pattern of increased risk may be due to an earlier diagnosis of breast cancer in OC patients, the biological effects of OCs or a combination of both. The breast cancers diagnosed in patients of OCs tend to be less advanced clinically than the cancers diagnosed in those who have never used OCs.
The risk of having breast cancer diagnosed in patients of progestogen-only preparations is possibly of similar magnitude to that associated with COC. However, for progestogen-only preparations, the evidence is based on much smaller populations of patients and so is less conclusive than that for COCs.
Other tumours.
In rare cases, benign liver tumours, and even more rarely, malignant liver tumours have been reported in patients of combined hormonal contraceptives. In isolated cases, these tumours have led to life-threatening intra-abdominal haemorrhages. A hepatic tumour should be considered in the differential diagnosis when severe upper abdominal pain, liver enlargement or signs of intra-abdominal haemorrhage occur.
Ectopic pregnancy.
The protection with traditional POPs 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 POPs. Despite the fact that Slinda consistently inhibits ovulation ectopic pregnancy should be taken into account in the differential diagnosis if the patient presents amenorrhoea or abdominal pain.
Liver function.
Discontinue Slinda if jaundice develops. Steroid hormones may be poorly metabolised in patients with impaired liver function. Acute or chronic disturbances of liver function may require the discontinuation of Slinda use until markers of liver function return to normal and Slinda causation has been excluded.
Diabetes.
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 POPs such as Slinda. However, diabetic patients should be carefully observed during the first months of use. Special attention should be paid to diabetic patients with vascular involvement.
Other conditions.
If a sustained hypertension develops during the use of Slinda, or if a significant increase in blood pressure does not adequately respond to antihypertensive therapy, the discontinuation of Slinda should be considered.
Like with any other hormonal contraceptive, chloasma may occasionally occur, especially in patients with a history of chloasma gravidarum. Patients with a tendency to chloasma should avoid exposure to the sun or ultraviolet radiation whilst taking Slinda.
Depressed mood and depression are well-known undesirable effects of hormonal contraceptive use (see Section 4.8 Adverse Effects (Undesirable Effects)). Depression can be serious and is well-known risk factor for suicidal behaviour and suicide. Patients should be advised to contact their physician in case of mood changes and depressive symptoms, including shortly after initiating the treatment.
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.
Excipients with known effect.
Each white active tablet contains 17.50 mg of lactose and each green placebo tablet contains 55.50 mg of lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Medical examination/consultation.
Prior to the initiation or reinstitution of Slinda 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 contra-indications (see Section 4.3 Contraindications) and warnings (see Section 4.4 Special Warnings and Precautions for Use). The patient should also be instructed to carefully read the patient 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 patient.
Patients should be advised that oral contraceptives do not protect against HIV infections (AIDS) and other sexually transmitted diseases.
Changes in the menstrual bleeding pattern.
Disruption of the menstrual bleeding pattern may occur during use of hormonal contraceptives that inhibit ovulation, including Slinda (see Section 5.1 Pharmacodynamic Properties).
If the 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.
Reduced efficacy.
The efficacy of POPs may be reduced in the event of missed tablets (see Section 4.2 Dose and Method of Administration), gastro-intestinal disturbances (see Section 4.2 Dose and Method of Administration) or concomitant medication (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Use in hepatic impairment.
Discontinue Slinda if jaundice develops. Steroid hormones may be poorly metabolised in patients with impaired liver function. Acute or chronic disturbances of liver function may require the discontinuation of Slinda use until markers of liver function return to normal and Slinda causation has been excluded.
Use in renal impairment.
Slinda is contraindicated for use in patients with severe renal insufficiency or acute renal failure.
Use in the elderly.
No data available.
Paediatric use.
See Section 4.2 Dose and Method of Administration, Paediatric population.
Effects on laboratory tests.
The use of contraceptive steroids may influence the results of certain laboratory tests, including biochemical parameters of the 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.4.5 Interactions with Other Medicines and Other Forms of Interactions
Influence of other medicinal products on Slinda.
Interactions can occur between Slinda and other medicinal products that induce microsomal enzymes. This can result in increased clearance of sex hormones and may lead to breakthrough bleeding and/or contraceptive failure.
Management.
Enzyme induction can already be observed after a few days of treatment. Maximum enzyme induction is generally seen within a few weeks. After drug therapy is discontinued, enzyme induction may be sustained for about 4 weeks.
Short-term treatment.
Patients on treatment with enzyme inducing drugs should temporarily use a barrier method or another method of contraception in addition to the POP. The barrier method must be used during the whole time of the concomitant drug therapy and for 28 days after its discontinuation.
If the drug therapy runs beyond the end of the active tablets in the POP pack, the placebo tablets must be discarded, and the next POP pack should be started right away.
Long-term treatment.
In patients on long-term treatment with enzyme-inducing active substances, another reliable, nonhormonal, method of contraception is recommended.
The following interactions have been reported in the literature (mainly with combined contraceptives but occasionally also with POPs).
Substances increasing the clearance of contraceptive hormones (diminished contraceptive efficacy by enzyme induction) e.g.
Barbiturates, bosentan, carbamazepine, phenytoin, primidone, rifampicin and HIV medication ritonavir, nevirapine and efavirenz and possibly also felbamate, griseofulvin, oxcarbazepine, topiramate 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 sex hormones, many combinations of HIV protease inhibitors (e.g. ritonavir, nelfinavir) and non-nucleoside reverse transcriptase inhibitors (e.g. nevirapine, efavirenz) 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 patients on protease inhibitor or non-nucleoside reverse transcriptase inhibitor therapy.
Substances decreasing the clearance of contraceptive hormones (enzyme inhibitors).
The clinical relevance of potential interactions with enzyme inhibitors remain unknown.
Concomitant administration of strong or moderate CYP3A4 inhibitors such as azole antifungals (e.g. fluconazole, itraconazole, ketoconazole, voriconazole), verapamil, macrolides (e.g. clarithromycin, erythromycin), diltiazem and grapefruit juice can increase plasma concentrations of the progestogen.
In a multiple dose study evaluating the daily (10 days) co-administration of the strong CYP3A4 inhibitor ketoconazole with two drospirenone-containing hormone presentations (drospirenone 3 mg + estradiol 1.5 mg and drospirenone 3 mg + ethinylestradiol 0.02 mg) the AUC(0-24h) of drospirenone was 2.3-fold and 2.7-fold respectively.
Influence of Slinda on other medicinal products.
Hormonal contraceptives may affect the metabolism of certain other active substances. Accordingly, plasma and tissue concentrations may either increase (e.g. cyclosporine) or decrease (e.g. lamotrigine).
Based on in vitro studies and in vivo interaction studies in female volunteers using omeprazole, simvastatin and midazolam as marker substrate, a clinically relevant interaction of drospirenone with the cytochrome P450 mediated metabolism of other active substances is unlikely.
Pharmacodynamic interactions.
Published data did not show a significant effect on serum potassium following the concomitant use of drospirenone and ACE-inhibitors or NSAIDs in patients without renal insufficiency. The concomitant use of Slinda with aldosterone antagonists or potassium-sparing diuretics has not been studied. In this case, serum potassium should be tested during the first treatment cycle (see Section 4.4 Special Warnings and Precautions for Use).4.6 Fertility, Pregnancy and Lactation
Effects on fertility.
Slinda is indicated for the prevention of pregnancy.
(Category B3)
Slinda is contraindicated in pregnancy. If pregnancy occurs during treatment with Slinda, further intake should be stopped.
Epidemiological studies have revealed neither an increased risk of birth defects in children born to patients who used drospirenone prior to pregnancy, nor a teratogenic effect when drospirenone was taken inadvertently during pregnancy.
Drospirenone and/or its metabolites crossed the placenta and entered the fetus when administered orally to pregnant rats and rabbits.
Animal studies revealed adverse effects on embryofetal development. With dosing during the period of major organogenesis, drospirenone impaired fetal growth and development in rats at doses ≥ 15 mg/kg/day and in rabbits at ≥ 30 mg/kg/day (yielding systemic exposure 14 and 4 times higher in the respective species than that in patients at the maximum recommended human dose of Slinda, based on plasma AUC). Treatment at 100 mg/kg/day in rabbits caused abortions (relative exposure, 15). Feminisation of male fetuses was observed in rats with subcutaneous administration at ≥ 3 mg/kg/day during the period of sexual differentiation, consistent with drospirenone's known anti-androgenic activity.
Based on these animal data, undesirable effects due to hormonal action of the active compound cannot be excluded.
Negligible amounts of drospirenone are excreted in the breast milk. The daily dose of drospirenone in the baby is < 1% of the maternal dose. Thus, at therapeutic doses of Slinda, no effects on the breastfed newborns/infants are anticipated. Based on the available data Slinda may be used during lactation.4.7 Effects on Ability to Drive and Use Machines
No studies on the influence on the ability to drive and use machines have been performed with Slinda.
No effects on ability to drive and use machines have been observed in patients of oral hormonal contraceptives.
4.8 Adverse Effects (Undesirable Effects)
Changes in the bleeding pattern as an adverse reaction frequently reported in the clinical trials (see Section 5.1 Pharmacodynamic Properties).
The most commonly reported adverse reactions in long-term clinical trials of more than 9 cycles of treatment with drospirenone (2,700 patients) were acne (3.8%), metrorrhagia (2.9%), headache (2.7%) and breast pain (2.2%).
Tabulated list of adverse reactions.
Adverse reactions that have been reported in short- and long-term clinical trials with Slinda are listed in Table 1.
All adverse reactions are listed by system organ class and frequency: very common (> 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000).
Reporting of suspected adverse reactions.
Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting-problems.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 slight vaginal bleeding. There are no antidotes and further treatment should be symptomatic.
Drospirenone is a spironolactone analogue which has antimineralocorticoid properties. Serum potassium and sodium, and evidence of metabolic acidosis, should be monitored in cases of overdose.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).
5 Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmacotherapeutic group: Hormonal contraceptives for systemic use, progestogens; ATC code: G03AC10.
Mechanism of action.
Slinda is a progestogen-only-pill which contains the progestogen drospirenone, derived from spironolactone.
In a therapeutic dosage, drospirenone also possesses antiandrogenic and mild antimineralocorticoid properties. It has no estrogenic, glucocorticoid and antiglucocorticoid activity. This gives drospirenone a pharmacological profile closely resembling the natural hormone progesterone.
There are indications from clinical studies that for combined hormonal contraceptives containing 3 mg drospirenone and 0.02 mg ethinylestradiol, the mild antimineralocorticoid properties result in a mild antimineralocorticoid effect.
Pharmacodynamic effects.
The contraceptive effect of Slinda is achieved primarily by inhibition of ovulation. Drospirenone exhibits a strong anti-gonadotropic activity inhibiting follicular stimulation and ovulation by suppression of the luteinising hormone (LH). In addition, drospirenone has an effect on the cervix increasing the viscosity of the cervical mucus. Drospirenone also exerts progestational effects on the endometrium, which becomes thinner.
Clinical efficacy and safety.
The ovulation inhibition potential of Slinda (drospirenone 4 mg non-micronised administered daily for 24 days) as reflected by the ovarian activity [follicular growth, endogenous estradiol and progesterone serum concentrations (Hoogland score)] in comparison to 0.075 mg of desogestrel administered daily for 28 days over two treatment cycles was assessed in a randomised, open-label Phase II study conducted in 60 healthy young patients. In cycle 1, no ovulation was observed in either treatment. Whereas one ovulation was observed for Slinda and 0.075 mg of desogestrel group in cycle 2.
In a Phase II study performed in 130 patients, Slinda maintained the inhibition of ovulation in spite of four fixed scheduled delayed intakes of 24 hours each on day 3, 6, 11 and 22.
In two multicentre Phase III European clinical trials, one single-arm study and one controlled study vs. desogestrel 0.075 mg, 1596 patients have been treated for 9 up to 13 consecutive cycles with Slinda and 341 with desogestrel for 9 months. In the pooled analysis of these two studies the following Pearl Indexes were calculated:
Pearl Index (18-45 years of age), user + method failure: 0.73 (upper limit 95% confidence interval 1.43);
Pearl Index (18-35 years of age), user + method failure: 0.93 (upper limit 95% confidence interval 1.84).
In a single arm multicentre Phase III clinical trial performed in 39 US sites, the efficacy population consisted of 915 non-breastfeeding subjects aged ≤ 35 years with 5,337 evaluable cycles. The PI (95% CI) for evaluable cycles based on 915 subjects, 12 confirmed on-drug pregnancies and 5337 evaluable cycles was 2.9 (1.5; 5.1).
Bleeding pattern.
The bleeding pattern during use of Slinda was assessed in a 9-month comparative, double blind trial vs desogestrel 0.075 mg, used continuously.
The occurrence of a withdrawal bleeding (defined as a bleeding starting during the 4 hormone-free days of Slinda lasting for up to 8 consecutive days), was highest - occurring in less than 40% - during the first cycles and decreased with time. After 9 months of use, a withdrawal bleeding was recorded in less than 20% of patients.
The mean number of bleeding/spotting days in the Slinda group vs the desogestrel group during the cycles 2-4 was 13.1 ± 13.0 vs 16.9 ± 16.9, respectively. The mean number of bleeding/spotting days during cycles 7-9, was 9.7 ± 10.4 vs 10.8 ± 13.3, respectively.
In the same study, the proportion of subjects without any bleeding/spotting (amenorrhea) during cycles 2-4 was 20.1% for Slinda and 13.5% for desogestrel. The proportion of subjects with amenorrhea increased in cycles 7-9 to 26.7% for Slinda and to 32.1% in the desogestrel group.
The number of subjects with prolonged bleeding (> 10 consecutive days) for Slinda vs desogestrel was 18.1% and 26.1%, respectively, during cycles 2-4 and 9.1% and 16.7%, respectively, during cycles 7-9.
The rate of subjects who withdrew from the study due to bleeding related adverse events was 3.3% in the Slinda group and 6.6% in the desogestrel group.
Paediatric population.
A phase III study was conducted in Europe to evaluate tolerability, safety and acceptability of Slinda. 103 adolescents were included in a 6-cycle core part and 7 additional cycles (extension phase) for a total of 13 cycles, Slinda was well tolerated and accepted by the subjects.
Bleeding pattern with Slinda was assessed and data were generally consistent with those from the Phase 3 studies in adults. Slinda was associated with a decrease in the percentage of subjects experiencing bleeding or spotting over time.
5.2 Pharmacokinetic Properties
Absorption.
Orally administered drospirenone is rapidly and almost completely absorbed. Maximum concentrations of Slinda active substance in plasma of about 28 nanogram/mL are reached at about 3-4 h after single ingestion. Concomitant ingestion of food has no influence on the extent of absorption of drospirenone.
The pharmacokinetics of Slinda after single and repeated dose has been studied in comparison with the marketed product containing 3 mg of micronised drospirenone in combination with ethinyl estradiol. After multiple dose administration, the relative bioavailability of Slinda was 76.51% for AUCt,ss. The accumulation ratio expressed by Rac (AUC) was 1.9256 while it was 2.7684 for the combined product. These findings indicate that the total exposure to drospirenone is lower for Slinda than for the combined product on the market in a cycle of 28 days.
Distribution.
Drospirenone is 95% - 97% protein bound in serum. Drospirenone binds to serum albumin and does not bind to sex hormone binding globulin (SHBG) or corticosteroid binding globulin (CBG). The mean apparent volume of distribution of drospirenone is 4 L/kg.
Metabolism.
Drospirenone is extensively metabolised after oral administration. Two major non-pharmacologically active metabolites in the plasma are the acid form of drospirenone, generated by opening of the lactone ring, and the 4,5-dihydro-drospirenone-3-sulfate, both of which are formed without involvement of the cytochrome P450 system. Drospirenone is also subject to oxidative metabolism catalysed by CYP3A4.
In vitro, drospirenone is capable of inhibiting, from a weak to moderate level, the cytochrome P450 enzymes CYP1A1, CYP2C9, CYP2C19 and CYP3A4.
Elimination.
After oral administration, plasma drospirenone levels decrease with a terminal half-life of 32 h.
The metabolic clearance rate of drospirenone in serum is 1.5 ± 0.2 mL/min/kg. Drospirenone is excreted only in trace amounts in unchanged form. The metabolites of drospirenone are excreted with the faeces and urine at an excretion ratio of about 1.2 to 1.4.
Linearity/non-linearity.
The pharmacokinetics of oral drospirenone is dose proportional following single doses ranging from 1-10 mg.
Steady-state conditions.
During a treatment cycle, maximum steady-state concentrations of drospirenone in serum of about 40 nanogram/mL are reached after about 7 days of treatment. Plasma drospirenone levels accumulate by a factor of about 2 as a consequence of the ratio of terminal half-life and dosing interval.
Special populations.
Effect of renal impairment.
No studies have been conducted to evaluate the effect of renal impairment on the pharmacokinetics of Slinda. However, steady-state serum drospirenone levels in patients under treatment with a COC containing drospirenone with mild renal impairment (creatinine clearance CLcr, 50-80 mL/min) were comparable to those of patients with normal renal function. The serum drospirenone levels were on average 37% higher in patients with moderate renal impairment (CLcr, 30 - 50 mL/min) compared to those in patients with normal renal function. Drospirenone treatment was also well tolerated by patients with mild and moderate renal impairment. Drospirenone treatment did not show any clinically significant effect on serum potassium concentration.
Effect of hepatic impairment.
No studies have been conducted to evaluate the effect of hepatic disease on the pharmacokinetics of Slinda. However, steroid hormones may be poorly metabolised in patients with impaired liver function.
In a single dose study in patients taking a COC containing drospirenone, oral clearance (CL/F) was decreased approximately 50% in volunteers with moderate hepatic impairment as compared to those with normal liver function. The observed decline in drospirenone clearance in volunteers with moderate hepatic impairment did not translate into any apparent difference in terms of serum potassium concentrations. Even in the presence of diabetes and concomitant treatment with spironolactone (two factors that can predispose a patient to hyperkalaemia) an increase in serum potassium concentrations above the upper limit of the normal range was not observed. It can be concluded that drospirenone is well tolerated in patients with mild or moderate hepatic impairment (Child-Pugh B).
Ethnic groups.
No studies were performed to assess pharmacokinetics in ethnic groups.
5.3 Preclinical Safety Data
Genotoxicity.
Drospirenone was found to induce chromosome aberrations in human peripheral lymphocytes. However, drospirenone was not mutagenic in bacterial and mammalian cell gene mutation assays in vitro, and was not clastogenic in mouse micronucleus assays in vivo. Interactions between drospirenone and the DNA of liver cells, which indicate a genotoxic potential, were found in in vitro and in vivo studies in rats. No such finding was observed in human liver cells in vitro.
Carcinogenicity.
No treatment-related increase in tumour incidence was observed with drospirenone in 2-year studies in mice and rats, involving oral administration at doses up to 10 mg/kg/day (yielding systemic exposure 4.5 and 12 times higher in the respective species than that in patients at the maximum recommended human dose of Slinda, based on plasma AUC).
Although these long-term animal studies did not indicate carcinogenic activity for drospirenone, it should be borne in mind that sex steroids can promote the growth of certain hormone-dependent tissues and tumours.6 Pharmaceutical Particulars
6.1 List of Excipients
White active film-coated tablets.
Tablet core.
Microcrystalline cellulose, lactose, colloidal anhydrous silica, magnesium stearate.
Tablet coat.
Polyvinyl alcohol, titanium dioxide, macrogol 3350, purified-talc.
Green placebo film-coated tablets.
Tablet core.
Lactose monohydrate, maize starch, povidone, colloidal anhydrous silica, magnesium stearate.
Tablet coat.
Hypromellose, triacetin, polysorbate 80, titanium dioxide, indigo carmine, iron oxide yellow.
6.2 Incompatibilities
Not applicable.
6.3 Shelf Life
In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.
6.4 Special Precautions for Storage
Store below 25°C.
6.5 Nature and Contents of Container
Transparent PVC-PVDC/Aluminium blister containing 28 film-coated tablets (24 white active film-coated tablets and 4 green placebo film-coated tablets).
Pack sizes: calendar-packs containing 1x28 (starter pack), 1x28, 3x28 and 4x28 film-coated tablets.*
*Not all pack sizes may be marketed.
6.6 Special Precautions for Disposal
In Australia, any unused medicinal product or waste material should be disposed of in accordance with local requirements.
6.7 Physicochemical Properties
Chemical structure.
CAS number.
67392-87-4.
Molecular formula.
C24H30O3.
Molecular weight.
366.5 g/mol.7 Medicine Schedule (Poisons Standard)
Schedule 4 - Prescription Only Medicine.
Summary Table of Changes
