sign in sign up
<<
Home , Progestogen (medication)

SLINDA® ( 4 mg) TABLETS

AUSTRALIAN PRODUCT INFORMATION AUSTRALIAN PRODUCT 4.2 Dose And Method Of INFORMATION Administration SLINDA® (DROSPIRENONE) TABLETS Dose

How to take SLINDA

1. NAME OF THE One is to be taken daily for 28 Drospirenone consecutive days; one white active tablet daily during the first 24 days and one green inactive tablet 2. QUALITATIVE daily during the 4 following days. Tablets must be taken every day, at about AND QUANTITATIVE the same time of the day, so that the COMPOSITION interval between two tablets is always 24 hours. Tablets should be taken in White active film-coated tablets: the order shown on the blister. Stickers Each tablet contains 4 mg of marked with the 7 days of the week are drospirenone. provided. The patient should choose the sticker that starts with the day they Green film-coated tablets: begin taking the tablets and stick it on The tablet does not contain active the blister. substances. The first tablet of the treatment should Excipient(s) with known effect: be taken on the first day of menstrual Each white active film-coated tablet bleeding. Thereafter tablet taking contains 17.5 mg of lactose. is continuous. A subsequent pack is started immediately after finishing the Each green placebo film-coated tablet previous pack, without a break in daily contains 55.5 mg of lactose monohydrate. tablet intake.

For the full list of excipients, see section How to start SLINDA 6.1 List of Excipients. No preceding hormonal contraceptive use (in the past month) Tablet-taking has to start on day 1 of the 3. PHARMACEUTICAL FORM patient’s natural cycle (first day of her menstrual bleeding). When doing so, no Film-coated tablet additional contraceptive measures are necessary. The active tablet is a round, white tablet with the letters “E” and “D” debossed on Starting on days 2-5 is allowed, but opposite sides, with a diameter of 5 mm. during the first pill pack a barrier method should be used until the patient The placebo tablet is a round, green has completed 7 days of uninterrupted tablet with the letter “E” and the number white tablet-taking. “4” debossed on opposite sides, with a diameter of 5 mm. Following first-trimester abortion After first-trimester abortion it is recommended to start SLINDA immediately after abortion took place. 4. CLINICAL PARTICULARS In that case there is no need to use an 4.1 Therapeutic Indications additional contraceptive method.

Contraception Following delivery or second-trimester Management of missed tablets abortion The management of missed tablets can Contraceptive treatment with SLINDA is be guided by the following two basic recommended to start between 21 and rules: 28 days after delivery or second trimester 1. Seven days of uninterrupted taking abortion. If contraceptive treatment with SLINDA is initiated later but before the of active tablets is required to have returned, attain adequate suppression of the must be ruled out and an additional hypothalamic-pituitary-ovarian-axis. method of contraception should be used Active tablet-taking must never be for the first week. discontinued for longer than 7 days. For -feeding patients, see section 2. The greater the number of white 4.6. , Pregnancy and active tablets that are missed, and the closer they are to the green Changing from a combined hormonal placebo tablets, the higher the risk of contraceptive (combined oral a pregnancy. contraceptive (COC), or patch) The patient should start SLINDA If the patient is less than 24 hours preferably on the day after the last late in taking any white active tablet, active tablet (the last tablet containing contraceptive protection is not reduced. the active substances) of their previous The patient should take the tablet as COC or on the day of removal of their soon as they remember and should take vaginal ring or . In further tablets at the usual time. these cases, the use of an additional If the patient is more than 24 hours contraceptive is not necessary. late in taking any white active tablet, contraceptive protection may be The patient may also start SLINDA at reduced. the latest on the day following the usual The following advice can be given if a tablet-free, ring-free, patch-free or white active tablet is missed during: placebo tablet interval of their previous combined hormonal contraceptive, Day 1-7 but during the first 7 days of tablet taking an additional barrier method is The patient should take the last missed recommended. white active tablet as soon as they remember, even if this means taking Changing from a -only two tablets at the same time. The patient method (progestogen-only pill should then continue to take tablets at (POP), , implant) or from a the usual time. progestogen-releasing intrauterine system (IUS) In addition, a barrier method such as a The patient may switch any day condom should be used until they have from another POP and should start completed 7 days of uninterrupted SLINDA the day after, within 24 hours white active table-taking. of discontinuing the previous POP. A patient may switch from an implant If intercourse took place in the or following IUS removal on the same preceding 7 days, the possibility of a day that the implant or IUS is removed. pregnancy should be considered. A patient may switch from using an injectable contraceptive and should start SLINDA on the day the next injection Days 8-17 was due to occur. In all of these cases, the use of an additional contraceptive is The patient should take the last missed not necessary. tablet as soon as they remember, even if this means taking two tablets at the same Provided that in the 7 days preceding time. The patient should then continue to the first missed tablet the patient has take tablets at the usual time. taken all tablets correctly, there is no need to use extra contraceptive Provided that the patient has taken the precautions. active tablets correctly in the 7 days preceding the first missed tablet, there If the patient has missed a tablet is no need to use extra contraceptive during the preceding 7 days, then the precautions. However, if they have patient should use extra contraceptive missed more than 1 tablet, they should precautions for the next 7 days and be advised to use extra precautions follow option a) above. until they have completed 7 days of uninterrupted white active tablet-taking. If the patient missed tablets and subsequently has no withdrawal bleed Days 18-24 in the placebo tablet interval, the possibility of a pregnancy should be Contraceptive reliability is reduced. considered. Contraceptive protection can still be provided, by adhering to either of the Please note: If the patient is not sure following two options: about the number or colour of tablets missed and what advice to follow, a barrier method should be used a. The patient should take the last until they have completed 7 days of missed tablet as soon as they uninterrupted white active tablet-taking. remember, even if this means taking two tablets at the same time. They Green placebo tablets missed then continue to take tablets at the Contraceptive protection is not reduced. Green tablets from the last (4th) row usual time until the white active tablets of the blister can be disregarded. are used up. The 4 green placebo However, the missed tablets should tablets from the last row should be be discarded to avoid unintentionally discarded, and the next blister pack prolonging the placebo tablet phase. started straight away. The patient is unlikely to have a withdrawal bleed Advice in case of gastrointestinal until the end of the active tablets disturbances In case of severe gastrointestinal section of the second pack, but disturbances (e.g., vomiting or they may experience spotting or diarrhoea), absorption may not be breakthrough bleeding on active complete and additional contraceptive tablet-taking days. measures should be taken. b. Alternatively, the patient may be If vomiting or diarrhoea occurs within advised to discontinue active tablet- 3-4 hours after tablet-taking, a new taking from the current blister pack. (replacement) tablet should be taken They should immediately commence as soon as possible. The new tablet taking the green placebo tablets for should be taken within 12 hours of the a maximum of 3 days, such that the usual time of tablet-taking if possible. If more than 12 hours elapse, the advice total number of green placebo tablets concerning missed tablets, as given plus missed active white tablets is in Section 4.2 Dose and Method of not more than 4. The patient should Administration, “Management of missed subsequently commence taking active tablets”, is applicable. If the patient does white tablets from a new blister pack. not want to change their normal tablet- taking schedule, they have to take the extra tablet(s) from another blister pack. Paediatric population exacerbation or first appearance of any Safety and efficacy of SLINDA have been of these conditions, the patient should established in patients of reproductive contact their physician. The physician age. Safety and efficacy are expected should then decide whether SLINDA use to be the same for post pubertal should be discontinued. adolescents under the age of 18 and patients 18 years and older. Use of Hyperkalaemia this product before menarche is not Drospirenone is an indicated. antagonist with potassium sparing properties. In most cases, no increase Method of administration of potassium levels is to be expected. For oral use. However, it’s recommended to check serum potassium levels during the first 4.3 Contraindications treatment cycle in patients presenting with renal insufficiency and pre- Progestogen-only contraceptives (POCs) treatment serum potassium in the like SLINDA should not be used in the upper reference range, and during presence of any of the conditions listed concomitant use of potassium sparing below. Should any of the conditions medicinal products (see section 4.5 appear for the first time during SLINDA Interaction with other and use, the medicinal product should be other forms of interactions). discontinued immediately. Circulatory disorders From epidemiological studies there • Active venous thromboembolic is little evidence for an association disorder. between progestogen-only preparations and an increased risk of myocardial • Presence or history of severe hepatic infarction or cerebral thromboembolism. disease as long as function Rather, the risk of cardiovascular and values have not returned to normal. cerebral events is related to increasing age, , and . In • Severe renal insufficiency or acute patients with hypertension the risk of renal failure. may be slightly enhanced by progestogen-only preparations. • Known or suspected sex- sensitive malignancies. Although not statistically significant, some studies indicate that there may • Undiagnosed . be a slightly increased risk of venous • Known or suspected pregnancy. thromboembolism (deep venous , ) • Hypersensitivity to the active associated with the use of progestogen- substance or to any of the excipients only preparations. Generally recognised listed in Section 6.1 List of Excipients. risk factors for venous thromboembolism (VTE) include a positive personal or family history (VTE in a sibling or a parent 4.4 Special Warnings And Precautions at a relatively early age), age, obesity, For Use prolonged immobilisation, major surgery or major trauma. If any of the conditions/risk factors mentioned below are present, the Treatment should be stopped at once benefits of SLINDA should be weighed if there are symptoms of an arterial or against the possible risks for each venous thrombotic event or suspicion individual patient and discussed with the thereof and discontinuation of SLINDA patient before they decide to start using should be considered in case of prolonged SLINDA. In the event of aggravation, immobilisation due to surgery or illness.

Bone tumours have been reported in patients Treatment with SLINDA leads to of combined hormonal contraceptives. decreased serum levels, to In isolated cases, these tumours have a level corresponding with the early led to life-threatening intra-abdominal follicular phase. It is currently unknown haemorrhages. A hepatic tumour whether the decrease in estradiol serum should be considered in the differential levels may have a clinically relevant diagnosis when severe upper abdominal effect on bone mineral density. Loss of pain, liver enlargement or signs of intra- bone mineral density is of particular abdominal haemorrhage occur. concern during adolescence and early adulthood, a critical period of bone Ectopic pregnancy accretion. It is unknown if bone mineral The protection with traditional POPs density decrease in this population will against ectopic is not reduce peak bone mass and increase as good as with combined oral the risk for fracture in later life. contraceptives, which has been associated with the frequent occurrence of ovulations Breast during the use of POPs. Despite the fact A meta-analysis from 54 epidemiological that SLINDA consistently inhibits studies reported that there is a slightly ectopic pregnancy should be taken into increased (RR = 1.24) of account in the differential diagnosis if having diagnosed in the patient presents amenorrhoea or patients who are currently using oral abdominal pain. contraceptives (OCs), mainly using -progestogen preparations. Liver function The excess risk gradually disappears Discontinue SLINDA if jaundice during the course of the 10 years after develops. Steroid hormones may be cessation of combined OC (COC) use. poorly metabolised in patients with Because breast cancer is rare in patients impaired liver function. Acute or chronic under 40 years of age, the excess disturbances of liver function may number of breast cancer diagnoses in require the discontinuation of SLINDA current and recent COC patients is small use until markers of liver function return in relation to the overall risk of breast to normal and SLINDA causation has cancer. These studies do not provide been excluded. evidence for causation. The observed pattern of increased risk may be due to an earlier diagnosis of breast cancer Although may have an in OC patients, the biological effects effect on peripheral insulin resistance of OCs or a combination of both. The and glucose tolerance, there is no breast diagnosed in patients of evidence for a need to alter the OCs tend to be less advanced clinically therapeutic regimen in diabetics using than the cancers diagnosed in those POPs such as SLINDA. However, diabetic who have never used OCs. patients should be carefully observed during the first months of use. Special The risk of having breast cancer attention should be paid to diabetic diagnosed in patients of progestogen- patients with vascular involvement. only preparations is possibly of similar magnitude to that associated with Other conditions COC. However, for progestogen-only If a sustained hypertension develops preparations, the evidence is based on during the use of SLINDA, or if a much smaller populations of patients and significant increase in so is less conclusive than that for COCs. does not adequately respond to antihypertensive therapy, the Other tumours discontinuation of SLINDA should be In rare cases, benign liver tumours, considered. and even more rarely, malignant liver Like with any other hormonal patient leaflet and to adhere to the contraceptive, chloasma may advice given. The frequency and nature occasionally occur, especially in patients of examinations should be based on with a history of chloasma gravidarum. established practice guidelines and be Patients with a tendency to chloasma adapted to the individual patient. should avoid exposure to the sun or ultraviolet radiation whilst taking SLINDA. Patients should be advised that oral contraceptives do not protect against Depressed and HIV infections (AIDS) and other sexually are well-known undesirable effects transmitted diseases. of hormonal contraceptive use (see section 4.8 Adverse Effects (Undesirable Changes in the menstrual bleeding Effects)). Depression can be serious pattern and is well-known risk factor for suicidal Disruption of the menstrual bleeding behaviour and suicide. Patients should pattern may occur during use of be advised to contact their physician in hormonal contraceptives that inhibit case of mood changes and depressive ovulation, including SLINDA (see section symptoms, including shortly after 5.1 Pharmacodynamic Properties). initiating the treatment. If the bleeding is very frequent and irregular, another contraceptive method The following conditions have been should be considered. If the symptoms reported both during pregnancy persist, an organic cause should be and during sex steroid use, but an ruled out. Management of amenorrhoea association with the use of progestogens during treatment depends on whether has not been established: jaundice or not the tablets have been taken in and/or pruritus related to cholestasis; accordance with the instructions and gallstone formation; porphyria; systemic may include a pregnancy test. lupus erythematosus; haemolytic uraemic syndrome; Sydenham’s chorea; The treatment should be stopped if a herpes gestationis; otosclerosis-related pregnancy occurs. hearing loss; (hereditary) angioedema. Reduced efficacy Excipients with known effect The efficacy of POPs may be reduced in Each white active tablet contains the event of missed tablets (see section 17.50 mg of lactose and each green 4.2 Dose and Method of Administration), placebo tablet contains 55.50 mg of gastro-intestinal disturbances (see section lactose monohydrate. Patients with 4.2 Dose and Method of Administration) rare hereditary problems of galactose or concomitant medication (see section intolerance, lactase deficiency or 4.5 Interaction with Other Medicines and glucose-galactose malabsorption Other Forms of Interactions). should not take this medicine. Use in hepatic impairment Medical examination/consultation Discontinue SLINDA if jaundice Prior to the initiation or reinstitution develops. Steroid hormones may be of SLINDA a complete medical history poorly metabolised in patients with (including family history) should impaired liver function. Acute or chronic be taken and pregnancy must be disturbances of liver function may require ruled out. Blood pressure should be the discontinuation of SLINDA use until measured, and a physical examination markers of liver function return to normal should be performed, guided by the and SLINDA causation has been excluded. contra-indications (see section 4.3 Contraindications) and warnings (see Use in renal impairment section 4.4 Special Warnings and SLINDA is contraindicated for use in Precautions for Use). The patient should patients with severe renal insufficiency also be instructed to carefully read the or acute renal failure. Use in the elderly the next POP pack should be started No data available. right away.

Paediatric use Long-term treatment Refer to Section 4.2 Dose and Method In patients on long-term treatment with of Administration, Paediatric population. -inducing active substances, another reliable, nonhormonal, method Effects on laboratory tests of contraception is recommended. The use of contraceptive may influence the results of certain laboratory The following interactions have been tests, including biochemical parameters reported in the literature (mainly of the liver, thyroid, adrenal and renal with combined contraceptives but function, serum levels of (carrier) occasionally also with POPs). proteins, e.g. binding globulin and lipid/lipoprotein fractions, Substances increasing the clearance of parameters of carbohydrate metabolism contraceptive hormones (diminished and parameters of and contraceptive efficacy by enzyme fibrinolysis. induction) e.g.: Barbiturates, bosentan, carbamazepine, 4.5 Interaction With Other Medicines phenytoin, primidone, rifampicin and HIV medication ritonavir, nevirapine and And Other Forms Of Interaction efavirenz and possibly also felbamate, griseofulvin, oxcarbazepine, topiramate Influence of other medicinal products and products containing the herbal on SLINDA remedy St. John’s wort (Hypericum Interactions can occur between perforatum). SLINDA and other medicinal products that induce microsomal . Substances with variable effects on the This can result in increased clearance clearance of contraceptive hormones: of sex hormones and may lead When co-administered with sex to breakthrough bleeding and/or hormones, many combinations of contraceptive failure. HIV protease inhibitors (e.g. ritonavir, nelfinavir) and non-nucleoside reverse Management transcriptase inhibitors (e.g. nevirapine, Enzyme induction can already be efavirenz) and/or combinations with observed after a few days of treatment. Hepatitis C virus (HCV) medicinal Maximum enzyme induction is generally products (e.g. boceprevir, telaprevir), seen within a few weeks. After drug can increase or decrease plasma therapy is discontinued, enzyme concentrations of progestins. The net induction may be sustained for about effect of these changes may be clinically 4 weeks. relevant in some cases.

Short-term treatment Therefore, the prescribing information Patients on treatment with enzyme of concomitant HIV/HCV inducing drugs should temporarily should be consulted to identify use a barrier method or another po¬tential interactions and any related method of contraception in addition recommendations. In case of any doubt, to the POP. The barrier method must an additional barrier contraceptive be used during the whole time of the method should be used by patients on concomitant drug therapy and for 28 protease inhibitor or non-nucleoside days after its discontinuation. reverse transcriptase inhibitor therapy.

If the drug therapy runs beyond the end Substances decreasing the clearance of the active tablets in the POP pack, the of contraceptive hormones (enzyme placebo tablets must be discarded, and inhibitors): The clinical relevance of potential 4.6 Fertility, Pregnancy And Lactation interactions with enzyme inhibitors remain unknown. Effects on Fertility SLINDA is indicated for the prevention Concomitant administration of strong of pregnancy. or moderate CYP3A4 inhibitors such as azole antifungals (e.g. Use in Pregnancy fluconazole, itraconazole, , Pregnancy Category B3 voriconazole), verapamil, macrolides SLINDA is contraindicated in pregnancy. (e.g. clarithromycin, erythromycin), If pregnancy occurs during treatment diltiazem and grapefruit juice can with SLINDA, further intake should be increase plasma concentrations of the stopped. progestogen. Epidemiological studies have revealed In a multiple dose study evaluating the neither an increased risk of birth defects daily (10 days) co-administration of the in children born to patients who used strong CYP3A4 inhibitor ketoconazole drospirenone prior to pregnancy, nor a with two drospirenone-containing teratogenic effect when drospirenone hormone presentations (drospirenone 3 was taken inadvertently during mg + estradiol 1.5 mg and drospirenone pregnancy. 3 mg + 0.02 mg) the AUC(0-24h) of drospirenone was 2.3- Drospirenone and/or its metabolites fold and 2.7-fold respectively. crossed the placenta and entered the fetus when administered orally to Influence of SLINDA on other pregnant rats and rabbits. medicinal products Hormonal contraceptives may affect Animal studies revealed adverse effects the metabolism of certain other active on embryofetal development. With substances. Accordingly, plasma dosing during the period of major and tissue concentrations may either organogenesis, drospirenone impaired increase (e.g. cyclosporine) or decrease fetal growth and development in rats (e.g. lamotrigine). at doses ≥15 mg/kg/day and in rabbits at ≥30 mg/kg/day (yielding systemic Based on studies and in vivo exposure 14 and 4 times higher in the interaction studies in female volunteers respective species than that in patients using omeprazole, simvastatin and at the maximum recommended human midazolam as marker substrate, dose of SLINDA, based on plasma AUC). a clinically relevant interaction of Treatment at 100 mg/kg/day in rabbits drospirenone with the caused abortions (relative exposure, mediated metabolism of other active 15). Feminisation of male fetuses was substances is unlikely. observed in rats with subcutaneous administration at ≥3 mg/kg/day during Pharmacodynamic interactions the period of sexual differentiation, Published data did not show a significant consistent with drospirenone’s known effect on serum potassium following anti-androgenic activity the concomitant use of drospirenone and ACE-inhibitors or NSAIDs in Based on these animal data, undesirable patients without renal insufficiency. effects due to hormonal action of the The concomitant use of SLINDA with active compound cannot be excluded. aldosterone antagonists or potassium- sparing diuretics has not been studied. Use in Lactation In this case, serum potassium should be Negligible amounts of drospirenone tested during the first treatment cycle are excreted in the breast milk. The daily (see section 4.4 Special Warnings and dose of drospirenone in the baby is <1% Precautions for Use). of the maternal dose. Thus, at therapeutic doses of SLINDA, in the clinical trials (see Section 5.1 no effects on the breastfed newborns/ Pharmacodynamic Properties). infants are anticipated. Based on the available data SLINDA may be used The most commonly reported adverse during lactation. reactions in long-term clinical trials of more than 9 cycles of treatment with 4.7 Effects On Ability To Drive And drospirenone (2,700 patients) were (3.8 %), metrorrhagia (2.9 %), Use Machines (2.7 %) and (2.2 %).

No studies on the influence on the Tabulated list of adverse reactions ability to drive and use machines have been performed with SLINDA. Adverse reactions that have been reported in short- and long- term clinical No effects on ability to drive and use trials with SLINDA are listed in the table machines have been observed in patients below. of oral hormonal contraceptives. All adverse reactions are listed by 4.8 Adverse Effects (Undesirable system organ class and frequency: very Effects) common (> 1/10), common (≥ 1/100 Changes in the bleeding pattern as an to < 1/10), uncommon (≥ 1/1,000 to < adverse reaction frequently reported 1/100), rare (≥ 1/10,000 to < 1/1,000).

System Organ Class (MedDRA Common Uncommon Rare version

Infections and Vaginal infection infestations

Neoplasms Uterine leiomyoma benign. malignant and unspecified

Blood and Anaemia lymphatic system disorders

Immune system Hypersensitivity disorders

Metabolism and disorder nutrition disorders Hyperkalaemia

Psychiatric symptoms disorders disorder Mood Depression disturbances

Nervous system Headache Dizziness disorders System Organ Class (MedDRA Common Uncommon Rare version

Eye disorders Contact lens intolerance

Vascular disorders Hot flush Hypertension

Gastrointestinal Vomiting disorders Abdominal pain Diarrhoea Constipation

Skin and Acne Alopecia subcutaneous Hyperhidrosis tissue disorders Rash Seborrhoea Pruritus Dermatitis

Renal and urinary Polyuria disorders

Reproductive Breast discomfort Amenorrhoea Breast cyst system and breast Metrorrhagia Menstrual disorders Cervical dysplasia disorders Vaginal Pelvic pain Galactorrhea haemorrhage Ovarian cyst Vulvovaginal Vulvovaginal pruritus dryness

General disorders and administration Peripheral oedema site conditions

Investigations Weight increased Transaminases Weight decreased increased Blood bilirubin increased Blood creatine phosphokinase increased Gamma- glutamyl transferase increased Blood triglycerides increased Reporting of suspected adverse reactions antiglucocorticoid activity. This gives drospirenone a pharmacological profile Reporting suspected adverse reactions closely resembling the natural hormone after registration of the medicinal . product is important. It allows continued monitoring of the benefit-risk balance There are indications from clinical of the medicinal product. Healthcare studies that for combined hormonal professionals are asked to report any contraceptives containing 3 suspected adverse reactions at www.tga. mg drospirenone and 0.02 gov.au/reporting-problems. mg ethinylestradiol, the mild antimineralocorticoid properties result 4.9 Overdose in a mild antimineralocorticoid effect.

There have been no reports of serious Pharmacodynamic effects deleterious effects from overdose. Symptoms that may occur in this case The contraceptive effect of SLINDA are nausea, vomiting and slight vaginal is achieved primarily by inhibition bleeding. There are no antidotes of ovulation. Drospirenone exhibits and further treatment should be a strong anti-gonadotropic activity symptomatic. inhibiting follicular stimulation and ovulation by suppression of the Drospirenone is a luteinising hormone (LH). In addition, analogue which has antimineralocorticoid drospirenone has an effect on the properties. Serum potassium and increasing the viscosity of the sodium, and evidence of metabolic cervical mucus. Drospirenone also acidosis, should be monitored in cases exerts progestational effects on the of overdose. , which becomes thinner.

For information on the management Clinical efficacy and safety of overdose, contact the Poisons Information Centre on 131126 (Australia). The ovulation inhibition potential of SLINDA (drospirenone 4 mg non- micronised administered daily for 24 5. PHARMACOLOGICAL days) as reflected by the ovarian activity [follicular growth, endogenous estradiol PROPERTIES and progesterone serum concentrations (Hoogland score)] in comparison to 5.1 Pharmacodynamic Properties 0.075 mg of administered daily for 28 days over two treatment Pharmacotherapeutic group: Hormonal cycles was assessed in a randomised, contraceptives for systemic use, open-label Phase II study conducted progestogens in 60 healthy young patients. In cycle 1, no ovulation was observed in either ATC code: G03AC10 treatment. Whereas one ovulation was observed for SLINDA and 0.075 mg of desogestrel group in cycle 2.

SLINDA is a progestogen-only-pill which In a Phase II study performed in 130 contains the progestogen drospirenone, patients, SLINDA maintained the derived from spironolactone. inhibition of ovulation in spite of four fixed scheduled delayed intakes of 24 In a therapeutic dosage, drospirenone hours each on day 3, 6, 11 and 22. also possesses antiandrogenic and mild antimineralocorticoid properties. In two multicentre Phase III European It has no estrogenic, and clinical trials, one single-arm study and one controlled study vs. desogestrel 20.1% for SLINDA and 13.5% for 0.075 mg, 1596 patients have been desogestrel. The proportion of subjects treated for 9 up to 13 consecutive cycles with increased in cycles 7-9 with SLINDA and 341 with desogestrel to 26.7% for SLINDA and to 32.1% in the for 9 months. In the pooled analysis of desogestrel group. these two studies the following Pearl Indexes were calculated: The number of subjects with prolonged bleeding (>10 consecutive days) for Pearl Index (18-45 years of age), user + SLINDA vs desogestrel was 18.1% and method failure: 0.73 (upper limit 95% 26.1 %, respectively, during cycles 1.43) 2-4 and 9.1% and 16.7%, respectively, during cycles 7-9. Pearl Index (18-35 years of age), user + method failure: 0.93 (upper limit 95% The rate of subjects who withdrew from confidence interval 1.84) the study due to bleeding related adverse events was 3.3 % in the SLINDA group and In a single arm multicentre Phase III 6.6 % in the desogestrel group. performed in 39 US sites, the efficacy population consisted of 915 Paediatric population non- subjects aged ≤ 35 years with 5,337 evaluable cycles. The A phase III study was conducted in PI (95% CI) for evaluable cycles based Europe to evaluate tolerability, safety on 915 subjects, 12 confirmed on-drug and acceptability of SLINDA. 103 pregnancies and 5337 evaluable cycles adolescents were included in a 6-cycle was 2.9 (1.5;5.1). core part and 7 additional cycles (extension phase) for a total of 13 cycles, Bleeding pattern SLINDA was well tolerated and accepted by the subjects. The bleeding pattern during use of SLINDA was assessed in a 9-month Bleeding pattern with SLINDA was comparative, double blind trial vs assessed and data were generally desogestrel 0.075 mg, used continuously. consistent with those from the Phase 3 studies in adults. SLINDA was associated The occurrence of a withdrawal bleeding with a decrease in the percentage of (defined as a bleeding starting during subjects experiencing bleeding or the 4 hormone-free days of SLINDA spotting over time. lasting for up to 8 consecutive days), was highest – occurring in less than 40% 5.2 Pharmacokinetic properties - during the first cycles and decreased with time. After 9 months of use, a Absorption withdrawal bleeding was recorded in less than 20% of patients. Orally administered drospirenone is rapidly and almost completely The mean number of bleeding/spotting absorbed. Maximum concentrations days in the SLINDA group vs the of SLINDA active substance in plasma desogestrel group during the cycles of about 28 ng/mL are reached at 2-4 was 13.1 ± 13.0 vs 16.9 ± 16.9, about 3-4 h after single ingestion. respectively. The mean number of Concomitant ingestion of food has no bleeding/spotting days during cycles influence on the extent of absorption of 7-9, was 9.7 ± 10.4 vs 10.8 ± 13.3, drospirenone. respectively. The of SLINDA In the same study, the proportion of after single and repeated dose has subjects without any bleeding/spotting been studied in comparison with the (amenorrhea) during cycles 2-4 was marketed product containing 3 mg of micronised drospirenone in combination Linearity/non-linearity with ethinyl estradiol. After multiple dose administration, the relative The pharmacokinetics of oral of SLINDA was 76.51 % for AUCt,ss. The drospirenone is dose proportional accumulation ratio expressed by Rac following single doses ranging from (AUC) was 1.9256 while it was 2.7684 for 1-10mg. the combined product. These findings indicate that the total exposure to Steady-state conditions drospirenone is lower for SLINDA than for the combined product on the market During a treatment cycle, maximum in a cycle of 28 days. steady-state concentrations of drospirenone in serum of about 40 ng/ Distribution mL are reached after about 7 days of treatment. Plasma drospirenone levels Drospirenone is 95 % - 97 % protein accumulate by a factor of about 2 as a bound in serum. Drospirenone binds consequence of the ratio of terminal to serum albumin and does not bind to half-life and dosing interval. binding globulin (SHBG) or corticosteroid binding globulin Special populations (CBG). The mean apparent volume of distribution of drospirenone is 4 L/kg. Effect of renal impairment

Metabolism No studies have been conducted to evaluate the effect of renal Drospirenone is extensively metabolised impairment on the pharmacokinetics after . Two major non- of SLINDA. However, steady-state pharmacologically active metabolites serum drospirenone levels in in the plasma are the acid form of patients under treatment with a COC drospirenone, generated by opening of containing drospirenone with mild the lactone ring, and the 4,5-dihydro- renal impairment (creatinine clearance drospirenone-3-sulfate, both of which CLcr, 50-80 mL/min) were comparable are formed without involvement of the to those of patients with normal renal cytochrome P450 system. Drospirenone function. The serum drospirenone levels is also subject to oxidative metabolism were on average 37% higher in patients catalysed by CYP3A4. with moderate renal impairment (CLcr, 30 - 50 mL/min) compared to In vitro, drospirenone is capable of those in patients with normal renal inhibiting, from a weak to moderate function. Drospirenone treatment was level, the cytochrome P450 enzymes also well tolerated by patients with CYP1A1, CYP2C9, CYP2C19 and mild and moderate renal impairment. CYP3A4. Drospirenone treatment did not show any clinically significant effect on serum Elimination potassium concentration.

After oral administration, plasma Effect of hepatic impairment drospirenone levels decrease with a terminal half-life of 32 h. No studies have been conducted to evaluate the effect of hepatic disease The metabolic clearance rate of on the pharmacokinetics of SLINDA. drospirenone in serum is 1.5 ± 0.2 mL/ However, steroid hormones may be min/kg. Drospirenone is excreted only poorly metabolised in patients with in trace amounts in unchanged form. impaired liver function. The metabolites of drospirenone are excreted with the faeces and urine at an In a single dose study in patients excretion ratio of about 1.2 to 1.4. taking a COC containing drospirenone, oral clearance (CL/F) was decreased than that in patients at the maximum approximately 50 % in volunteers recommended human dose of SLINDA, with moderate hepatic impairment as based on plasma AUC). compared to those with normal liver function. The observed decline in Although these long-term animal studies drospirenone clearance in volunteers did not indicate carcinogenic activity with moderate hepatic impairment for drospirenone, it should be borne in did not translate into any apparent mind that sex steroids can promote the difference in terms of serum potassium growth of certain hormone-dependent concentrations. Even in the presence tissues and tumours. of diabetes and concomitant treatment with spironolactone (two factors that can predispose a patient to hyperkalaemia) 6. PHARMACEUTICAL an increase in serum potassium PARTICULARS concentrations above the upper limit of the normal range was not observed. It can be concluded that drospirenone 6.1 List Of Excipients is well tolerated in patients with mild or moderate hepatic impairment (Child- White active film-coated tablets: Pugh B). Tablet core: Ethnic groups Microcrystalline cellulose Lactose No studies were performed to assess Colloidal anhydrous silica pharmacokinetics in ethnic groups. Magnesium stearate Tablet coat: Polyvinyl alcohol 5.3 Preclinical Safety Data Titanium dioxide Macrogol 3350 Genotoxicity Purified-Talc

Drospirenone was found to induce Green placebo film-coated tablets: chromosome aberrations in human peripheral lymphocytes. However, Tablet core: drospirenone was not mutagenic in Lactose monohydrate bacterial and mammalian gene Maize starch mutation assays in vitro, and was not Povidone clastogenic in mouse micronucleus Colloidal anhydrous silica assays in vivo. Interactions between Magnesium stearate drospirenone and the DNA of liver cells, which indicate a genotoxic potential, Tablet coat: were found in in vitro and in vivo studies Hypromellose in rats. No such finding was observed in Triacetin human liver cells in vitro. Polysorbate 80 Titanium dioxide Carcinogenicity Indigo Carmine Iron Oxide Yellow No treatment-related increase in tumour was observed with drospirenone in 2-year studies in mice 6.2 Incompatibilities and rats, involving oral administration at doses up to 10 mg/kg/day (yielding Not applicable. systemic exposure 4.5 and 12 times higher in the respective species 6.3 Shelf Life CAS Number: 67392-87-4

In Australia, information on the shelf life Molecular Formula: C24H30O3 can be found on the public summary of the Australian Register of Therapeutic Molecular weight: 366.5 g/mol Goods (ARTG). The expiry date can be found on the packaging. 7. MEDICINE SCHEDULE 6.4 Special Precautions For Storage (POISONS STANDARD)

Store below 25ºC Schedule 4 - Prescription Only Medicine

6.5 Nature And Contents Of Container 8. SPONSOR Transparent PVC-PVDC/Aluminium blister containing 28 film-coated tablets Besins Healthcare Australia Pty Ltd (24 white active film-coated tablets and Level 16, Tower 2, 4 green placebo film-coated tablets). Darling Park, 201 Sussex Street, Pack sizes: calendar-packs containing Sydney NSW 2000 1x28 (starter pack), 1x28, 3x28 and 4x28 film-coated tablets.*

*Not all pack sizes may be marketed. 9. DATE OF FIRST APPROVAL 5 July 2021 6.6 Special Precautions For Disposal

In Australia, any unused medicinal product or waste material should be 10. DATE OF REVISION disposed of in accordance with local requirements. Summary table of changes

6.7 Physiochemical Properties Section Summary of new Chemical Structure: Changed information

O

O

H CH3 CH3

H H

O