SLINDA (DROSPIRENONE 4 mg) TABLETS - AUSTRALIAN PRODUCT INFORMATION - Besins ...
←
→
Page content transcription
If your browser does not render page correctly, please read the page content below
SLINDA® (DROSPIRENONE 4 mg) TABLETS AUSTRALIAN PRODUCT INFORMATION
AUSTRALIAN PRODUCT 4.2 Dose And Method Of
Administration
INFORMATION
SLINDA® (DROSPIRENONE) TABLETS Dose
How to take SLINDA
1. NAME OF THE MEDICINE One tablet 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 placebo 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
4. CLINICAL PARTICULARS immediately after abortion took place.
In that case there is no need to use an
4.1 Therapeutic Indications additional contraceptive method.
ContraceptionFollowing 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
menstruations have returned, pregnancy 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 breast-feeding patients, see section 2. The greater the number of white
4.6. Fertility, Pregnancy and Lactation 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), vaginal ring or
transdermal 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 transdermal patch. 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 progestogen-only two tablets at the same time. The patient
method (progestogen-only pill should then continue to take tablets at
(POP), injection, 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
Days 8-17
SLINDA on the day the next injection
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 ifthis 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 aldosterone
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 medicines 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 liver function Rather, the risk of cardiovascular and
values have not returned to normal. cerebral events is related to increasing
age, hypertension, and smoking. In
• Severe renal insufficiency or acute patients with hypertension the risk of
renal failure. stroke may be slightly enhanced by
progestogen-only preparations.
• Known or suspected sex-steroid
sensitive malignancies. Although not statistically significant,
some studies indicate that there may
• Undiagnosed vaginal bleeding.
be a slightly increased risk of venous
• Known or suspected pregnancy. thromboembolism (deep venous
thrombosis, pulmonary embolism)
• 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 metabolism tumours have been reported in patients
Treatment with SLINDA leads to of combined hormonal contraceptives.
decreased estradiol 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 pregnancies 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 Cancer during the use of POPs. Despite the fact
A meta-analysis from 54 epidemiological that SLINDA consistently inhibits ovulation
studies reported that there is a slightly ectopic pregnancy should be taken into
increased relative risk (RR = 1.24) of account in the differential diagnosis if
having breast cancer diagnosed in the patient presents amenorrhoea or
patients who are currently using oral abdominal pain.
contraceptives (OCs), mainly using
estrogen-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 Diabetes
to an earlier diagnosis of breast cancer Although progestogens 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 cancers 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 blood pressure
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 liverLike 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 mood and depression 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. enzyme-inducing active substances,
another reliable, nonhormonal, method
Effects on laboratory tests of contraception is recommended.
The use of contraceptive steroids 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. corticosteroid binding
globulin and lipid/lipoprotein fractions, Substances increasing the clearance of
parameters of carbohydrate metabolism contraceptive hormones (diminished
and parameters of coagulation and contraceptive efficacy by enzyme
fibrinolysis. induction) e.g.:
Barbiturates, bosentan, carbamazepine,
4.5 Interaction With Other Medicines phenytoin, primidone, rifampicin and
And Other Forms Of Interaction HIV medication ritonavir, nevirapine and
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 enzymes. 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 medications
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, ketoconazole, 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 + ethinylestradiol 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 in vitro 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 cytochrome P450 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 isThus, 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 acne
Use Machines (3.8 %), metrorrhagia (2.9 %), headache
(2.7 %) and breast pain (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 Appetite disorder
nutrition disorders Hyperkalaemia
Psychiatric Libido Anxiety symptoms
disorders disorder Mood Depression
disturbances
Nervous system Headache Dizziness
disordersSystem Organ
Class (MedDRA Common Uncommon Rare
version
Eye disorders Contact lens
intolerance
Vascular disorders Hot flush
Hypertension
Gastrointestinal Nausea 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
Dysmenorrhea Vulvovaginal pruritus
Menstruation dryness
General disorders Fatigue
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
increasedReporting 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 progesterone.
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 spironolactone luteinising hormone (LH). In addition,
analogue which has antimineralocorticoid drospirenone has an effect on the
properties. Serum potassium and cervix 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. endometrium, 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
PROPERTIES [follicular growth, endogenous estradiol
and progesterone serum concentrations
(Hoogland score)] in comparison to
5.1 Pharmacodynamic Properties 0.075 mg of desogestrel 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
Mechanism of action 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, glucocorticoid and clinical trials, one single-arm study andone 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 amenorrhea 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
confidence interval 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.
clinical trial performed in 39 US sites,
the efficacy population consisted of 915 Paediatric population
non-breastfeeding 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 pharmacokinetics 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 ofmicronised drospirenone in combination Linearity/non-linearity
with ethinyl estradiol. After multiple dose
administration, the relative bioavailability 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.
sex hormone 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 oral administration. 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 cell 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 incidence 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 species6.3 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.*
9. DATE OF FIRST APPROVAL
*Not all pack sizes may be marketed.
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
CH3 H CH3
H H
OYou can also read
