Drospirenone/ Estetrol

Registered South African indications

• Contraception

Registered South African contraindications

As no epidemiological data are yet available for estetrol-containing combined hormonal contraceptives (CHCs), the contraindications for ethinylestradiol-containing CHCs are considered applicable to the use of drospirenone/estetrol. CHCs should not be used in the following conditions. Should any of the conditions appear for the first time during drospirenone/estetrol use, the medicine should be stopped immediately

• Hypersensitivity to the active ingredient or any of the excipients in this combination product
• Presence or risk of venous thromboembolism (VTE)
  - VTE - current VTE (on anticoagulants) or history of VTE (e.g., deep venous thrombosis [DVT] or pulmonary embolism [PE])
  - Known hereditary or acquired predisposition for venous thromboembolism, such as activated protein C (APC)-resistance (including factor V Leiden), antithrombin-III deficiency, protein C deficiency, protein S deficiency
  - Major surgery with prolonged immobilisation
  - A high risk of venous thromboembolism due to the presence of multiple risk factors
• Presence or risk of arterial thromboembolism (ATE)
  - ATE - current ATE, history of ATE (e.g., myocardial infarction [MI]) or prodromal condition (e.g., angina pectoris)
  - Cerebrovascular disease – current stroke, history of stroke or prodromal condition (e.g., transient ischaemic attack [TIA])
  - Known hereditary or acquired predisposition for arterial thromboembolism, such as hyperhomocysteinaemia and antiphospholipid-antibodies (anticardiolipin-antibodies, lupus anticoagulant)
  - History of migraine with focal neurological symptoms
  - A high risk of arterial thromboembolism due to multiple risk factors or to the presence of one serious risk factor such as: diabetes mellitus with vascular symptoms, severe hypertension, severe dyslipoproteinaemia
• 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
• Presence or history of liver tumours (benign or malignant)
• Known or suspected sex steroid-influenced malignancies (e.g., of the genital organs or the breasts)
• Undiagnosed vaginal bleeding

South African recommendations

Caution in the following patient groups

• Breastfeeding
• Mild to moderate renal impairment
• Mild to moderate hepatic impairment

Clinical considerations and risk assessment

• If any of the conditions or risk factors mentioned below is present, the suitability of drospirenone/estetrol should be discussed with the woman before she decides to start using this product 
• In the event of aggravation, or first appearance of any of these conditions or risk factors, the woman should be advised to contact her doctor to determine whether the use of drospirenone/estetrol should be discontinued
• All data presented below are based upon epidemiological data obtained with CHCs containing ethinylestradiol. drospirenone/estetrol contains estetrol
• As no epidemiological data are yet available with estetrol containing-CHCs, the warnings are considered applicable to the use of drospirenone/estetrol
• In case of suspected or confirmed VTE or ATE, CHC use must be discontinued
• In case anticoagulant therapy is started, adequate alternative non-hormonal contraception should be initiated because of the teratogenicity of anticoagulant therapy (coumarins)

Circulatory disorders: Risk of VTE

• The use of any CHC increases the risk of VTE compared with no use
• Medicines that contain low dose ethinylestradiol (< 50µg ethinylestradiol) combined with levonorgestrel, norgestimate or norethisterone are associated with the lowest risk of VTE
• It is not yet known how the risk with drospirenone/estetrol compares with these lower risk medicines
• The decision to use any medicine other than one known to have the lowest VTE risk should be taken only after a discussion with the woman to ensure she understands the risk of VTE with CHCs, how her current risk factors influence this risk, and that her VTE risk is highest in the first ever year of use
• There is also some evidence that the risk is increased when a CHC is re-started after a break in use of 4 weeks or more
• In women who do not use a CHC and are not pregnant about 2 out of 10 000 will develop a VTE over the period of one year. However, in any individual woman the risk may be far higher, depending on her underlying risk factors
• Epidemiological studies in women who use low dose (< 50µg ethinylestradiol) combined hormonal contraceptives have found that some women will develop a VTE in one year
• Clinical data indicate that the risk of venous thromboembolism is higher in women using CHCs containing drospirenone than in those using levonorgestrel-containing products. This increased risk must be weighed against the benefits of the product and the patient’s baseline risk for thromboembolic events
• These incidences were estimated from the totality of the epidemiological study data, using relative risks for the different medicines compared with levonorgestrel-containing CHCs
• It is not yet known how the risk of VTE with CHC containing estetrol and drospirenone compares with the risk with low dose levonorgestrel-containing CHCs
• The number of VTEs per year with low-dose CHCs is fewer than the number expected in women during pregnancy or in the postpartum period
• VTE may be fatal in 1-2% of cases
• Thrombosis has been reported to occur in some CHC users in other blood vessels, e.g., hepatic, mesenteric, renal or retinal veins and arteries

Risk factors for VTE

• The risk for venous thromboembolic complications in CHC patients may increase substantially in a woman with additional risk factors, particularly if there are multiple risk factors
• Drospirenone/estetrol is contraindicated if a woman has multiple risk factors that put her at high risk of venous thrombosis
• If a woman has more than one risk factor, it is possible that the increase in risk is greater than the sum of the individual factors – in this case her total risk of VTE should be considered
• If the balance of benefits and risks is considered to be negative a CHC should not be prescribed
• Risk factors include obesity (body mass index [BMI] over 30 kg/m²), where the risk increases substantially as BMI rises. This is particularly important to consider if other risk factors are also present
• Prolonged immobilisation, major surgery, any surgery to the legs or pelvis, neurosurgery, or major trauma are risk factors. Temporary immobilisation including air travel > 4 hours can also be a risk factor for VTE, particularly in women with other risk factors
• In these situations, it is advisable to discontinue use of the pill (in the case of elective surgery at least four weeks in advance) and not resume until two weeks after complete remobilisation
• Another method of contraception should be used to avoid unintentional pregnancy
• Antithrombotic treatment should be considered if drospirenone/estetrol has not been discontinued in advance
• A positive family history (VTE ever in a sibling or parent especially at a relatively early age, e.g., before 50 years) is a risk factor. If a hereditary predisposition is suspected, the woman should be referred to a specialist for advice before deciding about any CHC use
• Other medical conditions associated with VTE include cancer, systemic lupus erythematosus, haemolytic uraemic syndrome, chronic inflammatory bowel disease (Crohn's disease or ulcerative colitis) and sickle cell disease
• Increasing age is a risk factor, particularly above 35 years
• There is no consensus about the possible role of varicose veins and superficial thrombophlebitis in the onset or progression of venous thrombosis
• The increased risk of thromboembolism in pregnancy, and particularly the 6-week period of the puerperium, must be considered

Symptoms of VTE (DVT and PE)

• In the event of symptoms, women should be advised to seek urgent medical attention and to inform the healthcare professional that she is taking a CHC
• Symptoms of DVT can include unilateral swelling of the leg and/or foot or along a vein in the leg; pain or tenderness in the leg which may be felt only when standing or walking; increased warmth in the affected leg; red or discoloured skin on the leg
• Symptoms of PE can include sudden onset of unexplained shortness of breath or rapid breathing; sudden coughing which may be associated with haemoptysis; sharp chest pain; severe light headedness or dizziness; rapid or irregular heartbeat
• Some of these symptoms (e.g., shortness of breath, coughing) are non-specific and might be misinterpreted as more common or less severe events (e.g., respiratory tract infections)
• Other signs of vascular occlusion can include sudden pain, swelling and slight blue discolouration of an extremity
• If the occlusion occurs in the eye symptoms can range from painless blurring of vision which can progress to loss of vision. Sometimes loss of vision can occur almost immediately

Risk of ATE

• Epidemiological studies have associated the use of CHCs with an increased risk for arterial thromboembolism (myocardial infarction [MI]) or for cerebrovascular accident (e.g., TIA, stroke)
• Arterial thromboembolic events may be fatal

Risk factors for ATE

• The risk of arterial thromboembolic complications or of a cerebrovascular accident in CHC users increases in women with risk factors
• Drospirenone/estetrol is contraindicated if a woman has one serious or multiple risk factors for ATE that puts her at high risk of arterial thrombosis
• If a woman has more than one risk factor, it is possible that the increase in risk is greater than the sum of the individual factors; in this case her total risk should be considered
• If the balance of benefits and risks is considered to be negative a CHC should not be prescribed
• Increasing age is a risk factor, particularly above 35 years
• Smoking is a risk factor. Women should be advised not to smoke if they wish to use a CHC. Women over 35 years who continue to smoke should be strongly advised to use a different method of contraception
• Hypertension is a risk factor for ATE
• Obesity (BMI over 30 kg/m²) is a risk factor, with risk increasing substantially as BMI increases. This is particularly important in women with additional risk factors
• A positive family history (arterial thromboembolism ever in a sibling or parent especially at relatively early age, e.g., below 50 years) is a risk factor. If a hereditary predisposition is suspected, the woman should be referred to a specialist for advice before deciding about any CHC use
• Migraines are a risk factor. An increase in frequency or severity of migraine during CHC use (which may be prodromal of a cerebrovascular event) may be a reason for immediate discontinuation
• Other medical conditions associated with adverse vascular events include diabetes mellitus, hyperhomocysteinaemia, valvular heart disease and atrial fibrillation, dyslipoproteinaemia and systemic lupus erythematosus

Symptoms of ATE

• In the event of symptoms women should be advised to seek urgent medical attention and to inform the healthcare professional that she is taking a CHC
• Symptoms of a cerebrovascular accident can include sudden numbness or weakness of the face, arm or leg, especially on one side of the body; sudden trouble walking, dizziness, loss of balance or coordination; sudden confusion, trouble speaking or understanding; sudden trouble seeing in one or both eyes; sudden, severe or prolonged headache with no known cause; loss of consciousness or fainting with or without seizure
• Temporary symptoms suggest the event is a transient ischaemic attack (TIA)
• Symptoms of myocardial infarction (MI) can include pain, discomfort, pressure, heaviness, sensation of squeezing or fullness in the chest, arm, or below the breastbone; discomfort radiating to the back, jaw, throat, arm, stomach; feeling of being full, having indigestion or choking; sweating, nausea, vomiting or dizziness; extreme weakness, anxiety, or shortness of breath; rapid or irregular heartbeats

Tumours

• An increased risk of cervical cancer in long-term users of CHCs containing ethinylestradiol (>5 years) has been reported in some epidemiological studies, but there continues to be controversy about the extent to which this finding is attributable to the confounding effects of sexual behaviour and other factors such as human papilloma virus (HPV)
• With the use of the higher-dosed CHCs (50µg ethinylestradiol) the risk of endometrial and ovarian cancer is reduced. Whether this also applies to estetrol-containing CHCs remains to be confirmed
• A study found that there is an increased relative risk of having breast cancer diagnosed in women who are currently using CHCs containing ethinylestradiol
• The excess risk gradually disappears during the course of the 10 years after cessation of CHC use
• In some cases, benign liver tumours, and malignant liver tumours have been reported in patients of CHCs containing ethinylestradiol
• In isolated cases, these tumours have led to life threatening intra-abdominal haemorrhages
• Therefore, a hepatic tumour should be considered in the differential diagnosis when severe upper abdominal pain, liver enlargement or signs of intra-abdominal haemorrhage occur in women taking CHCs

Hepatitis C

• During clinical studies with patients treated for hepatitis C virus (HCV) infection with medicines containing ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin, ALT elevations higher than 5 times the upper limit of normal occurred significantly more frequently in women using ethinylestradiol-containing medicines such as CHCs
• Additionally, also in patients treated with glecaprevir/pibrentasvir or sofosbuvir/velpatasvir/voxilaprevir, ALT elevations were observed in women using ethinylestradiol-containing medications such as CHCs
• Women using medicines containing oestrogens other than ethinylestradiol had a rate of ALT elevation similar to those not receiving any oestrogens; however, due to the limited number of women taking these other oestrogens, caution is warranted for co-administration with the combination therapeutic regimen ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin and also the regimen glecaprevir/pibrentasvir or sofosbuvir/velpatasvir/voxilaprevir

Other conditions

• The progestogen component in drospirenone/estetrol, drospirenone, is an aldosterone antagonist with potassium sparing properties
• In most cases, no increase of potassium levels would be expected
• In a clinical study with drospirenone, however, in some patients with mild or moderate renal impairment and concomitant use of potassium-sparing medicines, serum potassium levels increased slightly, but not significantly, during intake of 3mg drospirenone for 14 days
• Therefore, it is recommended to check serum potassium during the first treatment cycle with estetrol and drospirenone in patients presenting with renal insufficiency and a pre-treatment serum potassium in the upper reference range, and particularly during concomitant use of potassium sparing medicines
• Women with hypertriglyceridaemia, or a family history thereof, may be at an increased risk of pancreatitis when using CHCs
• Small increases in blood pressure have been reported in many women taking CHC. A relationship between CHC use and clinical hypertension has not been established
• However, if a sustained clinically significant hypertension develops during the use of a CHC, then it is prudent for the healthcare professional to suspend the intake of the tablets and treat the hypertension
• Where considered appropriate, CHC use may be resumed if normotensive values can be achieved with antihypertensive therapy
• The following conditions have been reported to occur or deteriorate with both pregnancy and CHC use, but the evidence of an association with CHC use is inconclusive: 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
• In women with hereditary angioedema, exogenous oestrogens may induce or exacerbate symptoms of angioedema
• Acute or chronic disturbances of liver function may necessitate the discontinuation of CHC use until markers of liver function return to normal
• Recurrence of cholestatic jaundice which occurred first during pregnancy or previous use of sex steroids necessitates the discontinuation of CHCs
• Although CHCs 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 low-dose CHCs (containing < 50µg ethinylestradiol)
• However, diabetic women should be carefully observed, particularly in the early stage of CHC use
• Worsening of endogenous depression, of epilepsy, of Crohn’s disease and ulcerative colitis has been reported during CHC use
• Depressed mood and depression are well-known undesirable effects of hormonal contraceptive use
• Depression can be serious and is a well-known risk factor for suicidal behaviour and suicide
• Women should be advised to contact their healthcare professional in case of mood changes and depressive symptoms, including shortly after initiating the treatment
• Chloasma may occasionally occur, especially in women with a history of chloasma gravidarum
• Women with a tendency to chloasma should avoid exposure to the sun or ultraviolet radiation whilst taking CHCs

Medical examination/consultation

• Prior to the initiation or reinstitution of drospirenone/estetrol a complete medical history (including family history) should be taken, and pregnancy must be ruled out
• Blood pressure should be measured, and a physical examination should be performed, guided by the contraindications and warnings
• It is important to draw a woman’s attention to the information on venous and arterial thrombosis, including the risk of drospirenone/estetrol compared with other CHCs, the symptoms of VTE and ATE, the known risk factors and what to do in the event of a suspected thrombosis
• The woman 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 woman
• Women should be advised that hormonal contraceptives do not protect against human immunodeficiency virus (HIV) infection and/or acquired immunodeficiency syndrome (AIDS) and other sexually transmitted diseases

Reduced efficacy

• The efficacy of CHCs may be reduced in the event of missed tablets, gastro-intestinal disturbances during active tablet taking or concomitant medicines

Cycle control

• With all CHCs, unscheduled bleeding (spotting or bleeding) may occur, especially during the first months of use
• Therefore, the evaluation of any irregular bleeding is only meaningful after an adaptation interval of about three cycles
• Unscheduled bleeding or spotting occurred in 14% to 20% of women using drospirenone/estetrol. Most of these episodes concerned spotting only
• If bleeding irregularities persist or occur after previously regular cycles, then non-hormonal causes should be considered, and adequate diagnostic measures are indicated to exclude malignancy or pregnancy. These may include curettage
• In a small percentage of women, withdrawal bleeding may not occur during the placebo tablet phase
• If absence of withdrawal bleeding occurs and drospirenone/estetrol has been taken according to the instructions, pregnancy is unlikely
• However, pregnancy must be ruled out before use is continued, if drospirenone/estetrol has not been taken as directed, or if two consecutive withdrawal bleeds do not occur

Laboratory tests

• The use of contraceptive steroids may influence the results of certain laboratory tests, including biochemical parameters of liver, thyroid, adrenal and renal function, plasma levels of (carrier) proteins, e.g., corticosteroid binding globulin (CBG) and lipid/lipoprotein fractions, parameters of carbohydrate metabolism and parameters of coagulation and fibrinolysis
• Changes generally remain within the normal laboratory range
• Drospirenone causes an increase in plasma renin activity and plasma aldosterone induced by its mild anti-mineralocorticoid activity

Excipients

• Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take drospirenone/estetrol
• Drospirenone/estetrol contains less than 1 mmol sodium (23mg) per tablet, that is to say it is essentially ‘sodium-free’

Forms avail. in SA and covered in this monograph: fct

South African registered indications and dosages

Contraception

Drospirenone/ Estetrol
3/14.2 (mg)

• Oral (fct): 1 tablet, dly for 24 days

THEN

Inactive tablets

• Oral (fct): 1 tablet, dly for 4 days

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The decision to prescribe drospirenone/estetrol should take into consideration the individual woman’s current risk factors, particularly those for venous thromboembolism (VTE), and how the risk of VTE with drospirenone/estetrol compares with other combined hormonal contraceptives (CHCs)

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One tablet is to be taken daily for 28 consecutive days. Tablets to be taken every day at about the same time for 28 consecutive days, if necessary, with a little liquid, in the order shown on the blister pack. Each pack starts with 24 active tablets, followed by 4 placebo tablets. Each subsequent pack is started the day after the placebo tablet of the previous pack. Stickers marked with the 7 days of the week are provided, and the relevant weekday sticker should be stuck on the tablet blister as an indicator of when the first tablet has been taken

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Withdrawal bleeding usually starts on day 2-3 after starting the placebo tablets and may not have finished before the next pack is started

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See additional prescribing points for initiation of treatment and management of missed tablets

Not established for use in adolescents under 16 years

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Only indicated after menarche (first menstrual cycle)

Pregnancy

South African recommendations

• Not indicated for use in pregnancy
• If pregnancy occurs while taking drospirenone/estetrol, further intake must be stopped
• There are limited amount of data from the use of drospirenone/estetrol in pregnant women. Studies in animals have shown reproductive toxicity
• Based on animal experience, harmful effects due to hormonal action of the active substances cannot be excluded. The increased risk of VTE during the postpartum period should be considered when re-starting drospirenone/estetrol

Breastfeeding

South African recommendations

• Caution; not recommended
• Small amounts of the contraceptive steroids and/or their metabolites may be excreted with the breast milk and might affect the child. Breastfeeding may be influenced by combined hormonal contraceptives (CHC)s as they may reduce the quantity and change the composition of breast milk. Therefore, the use of CHCs should not be recommended until the breastfeeding mother has completely weaned her child and an alternative method of contraception should be proposed to women wishing to breastfeed

Fertility

South African recommendations

• Drospirenone/estetrol is indicated for oral contraception

South African recommendations

• Mild to moderate: Caution; no information available
  Drospirenone/ estetrol has not been specifically studied in patients with renal impairment
• Severe: Contraindicated
• Acute renal failure: Contraindicated

South African recommendations

• Mild to moderate: Caution; no information available
  No clinical studies have been performed
• Severe: Contraindicated
  As long as liver function values have not returned to normal

South African recommendations

• Not indicated after menopause

Infections and Infestations

Uncommon

• Fungal infection
• Vaginal infection
• Urinary tract infection

Rare

• Mastitis

Neoplasms Benign, Malignant and Unspecified (including cysts and polyps)

Rare

• Fibroadenoma of breast

Immune System Disorders

Rare

• Hypersensitivity

Metabolism and Nutrition Disorders

Uncommon

• Appetite disorder

Rare

• Hyperkalaemia
• Fluid retention

Psychiatric Disorders

Common

• Mood disorders and disturbances
  - Affect lability
  - Anger
  - Euphoric mood
  - Irritability
  - Altered mood and mood swings
• Libido disorder

Uncommon

• Depression
  - Depressed mood
  - Depressive symptom
  - Tearfulness
  - Depression
• Anxiety disorder
  - Agitation
  - Anxiety
  - Generalised anxiety disorder
  - Panic attack
• Insomnia
• Emotional disorder
  - Emotional disorder
  - Emotional distress
  - Crying
• Stress

Rare

• Nervousness

Nervous System Disorders

Common

• Headache

Uncommon

• Migraine
• Dizziness
• Paraesthesia
• Somnolence

Rare

• Amnesia

Eye Disorders

Rare

• Visual impairment
• Blurred vision
• Dry eye

Ear and Labyrinth Disorders

Rare

• Vertigo

Vascular Disorders

Uncommon

• Hot flush

Rare

• Hypertension
• Venous thrombosis
• Thrombophlebitis
• Hypotension
• Varicose vein

Gastrointestinal Disorders

Common

• Abdominal pain
• Nausea

Uncommon

• Abdominal distension
• Vomiting
• Diarrhoea

Rare

• Gastroesophageal reflux disease
• Colitis
• Gastrointestinal motility disorder
• Constipation
• Dyspepsia
• Flatulence
• Dry mouth
• Lip swelling

Skin and Subcutaneous Tissue Disorders

Common

• Acne

Uncommon

• Alopecia
• Hyperhidrosis
  - Night sweats
  - Hyperhidrosis
  - Cold sweat
• Skin disorders
  - Dry skin
  - Rash
  - Skin swelling

Rare

• Dermatitis
  - Dermatitis and eczema
• Pigmentation disorder
  - Chloasma
  - Skin hyperpigmentation
• Hirsutism
• Seborrhoea
• Pruritus
• Swelling of face
• Urticaria
• Skin discolouration

Musculoskeletal and Connective Tissue Disorders

Uncommon

• Back pain

Rare

• Muscle spasms
• Limb discomfort
• Joint swelling
• Pain in extremity

Renal and Urinary Disorders

Rare

• Bladder spasm
• Abnormal urine odour

Pregnancy, Puerperium and Perinatal Conditions

Rare

• Ectopic pregnancy

Reproductive System and Breast Disorders

Common

• Breast pain
• Metrorrhagia
• Vaginal haemorrhage
• Dysmenorrhoea
• Menorrhagia

Uncommon

• Abnormal withdrawal bleeding
  - Abnormal withdrawal bleeding
  - Amenorrhoea
  - Menstrual disorder
  - Irregular menstruation
  - Oligomenorrhoea
  - Polymenorrhoea
• Breast swelling
• Vulvovaginal disorder
  - Vaginal odour
  - Vulvovaginal discomfort
  - Vulvovaginal dryness
  - Vulvovaginal pain
  - Vulvovaginal pruritus
  - Vulvovaginal burning sensation
• Vaginal discharge
• Premenstrual syndrome
• Breast mass
  - Breast mass
  - Fibrocystic breast disease
• Uterine spasm
• Uterine haemorrhage
• Menometrorrhagia
• Dyspareunia

Rare

• Ovarian cyst
• Lactation disorders
• Endometrial disorder
• Dysfunctional uterine bleeding
• Pelvic pain
• Nipple disorder
• Breast discolouration
• Coital bleeding

General Disorders and Administration Site Conditions

Uncommon

• Fatigue
• Oedema
• Chest pain
• Feeling abnormal

Rare

• Malaise
  - Decreased performance status
• Pain
• Hyperthermia

Investigations

Common

• Weight fluctuation

Uncommon

• Increased hepatic enzyme
• Abnormal lipids

Rare

• Increased blood pressure
• Abnormal renal function test
• Increased blood potassium
• Increased blood glucose
• Decreased haemoglobin
• Decreased serum ferritin
• Blood in urine

• Ombitasvir/paritaprevir/ritonavir
• Dasabuvir with or without ribavirin
• Glecaprevir/pibrentasvir
• Sofosbuvir/velpatasvir/voxilaprevir
• Microsomal enzyme inducer 
• Barbiturates
• Bosentan
• Carbamazepine
• Phenytoin
• Primidone
• Rifampicin
• Antiretrovirals 
• Ritonavir
• Nevirapine
• Efavirenz
• Felbamate
• Griseofulvin
• Oxcarbazepine
• Topiramate
• HIV protease inhibitors
• Non-nucleoside reverse transcriptase inhibitors
• Hepatitis C virus inhibitors
• Strong CYP3A4 inhibitors 
• Ketoconazole
• Ciclosporin
• Lamotrigine
• Other pharmacodynamic interactions (see Additional Prescribing Points)

Other interactions

• Herbal St. John's wort (Hypericum perforatum)
• Certain laboratory tests (see Warnings and Precautions)

• Pregnancy status
• Physical examination
• Blood pressure

Specific cases may require

• Serum potassium
• Blood glucose
• Body mass index (BMI)

Additional observations

• Complete medical history (including family history)
• Mental status
• Signs and symptoms of thromboembolism
• Evaluation of irregular spotting or bleeding

How to start drospirenone/estetrol

No preceding hormonal contraceptive use (in the past month)

• Tablet-taking has to start on day 1 of the woman’s menstrual cycle, i.e., the first day of her menstrual bleeding, and when doing so, no additional contraceptive measures are necessary
• If the first tablet is taken on days 2 to 5 of the woman’s menstruation, drospirenone/estetrol will not be effective until after the first 7 consecutive days of active tablet-taking. A reliable barrier method of contraception such as a condom must therefore be used additionally during these first 7 days
• The possibility of pregnancy should be considered before starting drospirenone/estetrol

Changing from a CHC (combined oral contraceptive (COC), vaginal ring or transdermal patch)

• The woman should start with drospirenone/estetrol preferably on the day after the last active tablet (the last tablet containing the active substances) of her previous COC, but at the latest on the day following the usual tablet-free or placebo tablet interval of her previous COC
• In case a vaginal ring or transdermal patch has been used the woman should start using drospirenone/estetrol preferably on the day of removal, but at the latest when the next application would have been due 

Changing from a progestogen-only-method (progestogen-only pill, injection, implant) or from a progestogen-releasing intrauterine device (IUD)

• Patients may switch any day from the progestogen-only pill (from an implant or the IUD on the day of its removal, from an injectable when the next injection would be due) but should in all of these cases be advised to additionally use a barrier method for the first 7 consecutive days of tablet-taking

Following first-trimester abortion

The woman may start immediately. When doing so, she needs not take additional contraceptive measures
Following delivery or second-trimester abortion

• Women should be advised to start between day 21 and 28 after delivery or second-trimester abortion. When starting later, the woman should be advised to additionally use a barrier method for the first 7 days. However, if intercourse has already occurred, pregnancy should be excluded before the actual start of CHC use or the woman has to wait for her first menstrual period

Management of missed tablets

• Placebo tablets from the last row of the blister can be disregarded. However, they should be discarded to avoid unintentionally prolonging the placebo tablet phase
• The following advice only refers to missed active tablets: If the patient is less than 24 hours late in taking any active tablet, contraceptive protection is not reduced. The patient should take the tablet as soon as possible and should take further tablets at the usual time
• If she is more than 24 hours late in taking any active tablet, contraceptive protection may be reduced. The management of missed tablets can be guided by the following two basic rules:
  • The recommended hormone-free tablet interval is 4 days, tablet-taking must never be discontinued for longer than 7 days
  • Seven days of uninterrupted active tablet-taking are required to attain adequate suppression of the hypothalamic-pituitary-ovarian-axis

Accordingly, the following advice can be given in daily practice

• Day 1-7
  • The user should take the last missed tablet as soon as possible, even if this means taking two tablets at the same time. She then continues to take tablets at her usual time. In addition, a barrier method such as a condom should be used until she has completed 7 days of uninterrupted active tablet-taking. If intercourse took place in the preceding 7 days, the possibility of a pregnancy should be considered. The more tablets are missed and the closer they are to the placebo tablet phase, the higher the risk of a pregnancy
• Day 8-17
  • The patient should take the last missed tablet as soon as possible, even if this means taking two tablets at the same time. She then continues to take tablets at her usual time. Provided that the woman has taken her tablets correctly in the 7 days preceding the first missed tablet, there is no need to use extra contraceptive precautions. However, if she has missed more than 1 tablet, the woman should be advised to use extra precautions until she has completed 7 days of uninterrupted active tablet taking
• Day 18-24
  • The risk of reduced reliability is imminent because of the forthcoming placebo tablet phase. However, by adjusting the tablet-intake schedule, reduced contraceptive protection can still be prevented
  • By adhering to either of the following two options, there is therefore no need to use extra contraceptive precautions, provided that in the 7 days preceding the first missed tablet the woman has taken all tablets correctly. If this is not the case, she should follow the first of these two options and use extra precautions until she has completed 7 days of uninterrupted active tablet-taking as well
    1. The user should take the last missed tablet as soon as possible, even if this means taking two tablets at the same time. She then continues to take tablets at her usual time until the active tablets are used up. The 4 placebo tablets from the last row must be discarded. The next blister pack must be started right away. The user is unlikely to have a withdrawal bleed until the end of the active tablets section of the second pack, but she may experience spotting or breakthrough bleeding on active tablet-taking days
    2. The woman may also be advised to discontinue active tablet-taking from the current blister pack. She should then take placebo tablets from the last row for up to 4 days, including the days she missed tablets, and subsequently continue with the next blister pack
• If the woman missed tablets and subsequently has no withdrawal bleeding in the placebo tablet phase, the possibility of a pregnancy should be considered

Advice in case of gastro-intestinal disturbances

• In case of severe gastro-intestinal disturbances (e.g., vomiting or diarrhoea), absorption may not be complete and additional contraceptive measures should be taken
• If vomiting occurs within 3-4 hours after active tablet-taking, a new (replacement) tablet should be taken as soon as possible. The new active tablet should be taken within 24 hours of the usual time of tablet-taking if possible
• If more than 24 hours elapse, the advice concerning missed tablets, as given above ‘Management of missed tablets’, is applicable
• If the woman does not want to change her normal tablet-taking schedule, she has to take the extra active tablet(s) from another blister pack

How to postpone a withdrawal bleed

• To delay a period the woman should continue with another blister pack of drospirenone/ estetrol without taking the placebo tablets from her current pack
• The extension can be carried on for as long as wished until the end of the active tablets in the second pack. During the extension, the woman may experience breakthrough-bleeding or spotting
• Regular intake of drospirenone/ estetrol is then resumed after the placebo tablet phase. To shift her periods to another day of the week than the woman is used to with her current scheme, she can be advised to shorten her forthcoming placebo tablet phase by as many days as she likes
• The shorter the interval, the higher the risk that she does not have a withdrawal bleed and will experience breakthrough-bleeding and spotting during the subsequent pack (just as when delaying a period)

Other pharmacodynamic interactions

• In patients without renal impairment, the concomitant use of drospirenone and angiotensin converting enzyme (ACE)-inhibitors or non-steroidal anti-inflammatory drugs (NSAIDs) did not show a significant effect on serum potassium. Nevertheless, concomitant use of drospirenone/estetrol with aldosterone antagonists or potassium-sparing diuretics has not been studied. In this case, serum potassium should be tested during the first treatment cycle

Drospirenone/ Estetrol contains the oestrogen estetrol and the progestogen drospirenone. Estetrol is an oestrogen that is only produced during pregnancy by the human foetal liver. Estetrol demonstrates anti-gonadotropic activity characterised by a dose-dependent decrease in both serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels. The progestogen drospirenone possesses progestagenic, antigonadotropic, antiandrogenic and mild antimineralocorticoid properties and has no oestrogenic, glucocorticoid or antiglucocorticoid activity. These properties are pharmacologically similar to the natural hormone progesterone. The contraceptive effect of drospirenone/ estetrol is based on the interaction of various factors, the most important of which is inhibition of ovulation.