Drospirenone/ Ethinylestradiol

These indications are based on manufacturer information for both originator and generic products. For product specific registered indications, please refer to product specific manufacturer information

Registered South African indications:

• Contraception
• Moderate acne vulgaris in women seeking oral contraception (3/0.02 (mg))
• Premenstrual dysphoric disorder in women who have chosen oral contraception as their method of birth control (3/0.02 (mg))

Contraindications 

• Hypersensitivity to the active ingredient or any of its excipients
• Moderate to severe renal impairment (GFR ≤49ml/min)
  - Including acute renal failure
• Moderate to severe hepatic impairment (Child-Pugh Class B & C)
  - Presence or history of severe hepatic disease as long as hepatic function values have not returned to normal
• Porphyria
• Presence or risk of venous thromboembolism (VTE), particularly those at high risk of VTE due to the presence of multiple risk factors:
  - Current VTE (on anticoagulants) or history of deep venous thrombosis (DVT) or pulmonary embolism (PE)
  - Known hereditary or acquired predisposition for VTE, such as APC-resistance (including Factor V Leiden), antithrombin-III-deficiency, protein C deficiency or protein S deficiency
  - Major surgery with prolonged immobilisation
• Presence or risk of arterial thromboembolism (ATE):
  - Current or history of ATE (e.g. myocardial infarction) or prodromal condition (e.g. angina pectoris)
  - Cerebrovascular disease such as current or history of stroke or prodromal condition (e.g. transient ischaemic attack, TIA)
  - Known hereditary or acquired predisposition for ATE, such as hyperhomocysteinaemia and antiphospholipid-antibodies (anticardiolipin-antibodies, lupus anticoagulant)
  - History of migraine with focal neurological symptoms
• High risk of ATE 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 hepatic tumours (benign or malignant)
• Known or suspected sex-steroid influenced malignancies (e.g. of the genital organs or the breasts)
• Undiagnosed vaginal bleeding
• Coadministration with products containing ombitasvir/ paritaprevir/ ritonavir and dasabuvir

Cautions

• Breastfeeding
• Circulatory disorders
• Obesity (body mass index over 30kg/m²)
• Prolonged immobilisation
  - Any surgery to the legs or pelvis or neurosurgery
  - Major trauma
• Regular temporary immobilisation including air travel >4 hours, particularly in women with other risk factors
• Presence of medical conditions associated with VTE
  - Cancer
  - Systemic lupus erythematosus
  - Haemolytic uremic syndrome
  - Chronic inflammatory bowel disease (Crohn's disease or ulcerative colitis)
  - Sickle cell disease
• 6 week period of the puerperium
• Increased age (particularly >35 years)
• Symptoms of deep vein thrombosis (DVT)
• Symptoms of pulmonary embolism (PE)
• Smoking
• Hypertension
  - Unresponsive hypertension
• Migraine
• Presence of medical conditions associated with adverse vascular events
  - Diabetes mellitus
  - Hyperhomocysteinaemia
  - Valvular heart disease
  - Atrial fibrillation
  - Dyslipoproteinaemia
• Symptoms of arterial thromboembolism
• Prolonged use
• Presence of family history of hypertriglyceridaemia
• Hereditary angioedema
• Endogenous depression
• Epilepsy
• History of chloasma gravidarum
• Tendency to chloasma
• Irregular use
• Gastrointestinal disturbances
• Risk factors for breast cancer
• Irregular bleeding after an adaptation interval of about 3 cycles
• Galactose intolerance
• Total lactase deficiency
• Glucose-galactose malabsorption

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

Contraception

Drospirenone/ Ethinyloestradiol
3/0.03 (mg)

• Oral (tab): 1 tablet, dly for 21 days

THEN

Inactive tablets

• Oral (tab): 1 tablet, dly for 7 days

Contraception
Acne vulgaris  
Premenstrual dysphoric disorder

Drospirenone/ Ethinyloestradiol
3/0.02 (mg)

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

THEN

Inactive tablets

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

---

Take tablets at the same time everyday

---

No preceding hormonal contraceptive use (in the past month): Initiate active tablets on day 1 of the menstrual cycle (1st day of menstruation = 1st day of cycle)

See additional prescribing points for initiation under special circumstances

---

A withdrawal bleed usually starts on days 2-3, after the last active tablet, and may not have finished before the next pack needs to be started

Not indicated for use in premenarchal children

Pregnancy

• Not indicated for use in pregnancy 
• If pregnancy occurs during use of drospirenone/ ethinylestradiol tablets the preparation should be withdrawn immediately
• Extensive epidemiological studies have revealed neither an increased risk of birth defects in children born to women who used combined oral contraceptives (COCs) prior to pregnancy nor a teratogenic effect when COCs were taken inadvertently during pregnancy
• Animal studies have shown undesirable effects during pregnancy. Based on these animal data, undesirable effects due to hormonal action of the active compounds cannot be excluded. However, general experience with COCs during pregnancy did not provide evidence for an actual undesirable effect in humans
• The available data regarding the use of drospirenone/ ethinylestradiol during pregnancy are too limited to permit conclusions concerning negative effects of drospirenone/ ethinylestradiol on pregnancy, health of the foetus or neonate. To date, no relevant epidemiological data are available
• The increased risk of venous thromboembolism during the postpartum period should be considered when re-starting drospirenone/ ethinylestradiol

Breastfeeding

• Caution; not recommended
• Lactation may be influenced by COCs as they may reduce the quantity and change the composition of breast milk. Therefore, the use of COCs should generally not be recommended until the breastfeeding mother has completely weaned her child. Small amounts of the contraceptive steroids and/or their metabolites may be excreted with the milk during COC use. These amounts may affect the child

Fertility

• Drospirenone/ ethinylestradiol is indicated for the prevention of pregnancy

Renal Impairment

• GFR ≥50-89ml/min: No dose adjustment recommended
• GFR ≤49ml/min: Contraindicated

Hepatic Impairment

• Child-Pugh Class A: No dose adjustment recommended
  Limit use for clinical conditions like premenstrual dysphoric disorder
• Child-Pugh Class B & C: Contraindicated

Elderly

• Not indicated for use in geriatric patients

Porphyria Information

• Probably porphyrinogenic (PRP)

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Depressed mood
• Decreased libido
• Increased libido
• Headache
• Migraine
• Emotional liability
• Depression
• Nervousness
• Somnolence
• Anorgasmia
• Insomnia
• Dizziness
• Paresthesia
• Tremor
• Asthenia

Cardiovascular Disorders

• Hypertension
• Hypotension
• Venous thromboembolism (VTE) disorders
• Arterial thromboembolism (ATE) disorders
• Tachycardia
• Varicose veins
• Phlebitis
• Vascular disorders
• Epistaxis
• Syncope

Respiratory Disorders

• Asthma

Gastrointestinal Disorders

• Nausea and vomiting
• Diarrhoea
• Abdominal pain
• Dyspepsia
• Flatulence
• Gastritis
• Enlarged abdomen
• Gastrointestinal fullness
• Hiatus hernia
• Oral candidiasis
• Constipation
• Dry mouth

Hepatobiliary Disorders

• Hepatic tumours
• Biliary pain
• Cholecystitis

Genitourinary Disorders

• Menstrual disorders
• Intermenstrual bleeding
• Leukorrhoea
• Vaginal moniliasis
• Vaginitis
• Metrorrhagia
• Amenorrhoea
• Vaginal candidiasis
• Pelvic pain
• Uterine/ vaginal bleeding
• Genital discharge
• Dysmenorrhea
• Hypomenorrhea
• Menorrhagia
• Vaginal dryness
• Suspicious papanicolaou smear
• Dyspareunia
• Vulvovaginitis
• Postcoital bleeding
• Withdrawal bleeding
• Cervical polyp
• Endometrial atrophy
• Ovarian cyst
• Uterine enlargement
• Increased sweating

Endocrine and Metabolic Disorders

• Breast pain
• Breast tenderness
• Breast enlargement
• Breast discharge
• Breast cyst
• Breast hyperplasia
• Breast neoplasm
• Fibrocystic breast
• Body weight changes
  - Increased weight
  - Decreased weight
• Increased appetite
• Anorexia
• Hyperkalemia
• Hyponatremia
• Hot flushes
• Increased sweating

Musculoskeletal Disorders

• Back pain
• Pain in extremity
• Muscle cramps

Skin and Subcutaneous Tissue Disorders

• Acne
• Eczema
• Pruritis
• Rash
• Alopecia
• Erythema nodosum
• Erythema multiforme
• Fluid retention
• Chloasma
• Dermatitis acneiform
• Dry skin
• Hypertrichosis
• Skin striae
• Contact dermatitis
• Photosensitive dermatitis
• Skin nodule

Immune, Blood and Lymphatic System Disorders

• Hypersensitivity reactions
• Exacerbated symptoms of angioedema
• Candidiasis
• Anaemia
• Thrombocythemia
• Allergic reeactions
• Oedema
  - Generalized oedema
  - Peripheral oedema
  - Face oedema

Sensory Disorders

• Hyperacusis
• Vertigo
• Conjunctivitis
• Dry eye
• Eye disorder

Others (occurrence or deterioration of conditions for which association with COC use is not conclusive)

• Crohn's disease
• Ulcerative colitis
• Epilepsy
• Uterine myoma
• Porphyria
• Systemic lupus erythematosus
• Herpes gestationis
• Sydenham's chorea
• Haemolytic uremic syndrome
• Cholestatic jaundice
• Chloasma
• Acute or chronic disturbances of hepatic function 

• Ombitasvir/ paritaprevir/ ritonavir and dasabuvir, with or without ribavirin
• Phenytoin
• Barbiturates
• Primidone
• Carbamazepine
• Rifampicin
• Bosentan
• Oxcarbazepine
• Topiramate
• Felbamate
• Griseofulvin
• Antibiotics
• Penicillins
• Tetracyclines
• Efavirenz
• HIV medication
• Nevirapine
• HIV protease inhibitors
• Ritonavir
• Non-nucleoside reverse transcriptase inhibitors
• Hepatitis C virus inhibitors
• Strong CYP3A4 inhibitors
• Ketoconazole
• Etoricoxib
• Ciclosporin
• Lamotrigine
• Omeprazole
• Simvastatin
• Midazolam
• CYP1A2 substrates
• Theophylline
• Tizanidine
• Agents that increase serum potassium
• Aldosterone antagonists
• Potassium-sparing diuretics

Other interactions

• St John's Wort
• Certain laboratory tests (See additional prescribing points)

• Pregnancy status
• Physical examination
• Blood pressure

Specific cases may require

• Serum potassium
• Blood glucose
• Endometrial cytology
• Lipid profile
• Weight

Additional observations

• Vision changes
• Signs and symptoms of thromboembolic disorders
• Signs and symptoms of depression

Symptoms of venous thromboembolism (deep vein thrombosis and pulmonary embolism)

• 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 combined hormonal contraceptive
• Symptoms of deep vein thrombosis (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 pulmonary embolism (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 lightheadedness 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 discoloration 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

Symptoms of arterial thromboembolism 

• 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 combined hormonal contraceptive
• 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

Initiating in special circumstances

• Post-partum or second-trimester abortion: Women should be advised to start at day 21-28 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 combined oral contraceptive (COC) use or the woman has to wait for her first menstrual period
• First-trimester abortion: The woman may start immediately. When doing so, she need not take additional contraceptive measures
• Changing from a combined hormonal contraceptive (COC, vaginal ring, or transdermal patch): Start 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/ ethinylestradiol tablets 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 system (IUS): The woman may switch any day from the progestogen-only pill (from an implant or the IUS 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 days of tablet taking

 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 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 antimineralocorticoid activity

Advice in case of gastrointestinal disturbances

• If vomiting occurs within 3-4 hours after tablet taking, a new (replacement) tablet should be taken as soon as possible
• The new tablet should be taken within 12 hours of the usual time of tablet-taking if possible
• If more than 12 hours elapse, the advice concerning missed tablets, is applicable and provided below
• If the woman does not want to change her normal tablet-taking schedule, she has to take the extra tablet(s) from another blister pack

Management of missed tablets

Drospirenone/ Ethinyloestradiol - 3mg/0.03mg tablets

• If the user is less than 12 hours late in taking any tablet, contraceptive protection is not reduced. The woman should take the tablet as soon as she remembers and should take further tablets at the usual time
• If she is more than 12 hours late in taking any tablet, contraceptive protection may be reduced. The management of missed tablets can be guided by the following two basic rules:

1. Tablet-taking must never be discontinued for longer than 7 days
2. 7 days of uninterrupted tablet-taking are required to attain adequate suppression of the hypothalamic-pituitary-ovarian-
axis.

Accordingly, the following advice can be given in daily practice:

• Week 1: The user should take the last missed tablet as soon as she remembers, 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 for the next 7 days. 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 regular tablet-free interval, the higher the risk of a pregnancy
• Week 2: The user should take the last missed tablet as soon as she remembers, 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 for 7 days
• Week 3: The risk of reduced reliability is imminent because of the forthcoming 7-day tablet-free interval. 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 for the next 7 days as well:

1. The user should take the last missed tablet as soon as she remembers, even if this means taking two tablets at the same time. She then continues to take tablets at her usual time. The next blister pack must be started as soon as the current blister pack is finished, i.e., no gap should be left between packs. The user is unlikely to have a withdrawal bleed until the end of the second pack, but she may experience spotting or breakthrough bleeding on tablet-taking days
2. The woman may also be advised to discontinue tablet-taking from the current blister pack. She should then have a tablet-free interval of up to 7 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 bleed in the first normal tablet-free interval, the possibility of a pregnancy should be considered

Drospirenone/ Ethinyloestradiol - 3mg/0.02mg tablets

• Placebo tablets from the last (4th) 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 user is less than 24 hours late in taking any tablet, contraceptive protection is not reduced. The woman should take the tablet as soon as she remembers and should take further tablets at the usual time
• If she is more than 24 hours late in taking any tablet, contraceptive protection may be reduced. The management of missed tablets can be guided by the following two basic rules:

1. The recommended hormone-free tablet interval is 4 days, tablet-taking must never be discontinued for longer than 7 days
2. 7 days of uninterrupted tablet-taking are required to attain adequate suppression of the hypothalamic-pituitary-ovarian-axis.

• Day 1-7: The user should take the last missed tablet as soon as she remembers, 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 for the next 7 days. 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 8-14: The user should take the last missed tablet as soon as she remembers, 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 for 7 days
• Day 15-24: 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 for the next 7 days as well

1. The user should take the last missed tablet as soon as she remembers, 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 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 bleed in the placebo tablet phase, the possibility of a pregnancy should be considered

How to postpone a withdrawal bleed

Drospirenone/ Ethinyloestradiol - 3mg/0.03mg and 3mg/0.02mg tablets

• To delay a period the woman should continue with another blister pack of drospirenone/ ethinylestradiol tablets without a tablet-free interval
• The extension can be carried on for as long as wished until the end of the second pack. During the extension the woman may experience breakthrough-bleeding or spotting
• Regular intake of drospirenone/ ethinylestradiol tablets is then resumed after the usual 7-day tablet-free interval
• 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 tablet-free interval 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)

Drospirenone/ ethinylestradiol is a combined oral contraceptive with ethinylestradiol and the progestogen drospirenone. The contraceptive effect of drospirenone/ ethinylestradiol is based on the interaction of various factors, the most important of which are seen as the inhibition of ovulation and the changes in the endometrium. In a therapeutic dosage, drospirenone also possesses antiandrogenic and mild antimineralocorticoid properties. It has no estrogenic, glucocorticoid and antiglucocorticoid activity. This gives drospirenone a pharmacological profile closely resembling the natural hormone progesterone. There are indications from clinical studies that the mild antimineralocorticoid properties of drospirenone/ ethinylestradiol result in a mild antimineralocorticoid effect.

COMBINATION PREPARATIONS

Drospirenone/ Ethinyloestradiol

Tablet 3mg/0.03mg

• Jarina (Bayer)
• Ruby (Pharma Dynamics)
• Yasmin (Bayer) originator
• Ynez (Adcock Ingram)

Tablet 3mg/0.02mg

• Yaz (Bayer) originator