Etonogestrel/ Ethinylestradiol

Registered South African indications:

• Contraception

Contraindications

South African manufacturer recommendations

• Hypersensitivity to the active ingredient or any of its excipients (including anaphylaxis and angioedema)
• Pregnancy
  - Known or suspected 
• Hepatic impairment
  - Presence or history of hepatic disease as long as liver function values have not returned to normal 
• Presence or history of venous thrombosis, with or without pulmonary embolism
• Presence or history of arterial thrombosis (e.g., cerebrovascular accident, myocardial infarction) or prodromi of a thrombosis (e.g., angina pectoris or transient ischaemic attack)
• Known predisposition for venous or arterial thrombosis, with or without hereditary involvement such as activated protein C (APC) resistance, antithrombin–III deficiency, protein C deficiency, protein S deficiency, hyperhomocysteinemia and antiphospholipid antibodies (anticardiolipin antibodies, lupus anticoagulant)
• Major surgery with prolonged immobilisation
• History of migraine with focal neurological symptoms
• Diabetes mellitus with vascular involvement
• The presence of a severe or multiple risk factor(s) for venous or arterial thrombosis (e.g., hypertension, a family history of thromboembolic events, prolonged immobilisation)
• Pancreatitis or a history thereof if associated with severe hypertriglyceridemia
• Presence or history of liver tumours (benign or malignant)
• Known or suspected malignant conditions of the genital organs or the breasts, if sex steroid-influenced
• Undiagnosed vaginal bleeding
• Coadministration with ombitasvir
• Coadministration with paritaprevir
• Coadministration with ritonavir
• Coadministration with dasabuvir

Recommendations in other jurisdictions

• Hypersensitivity to the active ingredient or any of its excipients
• Severe hepatic impairment 
  - Presence or history of severe hepatic disease as long as liver function values have not returned to normal  
• Presence or risk of venous thromboembolism (VTE)
  - Current VTE (on anticoagulants) or history of (e.g. deep venous thrombosis or pulmonary embolism)
  - Known hereditary or acquired predisposition for VTE, such as APC-resistance (including Factor V Leiden), antithrombin-III-deficiency, protein C deficiency, protein S deficiency
  - Major surgery with prolonged immobilisation
  - A high risk of VTE due to the presence of multiple risk factors
• Presence or risk of arterial thromboembolism (ATE)
  - Current ATE, history of ATE (e.g. myocardial infarction) or prodromal condition (e.g. angina pectoris)
  - Cerebrovascular disease e.g. current stroke, history of stroke or prodromal condition (e.g. transient ischaemic attack)
  - Known hereditary or acquired predisposition for ATE, such as hyperhomocysteinaemia and antiphospholipid-antibodies (anticardiolipin-antibodies, lupus anticoagulant)
  - History of migraine with focal neurological symptoms
  - A 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
• Pancreatitis or a history thereof if associated with severe hypertriglyceridemia
• Presence or history of liver tumours (benign or malignant)
• Known or suspected malignant conditions of the genital organs or the breasts, if sex steroid-influenced
• Undiagnosed vaginal bleeding
• Coadministration with ombitasvir
• Coadministration with paritaprevir
• Coadministration with ritonavir
• Coadministration with dasabuvir
• Coadministration with glecaprevir
• Coadministration with pibrentasvir

Cautions

South African manufacturer recommendations

• Breastfeeding
• Renal impairment
• Risk factors for venous thromboembolism (VTE)
  - First ever year of use
  - Obesity (body mass index over 30kg/m²)
  - Prolonged immobilisation
  - Major surgery
  - Any surgery to the legs
  - Major trauma
  - Positive family history
  - Increasing age
  - Superficial thrombophlebitis and varicose veins
• Risk factors for ATE (one serious or multiple risk factors)
  - Older age, especially older than 35 years
  - Hypertension
  - Smoking
  - Obesity (body mass index over 30kg/m²) 
  - Dyslipoproteinemia
  - Positive family history 
  - Atrial fibrillation
  - Valvular heart disease
  - Migraine
• Diabetes mellitus
• Systemic lupus erythematosus
• Haemolytic uraemic syndrome
• Chronic inflammatory bowel disease (Crohn's disease or ulcerative colitis)
• Sickle cell disease
• Puerperium
• Long-term use in women infected with human papillomavirus
• Current or family history of hypertriglyceridemia
• Jaundice and/or pruritus related to cholestasis
• Gallstones
• Porphyria
• Sydenham's chorea
• Herpes gestationis
• Otosclerosis-related hearing loss
• Hereditary angioedema
• Chloasma gravidarum
• Prolapse of the uterine cervix
• Cystocele
• Rectocele
• Severe or chronic constipation
• Incorrect positioning
• Non-compliance 
• Bleeding irregularities
• Tampon removal
• Sexual intercourse
• Coadministration with certain female barrier methods, such as a diaphragm, cervical cap, or female condom

Recommendations in other jurisdictions

• Breastfeeding
• Renal impairment 
• Mild to moderate hepatic impairment
• Risk factors for venous thromboembolism (VTE)
  - First ever year of use
  - Restarting combined hormonal contraceptive (CHC) after a break in use of 4 weeks or more
  - Obesity (body mass index over 30kg/m²)
  - Prolonged immobilisation
  - Major surgery
  - Any surgery to the legs or pelvis
  - Neurosurgery
  - Major trauma
  - Temporary immobilisation including air travel >4 hours
  - Positive family history
  - Other medical conditions associated with VTE e.g cancer, systemic lupus erythematosus, haemolytic uraemic syndrome, chronic inflammatory bowel disease (Crohn's disease or ulcerative colitis) and sickle cell disease
  - Increasing age
• Risk factors for ATE
  - Increasing age
  - Smoking
  - Hypertension
  - Obesity (body mass index over 30kg/m²) 
  - Positive family history 
  - Migraine
  - Other medical conditions associated with adverse vascular events e.g. diabetes mellitus, hyperhomocysteinaemia, valvular heart disease and atrial fibrillation, dyslipoproteinaemia and systemic lupus erythematosus
• Long-term use in women infected with human papillomavirus
• Current or family history of hypertriglyceridemia
• Jaundice and/or pruritus related to cholestasis
• Gallstones
• Porphyria
• Systemic lupus erythematosus
• Haemolytic uraemic syndrome
• Sydenham's chorea
• Herpes gestationis
• Otosclerosis-related hearing loss
• Hereditary angioedema
• Diabetes
• Crohn's disease
• Ulcerative colitis
• Chloasma gravidarum
• Prolapse of the uterine cervix
• Cystocele
• Rectocele
• Severe or chronic constipation
• Incorrect positioning
• Non-compliance 
• Bleeding irregularities
• Tampon removal
• Sexual intercourse
• Coadministration with certain female barrier methods, such as a diaphragm, cervical cap, or female condom

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

Contraception

Etonogestrel/ Ethinylestradiol
11.7/2.7 (mg)

• Vaginal (vri): 1 ring retained in the vagina, every 3 weeks 

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To achieve contraceptive effectiveness, the etonogestrel/ethinylestradiol vaginal ring must be used as directed

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 Must be removed after 3 weeks of use on the same day of the week as the ring was inserted. After a ring-free interval of one week a new ring is inserted. The withdrawal bleed usually starts 2-3 days after removal and may not have finished completely before the next ring insertion is due

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The woman herself can insert the ring in the vagina. Women should regularly check for the presence of the ring in the vagina (for example, before and after intercourse)

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

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May interfere with the correct placement and position of certain female barrier methods such as a diaphragm, cervical cap, or female condom. These methods should not be used as back-up methods 

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See additional prescribing points

Not established for use in children below than 18 years 

Pregnancy

South African manufacturer recommendations

• Contraindicated
• If pregnancy occurs with the vaginal ring in situ, the ring should be removed. 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 used inadvertently during early pregnancy. Although this probably applies to all COCs it is not clear whether this is also the case for the etonogestrel/ ethinyloestradiol vaginal ring
• A clinical study in a small number of women showed that despite the intravaginal administration, intrauterine concentrations of contraceptive steroids with the etonogestrel/ethinyloestradiol vaginal ring are likely to be higher than in COC users. Clinical experience of the outcomes of pregnancies exposed to the etonogestrel/ethinyloestradiol vaginal ring has not been reported

Recommendations in other jurisdictions

• Not indicated for use during pregnancy
• If pregnancy occurs with the etonogestrel/ethinyloestradiol vaginal ring in situ, the ring should be removed. 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 used inadvertently during early pregnancy
• A clinical study in a small number of women showed that despite the intravaginal administration, intrauterine concentrations of contraceptive steroids with the etonogestrel/ethinyloestradiol vaginal ring are similar to the levels observed in COC users. Clinical experience of the outcomes of pregnancies exposed to etonogestrel/ethinyloestradiol vaginal ring has not been reported
• The increased risk of venous thromboembolism during the postpartum period should be considered when re-starting etonogestrel/ethinyloestradiol

Breastfeeding

• Caution; not recommended 
• Lactation may be influenced by oestrogens, as they may reduce the quantity and change the composition of breast milk. Therefore, the use of the etonogestrel/ethinyloestradiol vaginal ring 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, but there is no evidence that this adversely affects the infant's health 

Fertility

• The etonogestrel/ethinylestradiol vaginal ring is indicated for the prevention of pregnancy. If the woman wants to stop using the ring because she wants to get pregnant, she is advised to wait until she has a natural period before trying to conceive as this will help her calculate when the baby is due

Renal Impairment

• Caution; no information available 

Hepatic Impairment 

South African manufacturer recommendations

• Contraindicated 
  Contraindicated in presence or history of hepatic disease as long as hepatic function values have not returned to normal. Steroid hormones may be poorly metabolised in women with impaired liver function 

Recommendations in other jurisdictions

• Mild to moderate: Caution; no information available 
• Severe: Contraindicated 
  Contraindicated in presence or history of severe hepatic disease as long as liver function values have not returned to normal. Steroid hormones may be poorly metabolised in women with impaired liver function

Elderly 

South African manufacturer recommendations

• Not indicated for use in geriatric patients 

Recommendations in other jurisdictions

• Not indicated for use in geriatric patients  
  Intended for women of fertile age. The safety and efficacy have been established in women aged 18-40 years 

Drugs in Sport

• Permitted - No warnings 

Central Nervous System Disorders

• Depression
• Decreased libido
• Labile affect
• Altered mood
• Mood swings
• Headache
• Migraine
• Dizziness
• Hypoaesthesia
• Fatigue
• Irritability

Cardiovascular Disorders

• Increased blood pressure 
• Hot flush
• Venous thromboembolism
• Arterial thromboembolism

Gastrointestinal Disorders

• Abdominal pain
• Nausea and vomiting
• Abdominal distension
• Diarrhoea
• Constipation

Genitourinary Disorders

• Dysuria
• Micturition urgency
• Pollakiuria
• Breast tenderness
• Genital pruritus (female)
• Dysmenorrhoea
• Pelvic pain
• Vaginal discharge
• Amenorrhoea
• Breast discomfort
• Breast enlargement
• Breast mass
• Cervical polyp
• Coital bleeding
• Dyspareunia
• Ectropion of cervix
• Fibrocystic breast disease
• Menorrhagia
• Metrorrhagia
• Pelvic discomfort
• Premenstrual syndrome
• Uterine spasm
• Vaginal burning sensation
• Vaginal odour
• Vaginal pain
• Vulvovaginal discomfort
• Vulvovaginal dryness
• Penis disorders
• Vaginal infection
• Cervicitis
• Cystitis
• Urinary tract infection
• Vaginal ring site tissue overgrowth 
• Vaginal ring discomfort
• Expelled vaginal ring 
• Vaginal ring complication
• Vaginal injury associated with ring breakage

Endocrine and Metabolic Disorders

• Increased appetite
• Galactorrhoea
• Increased weight 
• Hormone-dependent tumours
  - Hepatic tumours
  - Breast cancer

Musculoskeletal Disorders

• Back pain
• Muscle spasms
• Pain in extremity

Skin and Subcutaneous Tissue Disorders

• Acne
• Alopecia
• Eczema
• Pruritus
• Urticaria 
• Rash
• Chloasma

Immune, Blood and Lymphatic System Disorders

• Oedema  
• Hypersensitivity reactions
  - Angioedema
  - Anaphylaxis

Sensory Disorders

• Visual disturbance
• Sensation of foreign body

• CYP450 inducers
• Phenytoin
• Phenobarbital
• Primidone
• Bosentan
• Carbamazepine
• Rifampicin
• Oxcarbazepine
• Topiramate
• Felbamate
• Griseofulvin
• HIV protease inhibitors
• Ritonavir
• Nelfinavir
• Non-nucleoside reverse transcriptase inhibitors
• Efavirenz
• Nevirapine
• Hepatitis C virus agents
• Boceprevir
• Telaprevir
• Moderate and strong CYP3A4 inhibitors
• Ketoconazole
• Itraconazole
• Clarithromycin
• Fluconazole
• Diltiazem
• Erythromycin
• Ciclosporin
• Lamotrigine
• Ombitasvir
• Paritaprevir
• Dasabuvir
• Ribavirin
• Glecaprevir
• Pibrentasvir
• Intravaginal preparations e.g. antimycotic, antibiotic

Other interactions

• St. John's wort
• Vaginal lubricants
• Laboratory tests
  - Biochemical parameters of hepatic, thyroid, adrenal and renal function
  - Plasma levels of carrier proteins e.g. corticosteroid binding globulin and sex hormone binding globulin
  - Lipid/lipoprotein fractions
  - Parameters of carbohydrate metabolism
  - Parameters of coagulation and fibrinolysis

• Pregnancy status
• Blood pressure 

Specific cases may require

• Weight
• Glycaemic control
• Lipid profile 
• Endometrial sampling

Additional observations

• Health status
• Persistent urinary symptoms (possibility of incorrect bladder placement) 
• Personal or family history of thrombotic or thromboembolic disorders
• Vision changes 
• Signs and symptoms of
  - Thromboembolic disorder
  - Depression

How to start the etonogestrel/ethinylestradiol vaginal ring
No hormonal contraceptive use in the preceding cycle

• Has to be inserted on the first day of the woman's natural cycle (i.e. the first day of her menstrual bleeding)
• Starting on days 2-5 is allowed, but during the first cycle a barrier method is recommended in addition for the first 7 days of use

Changing from a combined oral contraceptive (COC)

• Insert the ring at the latest on the day following the usual tablet-free or placebo tablet interval of her previous COC
• If the woman has been using her previous method consistently and correctly and if it is reasonably certain that she is not pregnant she may also switch from her previous combined hormonal contraceptive on any day of the cycle
• The hormone-free interval of the previous method should never be extended beyond its recommended length

Changing from a progestogen-only method (minipill, implant or injection) or from a progestogen-releasing intrauterine system (IUS)

• May switch on any day from the minipill (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 use an additional barrier method for the first 7 days of use

Following first-trimester abortion

• May start immediately. When doing so, she needs not take additional contraceptive measures. If an immediate application is considered undesirable, the woman should follow the advice given for 'No hormonal contraceptive use in the preceding cycle'. In the meantime, she should be advised to use an alternative contraceptive method

Following delivery or second-trimester abortion

• Start during the 4th week 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 of use
• If intercourse has already occurred, pregnancy should be excluded or the woman has to wait for her first menstrual period, before inserting the ring 
• The increased risk of venous thromboembolism during the postpartum period should be considered when restarting etonogestrel/ ethinylestradiol 

Lengthened ring-free interval

• Insert a new ring as soon as she remembers. A barrier method such as a male condom should be used in addition for the next 7 days
• If intercourse took place during the ring-free interval, the possibility of a pregnancy should be considered.  The longer the ring-free interval, the higher the risk of a pregnancy

If the ring was temporarily outside the vagina

• The ring should be left in the vagina for a continuous period of 3 weeks. If the ring is accidentally expelled, it can be rinsed with cool to lukewarm (not hot) water and should be reinserted immediately
• If it has been out of the vagina for less than 3 hours contraceptive efficacy is not reduced. The woman should reinsert the ring as soon as possible, but at the latest within 3 hours
• If it has been out of the vagina, or is suspected to have been out of the vagina for more than 3 hours during the 1st or 2nd week of use, contraceptive efficacy may be reduced. The woman should reinsert the ring as soon as she remember. A barrier method such as a male condom should be used until it has been in the vagina continuously for 7 days. The longer the time it has been out of the vagina and the closer this is to the ring-free interval, the higher the risk of a pregnancy
• If the ring has been out of the vagina, or is suspected to have been out of the vagina for more than 3 hours during the 3rd week of the three-week use period, contraceptive efficacy may be reduced. The woman should discard that ring, and one of the following two options should be chosen:  
  -  Insert a new ring immediately (Note: inserting a new ring will start the next three-week use period. The woman may not experience a withdrawal bleed from her previous cycle. However breakthrough spotting or bleeding may occur)
  - Have a withdrawal bleeding and insert a new ring no later than 7 days (7x24 hours) from the time the previous ring was removed or expelled (Note: this option should only be chosen if the ring was used continuously for the preceding 7 days. If it was out of the vagina for an unknown amount of time, the possibility of pregnancy should be considered. A pregnancy test should be performed prior to inserting a new ring)

Lengthened ring-use

• Although this is not the recommended regimen, as long as the ring has been used for maximally 4 weeks, contraceptive efficacy is still adequate. The woman may maintain her one-week ring-free interval and subsequently insert a new ring
• If the ring has been left in place for more than 4 weeks, contraceptive efficacy may be reduced and pregnancy should be ruled out before inserting a new ring 
• If the woman has not adhered to the recommended regimen and subsequently has no withdrawal bleed in the following ring-free interval, pregnancy should be ruled out before inserting a new ring 

How to shift or delay a period

• If in exceptional cases a period needs to be delayed, the woman may insert a new ring without having a ring-free interval. The next ring can be used for up to 3 weeks again. The woman may experience bleeding or spotting. Regular use is then resumed after the usual one week ring-free interval
• To shift her period to another day of the week than the woman is used to with her current scheme, she can be advised to shorten her forthcoming ring-free interval by as many days as she likes. The shorter the ring-free interval, the higher the risk that she does not have a withdrawal bleed and will experience breakthrough bleeding and spotting during the use of the next ring

Etonogestrel is a 19-nortestosterone-derived progestogen and binds with high affinity to progesterone receptors in the target organs. Ethinyloestradiol is an oestrogen widely used in contraceptive products. The contraceptive effect of etonogestrel/ ethinylestradiol is based on various mechanisms, the most important of which is the inhibition of ovulation.

COMBINATION PREPARATION

Etonogestrel/ Ethinylestradiol

Vaginal ring 11.7mg/2.7mg

• NuvaRing (MSD) originator