Levonorgestrel/ Ethinylestradiol

Registered South African indications:

• Contraception
• Dysfunctional uterine bleeding
• Dysmenorrhoea

Contraindications

• Hypersensitivity to ethinylestradiol or levonorgestrel or to any of the excipients
• Personal and family history of breast cancer
• Patients known with inherited genetic mutations: BRCA1 and BRCA2 genes
• Early menstrual periods (before the age of 12 years)
• History of non-cancerous breast diseases (atypical hyperplasia or lobular carcinoma in situ)
• Previous treatment using radiation therapy to the chest or breast
• Previous exposure to diethylstilbestrol (DES)
• Concomitant use with ritonavir
• Patients with recurrent cholestatic jaundice, or impaired liver function
• Known or suspected estrogen-dependent neoplasia
• Thrombophlebitis or thromboembolic disorders, or a history thereof
• Inherited thrombophilia
• Severe migraine
• Cerebrovascular insufficiency
• Coronary artery disease
• Undiagnosed vaginal bleeding
• Patients where migraine becomes focal or when there is a loss of vision
• Onset of unexplained chest pain (medication should be discontinued immediately upon onset of these symptoms)
• Known or suspected carcinoma of the breast
• Benign or malignant liver tumours that developed during the use of oral contraceptives or estrogen-containing products
• Active liver disease
• The presence or history of severe hepatic disease, such as active viral hepatitis and severe cirrhosis, as long as liver function values have not returned to normal
• Previous pulmonary embolism
• Previous proven deep-vein thrombosis (DVT)
• The presence or risk of venous thromboembolism (VTE):
  • Current VTE (on anticoagulants) or history of VTE such as deep venous thrombosis (DVT) or pulmonary embolism (PE)
  • Known hereditary or acquired predisposition for venous thromboembolism, such as APC-resistance (including Factor V Leiden), antithrombin-III deficiency, protein C deficiency, protein S deficiency
  • Major surgery with prolonged immobilisation
  • High risk of venous thromboembolism due to the presence of multiple risk factors
• The presence or risk of arterial thromboembolism (ATE):
  • Current arterial thromboembolism, history of arterial thromboembolism (e.g. myocardial infarction) or prodromal condition (e.g. angina pectoris)
  • Cerebrovascular disease, including 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
• High risk of arterial thromboembolism due to multiple risk factors or the presence of one serious risk factor such as:
  • Diabetes mellitus with vascular symptoms
  • Severe hypertension
  • Severe dyslipoproteinaemia
• Relative contraindications include:
  • A history of diabetes mellitus
  • Epilepsy
  • Asthma
  • Hypertension
  • Depression
  • Porphyria
  • Dubin-Johnson’s syndrome
  • Rotor syndrome
  • States in which fluid retention occurs
• Pregnancy
• Lactation

Cautions

• Breastfeeding
• Renal impairment
• Diabetes mellitus with mild vascular disease or no vascular disease
• Mild to moderate hypertension
• Obesity
• Migraine
• Cardiovascular disease
• Hypertriglyceridemia or a family history thereof
• Any history of conditions that worsened during previous pregnancies
• History of chloasma gravidarum
• Galactose intolerance 
• Lapp lactase deficiency
• Fructose intolerance
• Glucose-galactose malasorption

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

Contraception
Dysfunctional uterine bleeding
Dysmenorrhoea

Low dose monophasic preparation

• Levonorgestrel 150μg/estradiol 30μg: Oral (tab): 1 tablet, dly for 21 days

THEN

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

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Initiate Levonorgestrel 150μg/estradiol 30μg tablet on day 1 of the menstrual cycle (1st day of menstruation = 1st day of cycle)

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High dose monophasic preparation

• Levonorgestrel 250μg/estradiol 50μg: Oral (tab): 1 tablet, dly for 21 days

THEN

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

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Initiate Levonorgestrel 250μg/estradiol 50μg tablet on day 1 of the menstrual cycle (1st day of menstruation = 1st day of cycle)

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Low dose triphasic preparation

• Inactive tablet: Oral (tab): 1 tablet, dly following the arrows on the pack

THEN

• Active tablets: Oral (tab): 1 tablet, dly following the arrows on the pack

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Initiate inactive tablet on day 1 of the menstrual cycle (1st day of menstruation = 1st day of cycle); The first inactive tablet should be selected from the inactive section of the pack that is marked with the appropriate day of the week

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High dose biphasic preparation

• Oral (tab): 1 tablet, dly as per manufacturer recommendations

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Missed dose: See additional prescribing points

Not indicated for use in premenarchal children

Pregnancy

• Contraindicated

Breastfeeding

• Contraindicated

Renal Impairment

• Caution; no dose adjustment recommended

Hepatic Impairment

• Contraindicated 

Elderly

• Not indicated for use in geriatric patients

Porphyria Information

• Probably porphyrinogenic (PRP)

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Headache
• Migraine
• Exacerbation of chorea
• Depressed mood

Cardiovascular Disorders

• Venous thromboembolism
• Arterial thromboembolism 

Gastrointestinal Disorders

• Nausea and vomiting
• Abdominal pain
• Diarrhoea
• Crohn's disease
• Ulcerative colitis

Hepatobiliary Disorders

• Liver function disturbances

Genitourinary Disorders

• Breast pain
• Breast tenderness
• Breast hypertrophy
• Vaginal discharge
• Breast discharge
• Reduced menstrual flow
• Spotting
• Breakthrough bleeding and missed withdrawal bleeding
• Post pill amenorrhoea
• Decreased libido
• Increased libido

Endocrine and Metabolic Disorders

• Increased weight
• Fluid retention
• Hypertriglyceridemia

Skin and Subcutaneous Tissue Disorders

• Rash
• Urticaria
• Erythema nodosum
• Erythema multiforme
• Chloasma

Immune, Blood and Lymphatic System Disorders

• Hypersensitivity
• Exacerbation of hereditary angioedema

Sensory Disorders

• Contact lens intolerance

• CYP3A4 inducers
• CYP3A4 inhibitors
• Ritonavir

• Breast exam
• Gynaecological exam
• Pregnancy test
• Blood pressure

Specific cases may require

• Lipid profile

Initiating in special circumstances

• Low-dose triphasic and low-dose monophasic preparation:
  Post-partum: Can be initiated 21 days post-partum if not breast feeding; Additional non-hormonal methods of contraception should be used for the first 7 days; Can be initiated 4 weeks post-partum if breastfeeding or if additional risk factors for venous thromboembolism  
  First-trimester abortion: Initiate immediately (in which case no additional contraceptive precautions are required)
• High-dose biphasic and high-dose monophasic: Can be initiated 4-6 weeks post partum

Special circumstances requiring additional contraception

• If vomiting or diarrhoea occurs within 4 hours of tablet-taking, current pack should be continued. Additional non-hormonal methods of contraception should be used during the gastro-intestinal upset and for 7 days; If these 7 days overrun the end of a pack, the next pack should be started without a break

Missed dose

• Missed 1 active pills: Take active pill as soon as possible; Continue taking the remaining pills at the usual time (even if it means taking 2 pills on the same day). No additional contraception needed
• Missed 2 doses (week 1-2): Take active pill as soon as possible; Continue taking the remaining pills at the usual time (even if it means taking 2 pills on the same day). Additional non-hormonal contraception required until she has taken 7 active tablets in a row
• Missed 2 doses in week 3 OR missed 3 or more doses during week 1-3: Discard current pack and start new pack on the same day; Additional non-hormonal contraception required until she has taken 7 active tablets in a row

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Low-dose monophasic preparations, Low-dose triphasic preparations: EML (Primary)

All other formulations: non-EML

Levonorgestrel/oestrogen is an oestrogen-progestogen combination which acts by inhibiting ovulation by suppression of the mid-cycle surge of luteinizing hormone, the inspissation of cervical mucus so as to constitute a barrier to sperm, and the rendering of the endometrium unreceptive to implantation.

COMBINATION PREPARATIONS

Low-dose monophasic preparations

Levonorgestrel/ Oestrogen

Tablet 0.15mg/0.03mg

• Levette (Actor)
• Nordette (Pharmacare)
• Oralcon (Mylan)

High-dose monophasic preparations

Tablet 0.25mg/0.05mg

• Nordiol (Pharmacare)

Low-dose triphasic preparations

Tablet 0.05mg/0.03mg

• Logynon ED (Bayer) originator
• Trigestrel (Mylan)
• Triphasil (Pharmacare)

High-dose biphasic preparations

Tablet 0.125mg/0.05mg

• Biphasil (Pharmacare)