Adult: Available preparation:
Cyproterone 2 mg and ethinylestradiol 0.035 mg tab
For women with moderate to severe androgen-dependent acne and/or hirsutism who desire an oral contraceptive for birth control: 1 tab once daily, exactly as directed from the blister pack. Doses must be taken continuously at the same time each day. Refer to individual product guideline for detailed dosing instructions. Child: For those who have achieved menarche: Same as adult dose.
Hepatic Impairment
Contraindicated.
Contraindications
Breast cancer (current or recent) or other oestrogen- or progestin-dependent malignancies, undiagnosed vaginal bleeding, presence or history of hepatic tumours (benign or malignant), venous or arterial thromboembolism (VTE/ATE) (e.g. DVT, pulmonary embolism, MI, angina pectoris, stroke, TIA), severe or multiple risk factors for VTE/ATE (e.g. severe hypertension, diabetes mellitus, severe dyslipoproteinaemia, pancreatitis, major surgery with prolonged immobilisation), hereditary or acquired predisposition to VTE (e.g. protein C and S deficiency, hyperhomocytsteinaemia, antiphospholipid antibodies), presence or history of CVA, history of migraine with aura. Hepatic impairment. Pregnancy and lactation, Concomitant use with hepatitis C combination therapy containing ombitasvir/paritaprevir/ritonavir and dasabuvir.
Special Precautions
Women with CV disease-related risk factors (e.g. hypercholesterolaemia, hyperlipidaemia, diabetes mellitus with mild vascular disease), disorders of the connective tissue (e.g. SLE, rheumatoid arthritis, synovitis), diseases exacerbated by fluid retention (e.g. asthma, epilepsy), hereditary angioedema, depression, visual disturbance, history of migraine, chloasma gravidarum, jaundice, pruritus associated with cholestasis, cholelithiasis, sickle cell anaemia, porphyria, gallstone formation, haemolytic uraemic syndrome, Sydenham’s chorea, otosclerosis-related hearing loss. Smokers, obese patients. Not indicated for use prior to menarche, or in postmenopausal women. Renal impairment.
Adverse Reactions
Significant: Breakthrough bleeding and missed withdrawal bleeding, amenorrhoea, increased risk of breast cancer, meningioma, impaired lipid levels, jaundice, pruritus associated with cholestasis, chloasma, porphyria, cholelithiasis, impaired hepatic function, Crohn’s disease, ulcerative colitis, severe headache/migraine, depression, altered mood, exacerbated angioedema, increased blood pressure. Eye disorders: Contact lens intolerance. Gastrointestinal disorders: Nausea, abdominal pain, vomiting, diarrhoea. Investigations: Weight gain or loss. Metabolism and nutrition disorders: Fluid retention. Reproductive system and breast disorders: Decreased or increased libido, breast pain, tenderness or hypertrophy; vaginal or breast discharge. Skin and subcutaneous tissue disorders: Rash, urticaria, erythema nodosum, erythema multiforme. Potentially Fatal: Increased risk of VTE, ATE (e.g. DVT, pulmonary embolism, MI, stroke).
Monitoring Parameters
Screen for pregnancy before initiating treatment. Perform adequate diagnostic measures to rule out malignancy in all cases of undiagnosed abnormal vaginal bleeding, physical exams concerning the breasts, pelvis, and cervical screening when necessary. Monitor blood pressure, LFT, BMI, vision changes. Assess for signs and symptoms of thromboembolic disorders, depression.
Drug Interactions
CYP3A4 inducers (e.g. phenytoin, rifampicin) may increase the risk of breakthrough bleeding and decrease overall efficacy. Increased plasma concentration is observed with concomitant use of CYP3A4 inhibitors (e.g. ketoconazole, etoricoxib, erythromycin). May increase the plasma concentration of ciclosporin. May decrease the plasma concentration of lamotrigine. Ethinylestradiol may increase the plasma concentration of drugs metabolised by CYP1A2 (e.g. theophylline, tizanidine). Potentially Fatal: Increased risk of ALT elevations with concomitant use of ombitasvir/paritaprevir/ritonavir and dasabuvir.
Food Interaction
Increased plasma concentrations are observed when given with grapefruit juice. Diminished efficacy with St. John’s wort.
Lab Interference
May alter the results for glucose tolerance, coagulation, liver function, thyroid function and lipoprotein tests.
Action
Description: Mechanism of Action: Cyproterone and ethinylestradiol treat the signs of androgenisation in women through different but complementary mechanisms. As a combined oral contraceptive, they suppress ovulation, decrease the receptivity of the endometrium to implantation, and thicken the cervical mucus to form a barrier to sperm.
Cyproterone is a steroidal anti-androgen that also has antigonadotropic and progestogen-like activity. It decreases the activity of androgens via competitive inhibition at the androgen receptor.
Ethinylestradiol is a synthetic oestrogen with similar effects as estradiol. It regulates the pituitary secretion of LH and FSH via negative feedback system. This increases the levels of sex hormone-binding globulin (SHBG), thereby reducing the number of free androgens in the body. Pharmacokinetics: Absorption: Cyproterone: Completely absorbed from the gastrointestinal tract. Bioavailability: 88%. Time to peak plasma concentration: 3-4 hours.
Ethinylestradiol: Rapidly and well absorbed from the gastrointestinal tract. Bioavailability: Approx 40-60%. Time to peak plasma concentration: 1-2 hours. Distribution: Enters breast milk.
Cyproterone: Plasma protein binding: 96%, mainly to albumin.
Ethinylestradiol: Plasma protein binding: Approx 98%, mainly to albumin. Metabolism: Cyproterone: Metabolised in the liver via hydroxylation and conjugation into its primary metabolite, 15β-hydroxycyproterone.
Ethinylestradiol: Metabolised in the liver via aromatic hydroxylation by CYP3A4 into 2-hydroxyethinylestradiol and other free metabolites. Excretion: Cyproterone: Mainly via faeces (60%); urine (33%, as conjugated metabolites). Elimination half-life: Approx 43 hours.
Ethinylestradiol: Excreted via urine and faeces as free metabolites. Elimination half-life: Approx 24 hours (terminal disposition phase).
Chemical Structure
Cyproterone acetate Source: National Center for Biotechnology Information. PubChem Database. Cyproterone acetate, CID=9880, https://pubchem.ncbi.nlm.nih.gov/compound/Cyproterone-acetate (accessed on Jan. 22, 2020)
Ethinylestradiol Source: National Center for Biotechnology Information. PubChem Compound Summary for CID 5991, Ethinylestradiol. https://pubchem.ncbi.nlm.nih.gov/compound/Ethinylestradiol. Accessed Apr. 27, 2022.
G03HB01 - cyproterone and estrogen ; Belongs to the class of antiandrogen preparations in combination with estrogens. Used to counter androgenic activities.
References
Anon. Cyproterone and Ethinyl Estradiol. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 03/06/2020.Anon. Cyproterone. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 03/06/2020.Buckingham R (ed). Cyproterone Acetate. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 03/06/2020.Buckingham R (ed). Ethinylestradiol. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 03/06/2020.Cyproterone Acetate 2.00 mg Ethinylestradiol 0.035 mg Coated tablets (Sandoz Limited). MHRA. https://products.mhra.gov.uk/. Accessed 03/06/2020.Douglas Pharmaceuticals Ltd. Estelle-35 ED Tablet data sheet 2 February 2018. Medsafe. http://www.medsafe.govt.nz/. Accessed 03/06/2020.
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