Summary for UKPID COMBINED ORAL CONTRACEPTIVES Helen Seymour, BPharm (Hons) National Poisons Information Service (Newcastle Centre) Regional Drug & Therapeutics Centre Wolfson Building Claremont Place Newcastle upon Tyne NE1 4LP UK This monograph has been produced by staff of a National Poisons Information Service Centre in the United Kingdom. The work was commissioned and funded by the UK Departments of Health, and was designed as a source of detailed information for use by poisons information centres. Peer review group: Directors of the UK National Poisons Information Service. SUMMARY Type of product Contraceptive Ingredients Contains an oestrogen and a progestogen. Toxicity Very low. Features May cause nausea and vomiting. Rarely, withdrawal bleeding may occur in pre-pubertal girls. Treatment None required. SUBSTANCE Combined Oral Contraceptives ORIGIN OF SUBSTANCE NAME Brand Name/ Loestrin 20 (P-D) Generic Name Norethisterone acetate 1mg, ethinylestradiol 20 micrograms - 21 tablets Mercilon (Organon) Desogestrel 150 micrograms, ethinylestradiol 20 micrograms - 21 tablets Eugynon 30 (Schering Health) Ovran 30 (Wyeth) Levonorgestrel 250 micrograms, ethinylestradiol 30 micrograms - 21 tablets Logynon (Schering Health) Trinordiol (Wyeth) Ethinylestradiol 30 micrograms, levonorgestrel 50 micrograms - 6 tablets Ethinylestradiol 40 micrograms, levonorgestrel 75 micrograms - 5 tablets Ethinylestradiol 30 micrograms, levonorgestrel 125 micrograms - 10 tablets Logynon ED (Schering Health) As above with the addition on 7 placebo tablets Microgynon 30 (Schering Health) Ovranette (Wyeth) Levonorgestrel 150 micrograms, ethinylestradiol 30 micrograms - 21 tablets Binovum (Ortho) Ethinylestradiol 35 micrograms, norethisterone 500 micrograms - 7 tablets Ethinylestradiol 35 micrograms, norethisterone 1mg - 14 tablets Brevinor (Searle) Ovysmen (Ortho) Norethisterone 500 micrograms, ethinylestradiol 35 micrograms - 21 tablets Loestrin 30 (P-D) Norethisterone acetate 1.5mg, ethinylestradiol 30 micrograms - 21 tablets Norimin (Searle) Norethisterone 1mg, ethinylestradiol 35 micrograms - 21 tablets Synphase (Searle) Ethinylestradiol 35 micrograms, norethisterone 500 micrograms - 7 tablets Ethinylestradiol 35 micrograms, norethisterone 1mg - 9 tablets Ethinylestradiol 35 micrograms, norethisterone 500 micrograms - 5 tablets Trinovum (Ortho) Ethinylestradiol 35 micrograms, norethisterone 500 micrograms - 7 tablets Ethinylestradiol 35 micrograms, norethisterone 750 micrograms - 7 tablets Ethinylestradiol 35 micrograms, norethisterone 1mg - 7 tablets Cilest (Cilag) Norgestimate 250 micrograms, ethinylestradiol 35 micrograms - 21 tablets Marvelon (Organon) Desogestrel 150 micrograms, ethinylestradiol 30 micrograms - 21 tablets Femodene (Schering Health) Minulet (Wyeth) Gestodene 75 micrograms, ethinylestradiol 30 micrograms - 21 tablets Femodene ED (Schering Health) As above plus 7 placebo tablets Triadene (Schering Health) Tri-Minulet (Wyeth) Ethinylestradiol 30 micrograms, gestodene 50 micrograms - 6 tablets Ethinylestradiol 40 micrograms, gestodene 70 micrograms - 5 tablets Ethinylestradiol 30 micrograms, gestodene 100 micrograms - 10 tablets Ovran (Wyeth) Levonorgestrel 250 micrograms, ethinylestradiol 50 micrograms - 21 tablets Norinyl-1 (Searle) Ortho-Novin 1.50 (Ortho) Norethisterone 1mg, mestranol 50 micrograms - 21 tablets Schering PC4 (Schering Health) Levonorgestrel 250 micrograms, ethinylestradiol 50 micrograms - 4 tablets CHEMICAL GROUP Combined oral contraceptives BNF 7.3.1 SUBSTANCE IDENTITY REFERENCE NUMBER CAS Product licence number: Loestrin 20 - 0018/0086 Loestrin 30 - 0018/0087 Mercilon - 0065/0085 Marvelon - 0065/0071 Eugynon 30 - 0053/0049 Logynon - 0053/0085 Logynon ED - 0053/0115 Microgynon 30 - 0053/0064 Femodene - 0053/0179 Femodene ED - 0053/0180 Triadene - 0053/0205 Schering PC4 - 0053/0162 Ovran 30 - 0011/0050 Ovranette - 0011/0041 Trinordiol - 0011/0066 Minulet - 0011/0135 Tri-Minulet - 011/0140 Ovran - 0011/0015 BiNovum - 0242/0208 Ovysmen - 0242/0253 TriNovum - 0242/0279 Ortho-Novin 1/50 - 0242/0252 Brevinor - 08821/0019 Norimin - Synphase - Norinyl-1 - Cilest - 0242/0209 MANUFACTURER Janssen-Cilag Ltd PO Box 79, Saunderton, High Wycombe, Bucks HP14 4HJ 01494 567567 Organon Laboratories Ltd Cambridge Science Park, Milton Road, Cambridge CB4 4FL 01223 423445 Ortho see Janssen-Cilag P-D Parke-Davis Medical, Lambert Court, Chestnut Avenue, Eastleigh, Hants SO53 3ZQ 01703 620500 Schering Health Care Ltd The Brow, Burgess Hill, West Sussex RH15 9NE 01444 232323 Searle Pharmaceuticals PO Box 53, Lane End Road, High Wycombe, Bucks HP12 4HL 01494 521124 Wyeth Laboratories Huntercombe Lane South, Taplow, Maidenhead, Berks SL6 0PH 01628 604377 PRESENTATION Form Tablets - see above for details of constituents Pack sizes See above under Brand name PHYSIOCHEMICAL PROPERTIES Chemical structure Ethinyloestradiol - 19-Nor-17alpha-pregna-1,3,5(10)-trien-20-yne- 3,17ß-diol Mestranol - 3-Methoxy-19-nor-17alpha-pregna-1,3,5(10) trien-20- yn-17ß-ol Desogestrel - 13ß-Ethyl-11-methylene-18,19-dinor-17alpha-pregn-4- en-20-yn-17ß-ol Gestodene - 13ß-Ethyl-17ß-hydroxy-18,19-dinor-17alpha-pregna- 4,15-dien-20-yn-3-one Levonorgestrel - 13-Ethyl-17ß-hydroxy-18,19-dinor-17alpha-pregn- 4-en-20-yn-3-one Norethisterone - 17alpha-Ethinyl-19-nortestosterone, 17ß-hydroxy- 19-nor-17alpha-pregn-4-en-20-yn-3-one, 17alpha-ethinyl-17ß- hydroxy-19-nor-androst-4-en-3-one Norgestimate - 13ß-Ethyl-3-hydroxyimino-18,19-dinor-17alpha- pregn-4-en-20-yn-17ß-yl acetate Physical structure at room temperature All are solid Colour Ethinyloestradiol - white - to creamy- or slightly yellowish- white Mestranol - white to creamy-white Desogestrel - NIF Gestodene - NIF Levonorgestrel - white or almost white Norethisterone - white or creamy-white Norgestimate - NIF Odour Ethinyloestradiol - odourless Mestranol - odourless Desogestrel - NIF Gestodene - NIF Levonorgestrel - odourless Norethisterone - odourless Norgestimate - NIF Viscosity NA pH NA Solubility Ethinyloestradiol - practically insoluble in water; freely soluble in alcohol and ether; sparingly soluble in chloroform; dissolves in dilute solutions of alkali hydroxides Mestranol - practically insoluble in water; sparingly soluble in alcohol; soluble in acetone, in dioxan, and in ether; freely soluble in chloroform; slightly soluble in methylalcohol. Desogestrel - NIF Gestodene - NIF Levonorgestrel - practically insoluble in water; slightly soluble in alcohol, in acetone and in ether; soluble in chloroform; sparingly soluble in methylene chloride. Norethisterone - practically insoluble in water; slight to sparingly soluble in alcohol; soluble in chloroform and in dioxan; slightly soluble in ether. Norgestimate - NIF USES Indications To prevent conception Therapeutic Dose One active tablet daily for 21 days and either 7 pill free days or one placebo tablet daily for 7 days Contraindications Pregnancy; severe or multiple risk factors for arterial disease, history of arterial or venous thromboembolis, valvular heart disease associated with pulmonary hypertension or risk of mural thrombi, ischaemic heart disease, severe hypertension, varicose veins (during sclerosing treatment or where history of thrombosis); conditions where risk of intravascular thrombosis is higher such as an atherogenic lipid profile (e.g. familial hyperlipidaemia together with cholesterol above 6.5 mmol/litre), or any known prothombotic coagulation abnormality; focal migraine, severe migraine, crescendo migraine, transient cerebral ischaemic attacks without headaches; liver disease including disorders of hepatic excretion (e.g. Dubin-Johnson or Rotor syndromes), infective hepatitis (until liver function returns to normal), porphyria and liver adenoma; gall-stones; after evacuation of hydatidiform mole (until return to normal of urine and plasma gonadotrophin values); history of haemolytic uraemic syndrome or during pregnancy of pruritus, chorea, pemphigoid gestationis, cholestatic jaundice, or deterioration of otosclerosis; breast or genital tract carcinoma; undiagnosed vaginal bleeding; breast feeding (until weaning or 6 months of age). Abuses NIF HAZARD/RISK CLASSIFICATION NIF PHARMACOKINETICS Absorption Ethinyloestradiol - 100% Mestranol - >90% Desogestrel - NIF Gestodene - NIF Levonorgestrel - 100% Norethisterone- 100% Norgestimate - NIF Distribution Ethinyloestradiol - Rapidly distributed throughout body tissues; more than 95% is protein bound. Mestranol - 98% protein bound Desogestrel - NIF Gestodene - NIF Levonorgestrel - 93-95% plasma bound Norethisterone- 95% plasma bound Norgestimate - NIF Metabolism Ethinyloestradiol - 50% is metabolised pre-systemically. Some hydroxylation occurs in the liver. Mestranol - metabolised to ethinyloestradiol by the liver. Ethinyloestradiol is metabolised by the gut wall and liver. Desogestrel - NIF Gestodene - NIF Levonorgestrel - Extensively metabolised by the liver Norethisterone- Metabolised in the intestinal wall and liver Norgestimate - NIF Elimination Ethinyloestradiol - 60% of the dose is excreted in the urine and 40% in the faeces Mestranol - Excreted in urine and bile Desogestrel - NIF Gestodene - NIF Levonorgestrel - 20-30% eliminated via the faeces and the rest via the urine Norethisterone - via urine and faeces Norgestimate - NIF Half-life Ethinyloestradiol - 8h Mestranol - 6-20h Desogestrel - NIF Gestodene - NIF Levonorgestrel - 10 - 26h Norethisterone - 5 -12h Norgestimate - NIF Breast Milk Ethinyloestradiol - oestrogens have been used to suppress lactation. Very small amounts are excreted in breast milk. Mestranol - As ethinyloestradiol Desogestrel - NIF Gestodene - NIF Levonorgestrel - Approximately 0.1% of the daily dose passes into breast milk Norethisterone - small amounts are excreted into breast milk, the concentration being 10-20% of that in plasma Norgestimate - NIF TOXICOKINETICS NIF EPIDEMIOLOGY OF POISONING In 1994, 2007 calls were made to UK NPIS centres about hormonal contraceptive poisoning. ADVERSE EFFECTS Nausea, vomiting, headache, breast tenderness, changes in body weight, thrombosis (more common in blood groups A,B and AB than O), changes in libido, depression, chloasma, hypertension, contact lenses may irritate, impairment of liver function, hepatic tumours, reduced menstrual loss, 'spotting' in early cycles, absence of withdrawal bleeding; rarely photosensitivity. Small increased risk of developing breast cancer during use and 10 years after stopping. INTERACTIONS Hepatic enzyme inducers such as barbiturates, primidone, phenobarbitone, phenytoin, phenylbutazone, rifampicin, carbamazepine, possibly lansoprazole and griseofulvin will accelerate metabolism. Broad spectrum antibiotics may impair absorption. Anticoagulant effect of nicoumalone, phenidione and warfarin may be antagonised. ACE Inhibitors and other anti-hypertensives, hypotensive effect may be antagonised. Antidiabetics, antagonism of hypoglycaemic effect. Cyclosporin, increased cyclosporin levels. Theophylline, increased theophylline levels. MECHANISM OF ACTION Inhibition of ovulation by suppression of mid-cycle surge of luteinising hormone, the inspissation of cervical mucus so as to constitute a barrier to sperm, and the rendering of the endometrium unreceptive to implantation. FEATURES OF POISONING Acute Ingestion Nausea and vomiting may occur. Withdrawal bleeding may occur in females even in pre-pubertal girls. Pregnancy There is no conclusive evidence to indicate that exposure to oral contraceptives during the first trimester of pregnancy is associated with an increased risk of congenital malformations, or any specific type of defect. Where inadvertent exposure occurs during the first few weeks of pregnancy, provided that there is no family history of malformations, it is unlikely that the risk of fetal toxicity will be any greater than that for the general population. The European Network of Teratology Information Services have prospective follow-up data on 15 women who took combined oral contraceptives during pregnancy. 11 women had taken therapeutic doses of oral contraceptives during the first trimester. There were 3 elective terminations, 7 normal babies, 1 of whom had severe birth asphyxia with neonatal convulsions and retinal haemorrhage, 1 mild talipes. 4 women had taken oral contraceptive overdoses; 1 at 9/40 together with alcohol abuse, she gave birth to a normal baby; 1 at 12/40 who gave birth to a normal baby; 1 at 8/40 who had an elective termination at 9/40; 1 at 27/40 who gave birth to a baby with an undescended right testicle. Postcoital pill/pregnancy There is no convincing evidence to suggest that the postcoital pill when used in the recommended way is associated with an increased risk of malformations or any particular pattern of defects. The consensus of opinion amongst teratologists is that even known teratogens will not produce malformations before organogenesis starts, which is much later than the 72 hours after fertilisation to which the use of Schering PC4 is licensed. During the pre-embryonic phase, which lasts until 17 days post- conception, the 'all or nothing' concept is thought to apply. During this period, cells damaged by a toxic insult, such as a drug exposure, will be replaced by extra divisions of the remaining cells which will then develop normally. If extensive damage occurs, failure of implantation and spontaneous abortion may occur. Thus, if the pregnancy is maintained, the risks to the fetus are likely to be no greater than those for the general population. If used after 6-9 weeks post conception (8-11/40) there is a possibility of causing virulisation of female fetuses. Approximately 1% of female fetuses exposed at this critical period of development develop genital anomalies e.g. enlarged clitoris and labial folds. Internal genitalia and subsequent pubertal development are not affected by norethisterone taken during pregnancy Although there have been occasional reports of male pseudohermaphroditism usually hypospadias, following maternal treatment with progestogens., there is no good evidence to suggest that any adverse effects occur in male fetuses. However, a recent meta-analysis of 14 studies involving 65,567 women concluded that there was no association between 1st trimester exposure to sex hormones generally, or to oral contraceptives specifically, and external genital malformations. NB. The post coital pill appears to affect only endometrial implantation, If a tubal pregnancy had already occurred this is unlikely to be affected & would remain in situ. There is no firm evidence to suggest that the post coital pill "causes" ectopic pregnancies. The European Network of Teratology Information Services (ENTIS) have prospective follow-up data on 4 exposures to Schering PC4 in the first trimester. Three women took Schering PC4 in the first week post conception, 2 women had elective terminations and one woman had a fullterm normal baby. One woman took Schering PC4 at 21 days post conception, she had a p.v. bleed 2 weeks later and had a complete abortion confirmed by ultra sound scan at 8 weeks of gestation. MANAGEMENT Symptomatic treatment only is required. Parents of prepubertal girls should be warned of the possibility of a withdrawal bleed several days after ingestion. CASE DATA Picchioni (1965) reported no untoward effects in children who ingested up to 30 2mg Ortho Novum tablets, they were lavaged. ANALYSIS NIF PREVENTION OF POISONING NIF OTHER TOXICOLOGICAL DATA Carcinogenicity: Long-term oral contraceptive use does not increase the risk of breast cancer and prolactinoma. Long-term oral contraceptive use has been shown to decrease the risk of endometrial and ovarian cancers. The risk of developing endometrial and ovarian cancer remained low even after stopping the oral contraception. Teratogenicity: There is no conclusive evidence to indicate that exposure to oral contraceptives during the first trimester of pregnancy is associated with an increased risk of congenital malformations, or any specific type of defect. Where inadvertent exposure occurs during the first few weeks of pregnancy, provided that there is no family history of malformations, it is unlikely that the risk of fetal toxicity will be any greater than that for the general population. Postcoital pill/pregnancy There is no convincing evidence to suggest that the postcoital pill when used in the recommended way is associated with an increased risk of malformations or any particular pattern of defects. If used after 6-9 weeks post conception (8-11/40) there is a possibility of causing virulisation of female fetuses. Approximately 1% of those fetuses exposed during this critical period when genital development begins are likely to be affected. NB. The post coital pill appears to affect only endometrial implantation. If a tubal pregnancy had already occurred this is unlikely to be affected & would remain in situ. There is no firm evidence to suggest that the post coital pill "causes" ectopic pregnancies. Author Helen Seymour, BPharm (Hons) National Poisons Information Service (Newcastle Centre) Regional Drug & Therapeutics Centre Wolfson Building Claremont Place Newcastle upon Tyne NE1 4LP UK This monograph was produced by the staff of the Newcastle Centre of the National Poisons Information Service in the United Kingdom. The work was commissioned and funded by the UK Departments of Health, and was designed as a source of detailed information for use by poisons information centres. Peer review was undertaken by the Directors of the UK National Poisons Information Service. Last updated January 1997 REFERENCES 1. Martindale: The Extra Pharmacopoeia. 31st Edition. Reynolds JEF (Ed.). Pharmaceutical Press 1996. 2. Therapeutic Drugs. Dollery C. (Ed.). Churchill Livingstone 1991. 3. ABPI Compendium of Data Sheets and Summaries of Product Characteristics. Datapharm Publications Ltd. 1996-97. 4. British National Formulary. Number 32 (September 1996). British Medical Association and Royal Pharmaceutical Society. 5. Poisindex System(c), Micromedex, Inc., Denver Colorado, Edition Expires 31.12.96. 6. National Teratology Information Service. 7. European Commission; Poison centres: Collection of the annual reports 1994, Analysis and synthesis, Final Report 31.8.96. 8. Picchioni AL. Acute overdose of oral contraceptives. Am J Hosp Pharm 1965; 22: 486.