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    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-
         3,17-diol

         Mestranol - 3-Methoxy-19-nor-17alpha-pregna-1,3,5(10) trien-20-
         yn-17-ol

         Desogestrel - 13-Ethyl-11-methylene-18,19-dinor-17alpha-pregn-4-
         en-20-yn-17-ol

         Gestodene - 13-Ethyl-17-hydroxy-18,19-dinor-17alpha-pregna-
         4,15-dien-20-yn-3-one

         Levonorgestrel - 13-Ethyl-17-hydroxy-18,19-dinor-17alpha-pregn-
         4-en-20-yn-3-one

         Norethisterone - 17alpha-Ethinyl-19-nortestosterone, 17-hydroxy-
         19-nor-17alpha-pregn-4-en-20-yn-3-one, 17alpha-ethinyl-17-
         hydroxy-19-nor-androst-4-en-3-one

         Norgestimate - 13-Ethyl-3-hydroxyimino-18,19-dinor-17alpha-
         pregn-4-en-20-yn-17-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.