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.