Summary for UKPID PROGESTOGENS 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 Used for a number of purposes, including treatment of amenorrhea, abnormal uterine bleeding, contraception, malignant disease and menopausal symptoms. Ingredients A progestogen. Toxicity Very low. Features May cause nausea and vomiting. Rarely, withdrawal bleeding may occur in pre-pubertal girls. Treatment None required. SUBSTANCE Progestogen ORIGIN OF SUBSTANCE Synthetic NAME Brand Name/Generic Name Cyclogest/ Progesterone Depo-Provera/Medroxyprogesterone Depostat/ Gestronol hexanoate Duphaston/ Dydrogesterone Duphaston HRT/Dydrogesterone Farlutal/ Medroxyprogesterone Femulen/ Ethynodiol diacetate Gestone/ Progesterone Megace/ Megesterol Acetate Menzol/ Norethisterone Micronor HRT/ Norethisterone Micronor/ Norethisterone Microval/ Levonorgestrel Mirena/Levonorgestrel Neogest/ Norgestrel Norgeston/ Levonorgestrel Noriday/ Norethisterone Noristat/ Norethisterone Norplant/ Levonorgestrel Primolut N/ Norethisterone Proluten Depot/ Hydroxyprogesterone Hexanoate Provera/ Medroxyprogesterone Acetate Utovlan/ Norethisterone CHEMICAL GROUP Progestogens BNF 188.8.131.52 Progestogen-Only contraceptives BNF 7.3.2 Progestogens BNF 8.3.2 SUBSTANCE IDENTITY REFERENCE NUMBER CAS Product licence number Cyclogest Pessaries 200mg 2343/0001 Cyclogest Pessaries 400mg 2343/0002 Depo-Provera 150mg/ml 0032/0082 Depostat 200mg in 2ml 0053/0190 Duphaston/Duphaston HRT 0512/5004R Farlutal 100mg tablets 3433/0056 Farlutal 250mg tablets 3433/0058 Farlutal 500mg tablets 3433/0080 Farlutal 200mg/ml, 2.5ml 3433/0045 Farlutal 200mg/ml, 5ml 3433/0045 Femulen 500mcg 08821/0015 Gestone 25mg 3194/0061 Gestone 50mg 3194/0062 Gestone 100mg 3194/0063 Megace 40mg tablets 0125/0144 Megace 160mg tablets 0125/0173 Menzol 5mg tablets Micronor Oral Contraceptives 0242/0234 Micronor HRT 0242/0241 Microval 0011/0040 Mirena 0484/0025 Neogest 0053/0062 Norgeston 0053/0068 Noriday 088210036 Noristerat 0053/0095 Norplant 0109/0249 Primolut N 0053/5033R Provera 2.5mg 0032/0168 Provera 5mg 0032/5035R Provera 10mg 0032/0151 Provera 100mg 0032/0111 Provera 200mg 0032/0112 Provera 400mg 0032/0131 Proluten Depot 250mg 0053/5031R Proluten Depot 500mg 0053/5032R MANUFACTURER Bristol-Myers Squibb Pharmaceuticals Ltd 141-149 Staines Rd Hounslow Middlesex TW3 3JA 0181 5727422 Ferring Pharmaceuticals Ltd Greville House Hatton Road Feltham Middlesex TW14 9PX 0181 8931543 Hoechst Rousell Ltd Broadwater Park Denham Uxbridge Middlesex UB9 5HP 01895 834343 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 Pharmacia-Leiras Ltd Pharmacia & Upjohn Davy Avenue Knowlhill Milton Keynes MK5 8PH 01908 661101 Roussell see Hoechst-Roussell Schering Health Care Ltd The Brow, Burgess Hill, West Sussex RH15 9NE 01444 232323 Schwarz Pharma Ltd Schwarz House East Street Chesham Bucks HP5 1DG 01494 772071 Searle Pharmaceuticals PO Box 53, Lane End Road, High Wycombe, Bucks HP12 4HL 01494 521124 Solvay Healthcare Ltd Hamilton House Gaters Hill West End Southampton SO18 3JD 01703 472281 Upjohn Ltd See Pharmacia-Upjohn Wyeth Laboratories Huntercombe Lane South, Taplow, Maidenhead, Berks SL6 0PH 01628 604377 PRESENTATION Form Cyclogest Pessaries 200mg pessaries Cyclogest Pessaries 400mg pessaries Depo-Provera 150mg/1ml, 3.3ml injection Depostat100mg/ml, 2ml injection Duphaston/Duphaston HRT 10mg tablets Farlutal 100mg,250mg, 500mg tablets Farlutal 200mg/ml, 2.5ml & 5ml injection Femulen 5mg tablets Gestone 25mg injection Gestone 50mg injection Gestone 100mg injection Megace 40mg, 160mg tablets Menzol 5mg tablets Micronor Oral Contraceptives tablets Micronor HRT tablets Microval 30mcg tablets Mirena 20mcg/24hours intra-uterine system Neogest 75mcg tablets Norgeston 30 mcg tablets Noriday 350mcg tablets Noristerat 200mg/ml injection Norplant 38mg implant capsule Primolut N 5mg tablets Provera 2.5mg tablets Provera 5mg tablets Provera 10mg tablets Provera 100mg tablets Provera 200mg tablets Provera 400mg tablets Proluten Depot 250mg injection Proluten Depot 500mg injection Utovlan 5mg tablets Pack sizes Cyclogest Pessaries 200mg - 15 Cyclogest Pessaries 400mg - 15 Depostat - 1 Depo-Provera 150mg, 3.3ml - 1 Depostat - 1 Duphaston - 60 Duphaston HRT - 42 Farlutal 100mg tablets - 20; 50 Farlutal 500mg tablets - 56 Farlutal 200mg/ml, 2.5ml - 1 Farlutal 200mg/ml, 5ml - 1 Femulen - 28 Gestone 25mg - 1 Gestone 50mg - 1 Gestone 100mg - 1 Megace 40mg - 20 Megace 160mg - 30 Menzol - 3 x 24; 3 x60 Micronor Oral Contraceptives - 3 x 28 Micronor HRT - 3 x 12 Microval - 35 Mirena - 1 Neogest - 35 Norgeston - 35 Noriday - 3 x 28 Noristerat - 1 Norplant - 6 implants Primolut N - 30 Provera 2.5mg - 30 Provera 5mg - 10 Provera 10mg - 10; 90 Provera 100mg - 60 Provera 200mg - 30 Provera 400mg - 30 Proluten Depot 250mg - 1 Proluten Depot 500mg - 1 PHYSIOCHEMICAL PROPERTIES Chemical structure Dydrogesterone - 6-Dehydro-9▀,10alpha-progesterone Ethynodiol acetate - 19-Nor-17alpha-pregn-4-en-20-yne-3▀ Gestronol - NIF Hydroxyprogesterone hexanoate - 17alpha-Hydroxypregn-4-ene-3,20- dione hexanoate Levonorgestrel - 13-Ethyl-17▀-hydroxy-18,19-dinor-17alpha-pregn- 4-en-20-yn-3-one Medroxyprogesterone acetate - 17alpha-Hydroxy-6alpha-methylpregn- 4-ene-3,20-dione acetate Megestrol Acetate - 6-Methyl-3,20-dioxopregna-4,6-dien-17alpha-yl acetate Norgestrel - (▒)-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 Progesterone - Pregn-4-ene-3,20-dione Physical structure at room temperature All are solid Colour Dydrogesterone - white to pale yellow Ethynodiol acetate - white or almost white Gestronol - NIF Hydroxyprogesterone hexanoate - white or creamy white Levonorgestrel - white or almost white Megestrol Acetate - white or creamy-white Medroxyprogesterone acetate - white or off-white Norgestrel - white or almost white Norethisterone - white or yellowish-white Progesterone - white or slightly yellowish-white Odour Dydrogesterone - odourless or almost odourless Ethynodiol acetate - odourless or almost odourless Gestronol - NIF Hydroxyprogesterone hexanoate - odourless or almost odourless Levonorgestrel - odourless Megestrol Acetate - odourless or almost odourless Medroxyprogesterone acetate - odourless Norgestrel - almost odourless Norethisterone - odourless Progesterone - odourless Viscosity NA pH NA Solubility Dydrogesterone - Practically insoluble in water; soluble 1 in 40 of alcohol, 1 in 2 of chloroform, and 1 in 200 of ether; soluble in acetone; sparingly soluble in methyl alcohol; slightly soluble in fixed oils Ethynodiol acetate - very slightly soluble to practically insoluble in water; soluble in alcohol; freely to very soluble in chloroform; freely soluble in ether; sparingly soluble in fixed oils Gestronol - NIF Hydroxyprogesterone hexanoate - practically insoluble in water; freely soluble in alcohol and ether; very soluble in chloroform; dissolves in fixed oils and esters Levonorgestrel - practically insoluble in water; slightly soluble in alcohol, in acetone and in ether; soluble in chloroform; sparingly soluble in methylene chloride. Megestrol Acetate - practically insoluble in water; sparingly soluble in alcohol; very soluble in chloroform; soluble in acetone; slightly soluble in ether and in fixed oils. Medroxyprogesterone acetate - practically insoluble in water; sparingly soluble in alcohol and in methylalcohol; slightly soluble in ether; freely soluble in chloroform; soluble in acetone and dioxan Norgestrel - practically insoluble in water; the BP states that it is slightly, and the USP that it is sparingly soluble in alcohol; sparingly soluble in methylene chloride; freely soluble in chloroform Norethisterone - practically insoluble in water; slight to sparingly soluble in alcohol; soluble in chloroform and in dioxan; slightly soluble in ether. Progesterone - BP solublities are: practically insoluble in water; freely soluble in dehydrated alcohol; very soluble in chloroform; sparingly soluble in acetone, in ether and in fixed oils. USP solubilities are: practically insoluble in water; soluble in alcohol, in acetone and in dioxan; sparingly soluble in vegetable oils USES Indications To prevent conception; as part of hormone replacement regimes; as a hormone antagonist in malignant disease. Therapeutic Dose Contraceptive: 1 tablet (of whichever preparation prescribed) daily at the same time each day, starting on 1st day of cycle then continuously. Dydrogesterone - Endometriosis, 10mg 2-3 times daily from 5th to 25th day of cycle or continuously; Infertility, irregular cycles, 10mg twice daily from 11th to 25th day for at least 6 cycles (but not recommended); Habitual abortion, 10mg twice daily from day 11 to day 25 of cycle until conception, then continuously until 20th week of pregnancy and gradually reduced; Dysfunctional uterine bleeding, 10mg twice daily (together with an oestrogen) for 5-7 days to arrest bleeding; 10mg twice daily (together with an oestrogen) from 11th to 25th day of cycle to prevent bleeding; Dysmenorrhoea, 10mg twice daily from 5th to 25th day of cycle; Amenorrhoea, 10mg twice daily form 11th to 25th day of cycle with oestrogen therapy from 1st to 25th day of cycle; Pre-menstrual syndrome, 10mg twice daily from 12th to 26th day of cycle, increased if necessary (but not recommended); HRT, 10mg daily on days 15-28 of each 28-day oestrogen HRT cycle, increased to 10mg twice daily if withdrawal bleed is early or endometrial biopsy shows inadequate progestational response. Hydroxyprogesterone hexanoate - Habitual abortion, 250-500mg weekly by slow intra-muscular injection during first half of pregnancy. Medroxyprogesterone acetate - Dysfunctional uterine bleeding, 2.5-10mg daily for 5-10 days beginning on 16th-21st day of cycle, repeated for 2 cycles, for secondary amenorrhoea repeat for 3 cycles; Mild to moderate endometriosis, 10mg 3 times daily for 90 consecutive days, beginning on 1st day of cycle; Endometrial, prostate and renal cancer, 100-500mg daily; Breast cancer, various doses in range 0.4-1.5g daily; by deep intramuscular injection for malignant disease, various doses in range 1g daily down to 250mg weekly. Megestrol Acetate - Breast cancer, 160mg daily in single or divided doses; endometrial cancer, 40-320mg daily in divided doses. Norethisterone - Endometriosis, 10mg daily starting on 5th day of cycle (increased if spotting occurs to 20-25mg daily, reduced once bleeding has stopped); Menorrhagia, 5mg 3 times daily for 10 days to arrest bleeding; to prevent bleeding 5mg twice daily from 19th to 26th day; Dysmenorrhoea, 5mg 3 times daily from 5th to 24th day for 3-4 cycles; Pre-menstrual syndrome, 5mg 2-3 times daily from 19th to 26th day for several cycles (but not recommended); Postponement of menstruation, 5mg three times daily starting 3 days before anticipated onset (menstruation occurs 2-3 days after stopping); HRT 1mg daily on days 15-26 of each 28-day oestrogen HRT cycle; Breast cancer, 40mg daily, increased to 60mg daily if required. Progesterone - Pre-menstrual syndrome, pessaries - 200mg daily to 400mg twice daily starting on day 12-14 and continued until onset of menstruation (but not recommended); rectally if barrier methods of contraception are used, or if vaginal infection; Embryo transfer, deep intramuscular injection as per data sheet. Contraindications Pregnancy (except where licensed);a history during pregnancy of idiopathic jaundice or severe pruritis. Acute or severe chronic liver diseases including liver tumours. Dubin-Johnson or Rotor syndrome. Undiagnosed abnormal vaginal bleeding. Thrombo-embolic disorders, thrombophlebitis, cerebrovascular disorders, coronary artery disease, myocardial infarction, angina, hyperlipidaemia or a history of these conditions. Abuses NIF HAZARD/RISK CLASSIFICATION NIF PHARMACOKINETICS Absorption Dydrogesterone NIF Ethynodiol acetate almost 100% Gestronol NIF Hydroxyprogesterone hexanoate 90% Megestrol Acetate about 100% Medroxyprogesterone acetate <100% Norgestrel NIF Norethisterone 100% Progesterone - extensive Distribution Dydrogesterone NIF Ethynodiol acetate 33l - extensively bound to albumin and more specifically to sex hormone binding globulin Gestronol NIF Hydroxyprogesterone hexanoate 5l Levonorgestrel 93-95% plasma bound Megestrol Acetate NIF Medroxyprogesterone acetate >20l, 94% is protein bound Norethisterone 95% plasma bound Norgestimate NIF Norgestrel NIF Progesterone 17-29l, 95-98% plasma protein bound Metabolism Dydrogesterone Metabolised to glucuronide conjugates Ethynodiol acetate Metabolised in liver or gut wall to norethisterone and then to sulphate and glucuronide conjugates. Gestronol NIF Hydroxyprogesterone hexanoate metabolised in liver Levonorgestrel Extensively metabolised by the liver Megestrol Acetate metabolised by liver to glucuronide conjugates Medroxyprogesterone acetate extensively metabolised in the liver Norgestimate NIF Norgestrel NIF Norethisterone Metabolised in the intestinal wall and liver Progesterone About 75% is metabolised presystemically to glucuronide conjugates by the liver Elimination Dydrogesterone 60% is excreted via the urine within 72 hours. Only small amounts are excreted via the faeces Ethynodiol acetate via urine and faeces Gestronol NIF Hydroxyprogesterone hexanoate NIF Levonorgestrel 20-30% eliminated via the faeces and the rest via the urine Megestrol Acetate excreted as metabolites via the urine and faeces Medroxyprogesterone acetate mainly as conjugated metabolites in the faeces Norethisterone 60% as metabolites in urine and faeces Norgestrel NIF Progesterone mainly as conjugates in the urine Half-life Dydrogesterone about 6h Ethynodiol acetate about 25h Gestronol NIF Hydroxyprogesterone hexanoate 2-11h, mean 4h Levonorgestrel 10.26h Megestrol Acetate 15-20h Medroxyprogesterone acetate about 30h Norgestrel NIF Norethisterone 5 -12h Progesterone distribution - 3-6min; elimination - 19-95min Breast Milk Dydrogesterone small quantities are have been measured in breast milk, but this is unlikely to present any risk to the infant Ethynodiol acetate norethisterone concentration appears to reach a peak at about 4-8h after ingestion of ethynodiol acetate, small amounts of norethisterone are excreted into breast milk, the concentration being 10-20% of that in plasma Gestronol NIF, contraindicated in lactation Hydroxyprogesterone hexanoate contraindicated in lactation Levonorgestrel Approximately 0.1% of the daily dose passes into breast milk Megestrol Acetate Disease states being treated would usually contraindicate breast-feeding Medroxyprogesterone acetate excreted into breast milk in concentrations similar to those in plasma. No special precautions are advised. Norgestrel NIF Norethisterone daily oral dose of 350micrograms for contraception were reported in one study to reduce milk volume somewhat but do not usually affect volume or composition. Intramuscular injections of 200mg each 8 weeks do not interfere with lactation. The plasma/milk ratio of the heptanoate is about 10 and only 0.1% of the dose, estimated as a maximum of 1.5micrograms daily, reaches the baby. this is unlikely to affect the bay and is undetectable in the baby's plasma at the time of the peak maternal plasma level. There is a theoretical risk of all steroids interfering with bilirubin conjugation, and maternal use of norethisterone should probably be avoided whilst a baby has neonatal jaundice. Progesterone excreted in low concentrations, which are unlikely to have any effect on the infant TOXICOKINETICS NIF EPIDEMIOLOGY OF POISONING In 1994, 2007 calls were made to UK NPIS centres about hormonal contraceptive poisoning. ADVERSE EFFECTS General - Headaches/migraine, nausea, vomiting, breast changes, change in weight, changes in libido, chloasma, breakthrough bleeding and spotting, rash, depression, irregular cycle length, ocular changes, increase in size uterine myofibromata and changes in carbohydrate, lipid or vitamin metabolism. Rarely dizziness, hirsutism, haemorrhagic eruption and colitis have been reported in users of progestogen-only oral contraceptives Megesterol - as above, rare reports of dyspnoea, heart failure, hypertension, hot flushes, mood changes, cushingoid faces, tumour flare (with or without hypercalcaemia), hyperglycaemia, alopecia and carpel tunnel syndrome. Prolonged administration may cause urticaria. Clinical and laboratory evidence of mild adrenal suppression INTERACTIONS Metabolism accelerated by rifamycins; increased plasma-cyclosporin levels (inhibition of metabolism); aminoglutethimide reduces plasma concentration of medroxyprogesterone MECHANISM OF ACTION Progestogens are synthetic compounds with actions similar to that of progesterone. Progesterone is the main hormone secreted by the corpus luteum. Large quantities are produced by the placenta during pregnancy. It acts on the endometrium by converting the proliferative phase induced by oestrogen to a secretory phase and preparing the uterus to receive the fertilised ovum. FEATURES OF POISONING Acute Ingestion Toxicity is unlikely following an acute overdose. Occasionally there may be nausea and vomiting. Withdrawal bleding may occur in females even in pre-pubertal girls. Chronic Ingestion/Injection Chronic or high dose therapy can result in jaundice, headache, dizziness, oligomenorrhea or amenorrhea, congestion of the breasts and decreased libido. Chronic toxicity may produce a thromboembolic state. Pregnancy 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. The maternal administration of norethisterone to several species of animals, including non-human primates, caused masculinisation of the external female genitalia of the offspring but did not increase the incidence of non-genital adverse fetal effects.1 There is no conclusive evidence of an association between progestogen exposure in early pregnancy and non-genital malformations. Androgenic hormones in human pregnancy have been associated with a small risk of genital abnormalities when exposure occurs around about 6-7 weeks of gestational age when the genitalia are beginning to develop.1-4 Approximately 1% of female fetuses exposed at this critical period of development develop genital anomalies e.g. enlarged clitoris and labial folds1,4. Internal genitalia and subsequent pubertal development are not affected by norethisterone taken during pregnancy. Male infants have an even smaller risk of genital anomalies, usually hypospadias which can be treated surgically. 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.5 The use of norethisterone during any stage of pregnancy is contra-indicated. A number of congenital malformations, including cardiovascular, central nervous system, multiple organ and limb defects, have been reported in infants exposed to the drug in utero.1,2,3,4 However, the role of norethisterone in the development of these anomalies has not been established due to the influence of other factors such as alcohol ingestion, cigarette smoking, concomitant drug therapy and maternal obstetric history.1,3 There are three prospective follow-up reports from the European Network of Teratology Information Services (ENTIS) following exposure to progestogens during pregnancy. One patient had Norplant removed after conception (details of timing of exposure not available), a normal full term infant was born; there were two reports of exposure to Depo-Provera, one woman had a dose at 1 week and 12 weeks of gestation, a normal fullterm infant was born, the second woman was exposed at 5 weeks of gestation and had an elective termination. References 1. Gilstrap III LC, Little BB. Drugs and Pregnancy. Amsterdam: Elsevier Science Publishing, 1992: 242-244 2. Folb PI, Dukes MNG (Eds). Drug Safety in Pregnancy. Amsterdam: Elsevier Science Publishing, 1990: 273-281 3. Briggs CG, Freeman RK, Yaffe SJ. Drugs in Pregnancy and Lactation. 4th ed. Baltimore: Williams and Wilkins, 1994 4. Schardein JL. Chemically Induced Birth Defects. 2nd ed. New York: Marcel Dekker, 1993 5. Raman-Wilms L et al. Obs Gyn 1995; 85: 141-9 MANAGEMENT Symptomatic treatment only is required. Parents of prepubertal girls should be warned of the possibility of a withdrawal bleed several days after ingestion. ANALYSIS NIF PREVENTION OF POISONING NIF OTHER TOXICOLOGICAL DATA Carcinogenicity In a retrospective study of 5000 black women who received depot medroxyprogesterone for contraception, no increased incidence in breast, ovarian, or uterine corpus cancer was seen up to 13 years later. (Liang et al 1993). There is considerable evidence suggesting that after induction by chemical carcinogens, sex hormones act as promoters of heptocarcinogenesis. Teratogenicity There is no conclusive evidence of an association between progestogen exposure in early pregnancy and non-genital malformations. Exposed female infant have a small risk (approximately 1%) of clitoral hypertrophy and fusion of the labioscrotal folds, when exposure occurs during the critical period of genital development. These anomalies can be corrected surgically. Male infants have an even smaller risk of genital anomalies, usually hypospadias which can be treated surgically. 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 Systemť, 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.