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CBD Oil and Pregnancy

Medically Reviewed by Dr. Kimberly Langdon and Written by Clarence Swader

Posted on 3 December 2019 | 5 minutes read | 7,968 views

Can CBD help with pregnancy, and is it safe to use when pregnant?

Results of a 1986 research, published in the International Journal of Andrology, indicate that either of the non-psychoactive cannabidiol (CBD) or cannabinol (CBN) may cause problems with the reproductive system of developing male fetuses(1).

However, to date, there has been no comprehensive study on humans investigating the effects of CBD alone on the developing fetus, expectant mother, or breastfed baby.

Still, the U.S. Food and Drug Administration (FDA) warns that there may be serious risks to using cannabis products, including those containing CBD, when pregnant or while breastfeeding.

Experts advise expectant mothers and those who are contemplating pregnancy or breastfeeding to do more research and consult with a medical professional before commencing a CBD regimen.

Why Some Pregnant Women May Be Thinking of Taking CBD During Pregnancy

Expectant mothers are looking to relieve common symptoms of pregnancy, such as morning sickness, cramping, headaches, nausea, vomiting, dizziness, and fatigue, and CBD is currently being marketed as a natural cure for most of these symptoms.

Those who seek a natural alternative to other pain medications may be inclined to turn to CBD, as anecdotal evidence shows that CBD may be used to help relieve and manage chronic pain in many cases.

A study, which was published in the Journal of Experimental Medicine, suggests that using CBD can reduce inflammation and pain(2).

However, more research is still needed, especially in long-term studies with human subjects. To date, there has been no comprehensive research investigating the effects of CBD alone on the developing fetus, expectant mother, or breastfed baby.

The FDA continues to gather and study the data on the potential hazards of CBD on both mother and baby during pregnancy and breastfeeding.

The Dangers of Using CBD Oil When Pregnant

While testimonials abound on the many potential benefits of CBD, scientists recognize that there are more questions than answers with regards to the safety of CBD.

Furthermore, there have been no studies conducted on CBD’s effects when used by pregnant women. Consequently, the FDA warns that CBD has the potential to harm people and that harm can happen even before they become aware of it.

The FDA cautions people that there may be serious risks to using cannabis products, including those containing CBD, when pregnant or while breastfeeding.

Not all CBD products are created equal. Even product labels may not be a reliable indication of a product’s actual CBD content or potency.

Many CBD products tested by the FDA were found to contain trace amounts of THC and contaminants like toxic heavy metals, pesticides, bacteria, and fungus.

Thus, as a general rule, experts warn all pregnant, as well as breastfeeding mothers, to avoid CBD products altogether to keep themselves and their babies free from any potential danger.

Understanding CBD

Some people often use the terms cannabis and marijuana interchangeably, although the two terms do not mean the same thing.

Cannabis is the broad term for all products derived from the Cannabis sativa plant. A cannabis plant contains over 100 components, called cannabinoids.

Cannabinoids that come from plants are specifically called phytocannabinoids. Endocannabinoids, another group of cannabinoids, also exist in the body. Cannabis impacts the body’s endocannabinoid system (ECS) and helps create balance for optimal bodily functions.

In technical terms, the family genus cannabis is where both marijuana plants and hemp plants belong. Both of these plants contain varying amounts of cannabidiol (CBD) and tetrahydrocannabinol (THC).

Marijuana is a cannabis plant that contains substantial amounts of THC, the cannabinoid that is primarily responsible for inducing a euphoric and intoxicating effect on the user.

Farmers do not use the fibers and stalks of marijuana commercially. Instead, they cultivate marijuana plants specifically for the flowers, which, among all the parts, contain the highest levels of THC.

Medical marijuana is the term used to describe the whole, unprocessed marijuana plant or its essential extracts to help treat symptoms of illnesses and disorders.

However, to date, the U.S. Food and Drug Administration (FDA) has not approved or recognized the marijuana plant as medicine.

Cannabis plants that contain less than 0.3% THC in dry weight are legally considered as hemp. The seeds and stalks of hemp plants are used to create a wide range of products, including food, medicine, nutritional supplements, plastic composites, paper, textiles, and building materials.

Hemp naturally contains a substantial amount of CBD, and the level of THC in hemp is 33 times less than that of the least potent marijuana strains. Hence, oil extracted from hemp is non-intoxicating, making it generally safe for use.

“People have an assumption that if it’s natural, then it’s safe, but that’s just not the case. We don’t have enough data to say if CBD is dangerous or safe.”

— Catherine Monk, Ph.D., Professor of Medical Psychology, Departments of Obstetrics and Gynecology, and Psychiatry at Columbia University Irving Medical Center in New York

Side Effects of CBD Use

In recent years, cannabis and cannabis-derived products have become increasingly accessible in the market. People looking to use these products as a natural alternative to pharmaceutical prescriptions have contributed to CBD’s widespread use in the form of edibles, beverages, supplements, and cosmetics.

While new and different types of products continue to emerge, these products also raise questions and concerns for many consumers. Understandably, pregnant women have more concerns as the products may not only pose risks to themselves but to their unborn babies as well.

Generally, CBD’s side effects include the following:

Somnolence, characterized by sleepiness or drowsiness, impacts an individual’s alertness.

Gastrointestinal distress, which may manifest as a decrease in appetite or diarrhea, is another typical effect of CBD use.

Mood changes, which may come in the form of agitation and irritability, may also be experienced by some CBD users.

Although these side effects should improve once CBD use is terminated or its doses substantially reduced, keeping one’s self well-informed is crucial to ensure the safety of all concerned.

There are more severe side effects of high doses and prolonged use of CBD, and they include the following:

CBD may cause liver injury. A 2019 animal study, which was published in the Multidisciplinary Digital Publishing Institute Journal, concluded that CBD manifested visible signs of hepatotoxicity, possibly from a reduction or prevention of bile flow(3).

This research suggests that anyone taking CBD regularly and in high doses may be prone to developing liver disease.

CBD impacts the metabolism of other drugs and causes grave side effects. CBD can reduce or increase the effects of certain prescribed pharmaceuticals by interacting with cannabinoid receptors throughout the endocannabinoid system within the body and by inhibiting the activity of cytochrome P450 enzymes.

A 2000 study, which was conducted by researchers from the Department of Pharmacy Services at Baylor University Medical Center in Texas, shows how CBD can temporarily deactivate the activity of cytochrome P450, which can affect how the body breaks down other compounds(4).

Both research and anecdotal evidence indicate that CBD use may cause nausea, drowsiness, diarrhea, reduced appetite, and dry mouth. Though they are often well-tolerated, these side effects may cause discomfort and pain.

The FDA’s Position on CBD

The use of CBD-infused products are widespread nowadays, and manufacturers are becoming increasingly creative as they offer CBD many forms and flavors that consumers would find appealing.

The 2018 Farm Bill legalized hemp, but the legal status of hemp-derived cannabidiol remains confusing.

While CBD can be derived from hemp or cannabis, it is technically a marijuana plant if the hemp plant contains over 0.3 percent THC.

The FDA released an advisory that reiterates the agency’s position on the regulation of CBD-infused products(5).

The FDA has seen only limited data about CBD safety. These data, while inconclusive in scope, point to factual risks that need to be considered before using CBD.

Some unscrupulous CBD product manufacturers market their goods with unproven medical claims to target buyers from different demographic groups.

The quality, potency, and purity of their products become questionable, primarily when they do not employ third-party lab testing to benefit the consumers.

The FDA emphasized in their consumer update that it is currently prohibited under federal law to add CBD to food products or label CBD as a dietary supplement.

The FDA has approved only one CBD product, Epidiolex, which is a prescription drug product to treat Lennox-Gastaut syndrome and Dravet syndrome. These two rare and severe conditions usually manifest in early childhood or infancy.

The FDA recognizes that the drug approval process remains to be the best way to ensure that new medicines, including cannabis-derived drugs, are safe and effective to use by patients in need of proper medical therapy.

More Research Needed

The FDA is dedicated to supporting the discovery and development of new drugs, including cannabis and cannabis-derived drugs. The agency is presently working to gather more information about the safety of CBD and its byproducts, including conducting investigations that would address essential topics, such as:

Cumulative Exposure to CBD: How much CBD is ingested, and how much is absorbed through the skin if people utilize it through a wide variety of consumer products?

For instance, what would be the effect of consuming CBD edibles, such as CBD gummies and CBD-infused beverages, in conjunction with the application of CBD-rich cosmetic products on the same day for an extended period?

Specific Populations: The effects of CBD on other particular groups of people, such as children, adolescents, the elderly, expectant moms, and breastfeeding mothers.

CBD and Animals: Is CBD safe to use in pets and other animals? Other factors should also be considered, including the animal’s species, breed, or class, as well as the safety of the human food products manufactured, like meat, milk, cheese, or eggs from food-producing species that use CBD.

There is no comprehensive research studying the effects of CBD on the developing fetus, pregnant mothers, or breastfed babies.

Dishonest, misleading, unverified, or false claims associated with CBD products may lead consumers to delay getting critical medical care, such as proper diagnosis, treatment, and supportive care. Thus, women who are pregnant or contemplating pregnancy must consult with their doctor.

Medical professionals, such as obstetricians and gynecologists, can advise on the most effective remedy to alleviate typical pregnancy symptoms or treat other issues during pregnancy using available treatment options approved by the FDA.

The FDA pledges to continue to update the public as it learns more about CBD through its investigatory new drug process.

The FDA’s top priority is to defend and promote public health. This priority includes making sure that consumers are kept well-informed about products that may put their health and safety at the highest risk.

CBD vs. Marijuana on Pregnancy

Studies that show the impact of cannabis on pregnancy are limited. However, there have been studies done on subjects with prolonged exposure to marijuana.

A 2013 study “Cannabidiol changes P-gp and BCRP expression in trophoblast cell lines”, conducted by the Department of Clinical Biochemistry and Pharmacology at Ben-Gurion University of the Negev, Israel, concluded that CBD use during pregnancy might change the physiological characteristics of the placenta.

However, it must be noted that the aforementioned study was not based on the exclusive use of CBD, which traditionally contains low to zero levels of THC, but rather on marijuana, which contains high levels of THC.

Marijuana contains varying levels of THC and CBD.

Unlike THC, its psychoactive counterpart, CBD is a non-intoxicating cannabis compound. CBD is also not addictive and is believed to be relatively safe to use for an extended period.

However, CBD’s long-term effects are largely unknown, and most CBD products are untested.

Meanwhile, marijuana has changed over time, as the marijuana available in certain products today is much stronger than in the previous formulations.

A 2016 study was conducted by researchers from the National Center for Natural Products Research School of Pharmacy of the University of Mississippi and the Department of Computer Science of the University of West Georgia(6).

Results of the aforementioned study showed that between 1995 and 2014, the THC concentration in cultivated marijuana plants had surged three-fold.

The U.S. Department of Health & Human Services, on its website, mentions a survey conducted among marijuana users in Washington. In the said survey, researchers found that marijuana available in dispensaries in some states has concentrations of THC between 17.7% and 23.2%(7).

Similarly, marijuana use by expectant mothers is on the rise, and the results of studies are alarming.

A 2017 study, which was published by the National Institutes of Health, was done to analyze the trends in marijuana use by females in California(8). Researchers of the study found that there was a 69% surge in marijuana use among pregnant women between 2009 and 2016.

In a 2018 study, researchers from the University of Colorado School of Medicine, the Colorado School of Public Health in Aurora, Colorado, the University of Utah Health in Salt Lake City, and Denver Health and Hospital Authority in Denver, Colorado, found that many retail dispensaries recommend marijuana to pregnant women for morning sickness(9).

Then, in 2019, a survey was conducted by researchers from the National Institute on Drug Abuse of the National Institutes of Health in Bethesda, Maryland and the Substance Abuse and Mental Health Services Administration in Rockville, Maryland on pregnant women in the United States(10).

The researchers compared recent data on self-reported medical and non-medical cannabis use among the subjects with that of the period between 2002 and 2017. Results showed that marijuana use among pregnant women doubled.

More research is necessary to comprehend better how marijuana may affect an expectant mother and her baby during pregnancy. Still, experts recommend that pregnant women do not use marijuana.

CBD is not the same as marijuana. Thus, it is difficult to draw any conclusions from the aforementioned studies.

Limited and inconclusive studies make doctors cautious about recommending the non-psychoactive CBD because of its close association with marijuana and because of the lack of research around CBD alone.

“I am emphasizing the importance of protecting our Nation from the health risks of marijuana use in adolescence and during pregnancy. Recent increases in access to marijuana and in its potency, along with misperceptions of safety of marijuana endanger our most precious resource, our nation’s youth.”

— Surgeon General VADM Jerome Adams

How Marijuana Impacts the Developing Fetus

There are no studies that specifically examine the effects of CBD on pregnant women. However, there are studies that show how marijuana may impact a developing fetus.

When a pregnant woman consumes or smokes marijuana, cannabinoids enter the blood.

Based on a 1987 animal study, which was published in the Toxicology and Applied Pharmacology Journal, results demonstrate that through the bloodstream, THC rapidly crosses the placenta and enters the fetal brain(11).

Although the study was not done on humans, the Endocannabinoid System (ECS) functions the same way in people as it does in other animals.

The ECS maintains homeostasis (balance) among body functions and plays key roles in the control of metabolic, nervous,, digestive, reproductive, and immune functions.

A 2016 research, published by theYale Journal of Biology and Medicine, suggests that marijuana may interfere with the body’s endocannabinoid system, which is essential for a healthy pregnancy and fetal brain development(12). Marijuana may also interrupt the delicate equilibrium of the ECS in the female reproductive system.

A research conducted by the Department of Obstetrics and Gynecology in Washington University in St. Louis, and the Washington University School of Medicine in St. Louis, Missouri indicated that the association between maternal marijuana use and adverse neonatal outcomes appears to be a result of concomitant tobacco use, among other confounding factors(13).

A 2017 review,“Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research”, which was published by the National Academy of Sciences, demonstrated that exposure to cannabis use in utero has an adverse influence on birth weight and increases the risk of an infant baby going into intensive care.

In the Pharmacology and Therapeutics Journal published in 2018, researchers of the study on “Cannabis Use during Pregnancy: Pharmacokinetics and Effects on Child Development” emphasized the fact that women should not smoke marijuana while pregnant. However, the study does not mention anything about CBD use during pregnancy.

In 2018, a study, which was published in the Journal of Pediatrics, was conducted to evaluate the relationship between prenatal cannabis use and adverse neonatal outcomes, such as small infant size for gestational age, low birth weight, and preterm birth(14).

It was reported that maternal marijuana use was linked to a 50% increased risk of low birth weight regardless of the mother’s age, ethnicity, education, and tobacco use.

However, since CBD and marijuana are not the same thing, it is difficult to draw any conclusions from the aforementioned studies.

Consequently, doctors are cautious about recommending the non-psychoactive CBD because of its close association with marijuana, and because of the lack of research around CBD alone.

“Smoking, the most common route of administration of THC, cannot be medically condoned during pregnancy and lactation. Therefore, obstetrician-gynecologists should be discouraged from prescribing or suggesting the use of marijuana for medicinal purposes during preconception, pregnancy, and lactation.”

— The American College of Obstetricians and Gynecologists (ACOG)

As a safety measure, the American College of Obstetricians and Gynecologists (ACOG) cautions pregnant women or those contemplating pregnancy not to start or discontinue marijuana use.

The American Academy of Pediatrics (AAP) recommended in 2018 that it is imperative to advise all adolescents and young women that marijuana should not be used anytime during pregnancy.

Also, a pregnant woman who uses marijuana may unknowingly put the baby’s health at risk after birth.

According to a study published in AAP’s Pediatrics Journal, small quantities of THC have been found in breast milk even after six days from the last recorded use(15).

Breastmilk that is tainted with THC may impact the newborn baby’s brain development.

A 2015 review by researchers from Denver Health Medical Center, Department of Obstetrics and Gynecology in Denver, CO and University of Colorado School of Medicine in Aurora, CO, revealed that THC might cause problems with neurological development, which may lead to reduced or impaired poor cognitive function and hyperactivity(16).

Also, since marijuana smoke contains many of the same harmful components as tobacco smoke, researchers of a 2008 study, which was published in the Chemical Research in Toxicology Journal, strongly discourage smoking or vaping of marijuana or tobacco around a baby(17).

The aforementioned studies were focused on marijuana and its active component, THC, and not on CBD.

It is essential to note that CBD is entirely different from marijuana. Thus, it is difficult to draw any conclusions from the aforementioned studies.

Given CBD’s close association to marijuana and the lack of research around CBD alone, doctors are cautious about recommending the non-psychoactive CBD

Conclusion

Pregnant women must understand the risks involved in using CBD-infused products or other cannabis products. It is not only the mother’s health that is in danger when complications arise from the use of products that have not been proven safe for use during pregnancy.

Pregnant women should be wary of the potential harm that the exposure or ingestion of CBD products may have on themselves and their unborn babies. It is wise for expectant mothers to consult with their doctors before they start a CBD regimen during their pregnancy.

  1. Dalterio SL, deRooij DG. “Maternal cannabinoid exposure. Effects on spermatogenesis in male offspring.” DOI: 10.1111/j.1365-2605.1986.tb00888.x.
  2. Wei Xiong, Tanxing Cui, Kejun Cheng, Fei Yang, Shao-Rui Chen, Dan Willenbring, Yun Guan, Hui-Lin Pan, Ke Ren, Yan Xu, and Li Zhang. “Cannabinoids suppress inflammatory and neuropathic pain by targeting α3 glycine receptors.” J Exp Med. 2012 Jun 4; 209(6): 1121–1134. DOI: 10.1084/jem.20120242.
  3. Ewing, Skinner, Quick, Kennon-McGill, McGill, Walker, ElSohly, Gurley, and Koturbash. “Hepatotoxicity of a Cannabidiol-Rich Cannabis Extract in the Mouse Model.” Molecules 2019, 24(9), 1694; https://doi.org/10.3390/molecules24091694.
  4. Ogu and Maxa. “Drug interactions due to cytochrome P450.” Proc (Bayl Univ Med Cent). 2000 Oct; 13(4): 421–423. DOI: 10.1080/08998280.2000.11927719.
  5. FDA Regulation of Cannabis and Cannabis-Derived Products, Including Cannabidiol (CBD). https://www.fda.gov/news-events/public-health-focus/fda-regulation-cannabis-and-cannabis-derived-products-including-cannabidiol-cbd
  6. ElSohly, Mehmedic, Foster, Gon, Chandra, and Church. “Changes in Cannabis Potency Over the Last 2 Decades (1995-2014): Analysis of Current Data in the United States.” Biol Psychiatry. 2016 Apr 1;79(7):613-9. doi: 10.1016/j.biopsych.2016.01.004. Epub 2016 Jan 19.
  7. Jikomes, N., & Zoorob, M. (2018). The Cannabinoid Content of Legal Cannabis in Washington State Varies Systematically Across Testing Facilities and Popular Consumer Products. Scientific reports, 8(1), 4519. doi:10.1038/s41598-018-22755-2.
  8. Young-Wolff, Tucker, Alexeeff, Armstrong, Conway, Weisner, and Goler. “Trends in Self-reported and Biochemically Tested Marijuana Use Among Pregnant Females in California From 2009-2016.” JAMA. 2017 Dec 26;318(24):2490-2491. DOI: 10.1001/jama.2017.17225.
  9. Dickson, Mansfield, Guiahi, Allshouse, Borgelt, Sheeder, Silver, and Metz. “Recommendations From Cannabis Dispensaries About First-Trimester Cannabis Use.” Obstet Gynecol. 2018 Jun;131(6):1031-1038. DOI: 10.1097/AOG.0000000000002619.
  10. Volkow, Han, Compton,, and McCance-Katz. “Self-reported Medical and Nonmedical Cannabis Use Among Pregnant Women in the United States.” JAMA. 2019 Jul 9;322(2):167-169. doi: 10.1001/jama.2019.7982.
  11. Bailey, Cunny, Paule, and Slikker Jr..”Fetal disposition of delta 9-tetrahydrocannabinol (THC) during late pregnancy in the rhesus monkey.”Toxicol Appl Pharmacol. 1987 Sep 15;90(2):315-21. DOI: 10.1016/0041-008x(87)90338-3.
  12. Brents LK. “Marijuana, the Endocannabinoid System and the Female Reproductive System.” Yale J Biol Med. 2016 Jun 27;89(2):175-91. eCollection 2016 Jun. PMCID: PMC4918871.
  13. Conner,Bedell, Lipsey, Macones, Cahill,and Tuuli. “Maternal Marijuana Use and Adverse Neonatal Outcomes: A Systematic Review and Meta-analysis.” Obstet Gynecol. 2016 Oct;128(4):713-23. doi: 10.1097/AOG.0000000000001649. DOI: 10.1097/AOG.0000000000001649.
  14. Crume, Juhl, Brooks-Russell, Hall, Wymore, and Borgelt. “Cannabis Use During the Perinatal Period in a State With Legalized Recreational and Medical Marijuana: The Association Between Maternal Characteristics, Breastfeeding Patterns, and Neonatal Outcomes.” J Pediatr. 2018 Jun;197:90-96. doi: 10.1016/j.jpeds.2018.02.005. Epub 2018 Mar 28. DOI: 10.1016/j.jpeds.2018.02.005.
  15. Bertrand, Hanan, Honerkamp-Smith, Best, and Chambers. “Marijuana Use by Breastfeeding Mothers and Cannabinoid Concentrations in Breast Milk.” Pediatrics September 2018, 142 (3) e20181076; DOI: https://doi.org/10.1542/peds.2018-1076.
  16. Metz and Stickrath. “Marijuana use in pregnancy and lactation: a review of the evidence.” Am J Obstet Gynecol. 2015 Dec;213(6):761-78. doi: 10.1016/j.ajog.2015.05.025. Epub 2015 May 15. DOI: 10.1016/j.ajog.2015.05.025.
  17. Moir, Rickert, Levasseur, Larose, Maertens, White, and Desjardins. “A comparison of mainstream and sidestream marijuana and tobacco cigarette smoke produced under two machine smoking conditions.” Chem Res Toxicol. 2008 Feb;21(2):494-502. Epub 2007 Dec 7. DOI: 10.1021/tx700275p.

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.

  1. 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.

  1. 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.

  1. Therapeutic Drugs. Dollery C. (Ed.). Churchill Livingstone 1991.
  1. ABPI Compendium of Data Sheets and Summaries of Product

Characteristics. Datapharm Publications Ltd. 1996-97.

  1. British National Formulary. Number 32 (September 1996). British

Medical Association and Royal Pharmaceutical Society.

  1. Poisindex System(c), Micromedex, Inc., Denver Colorado, Edition

Expires 31.12.96.

  1. National Teratology Information Service.
  1. European Commission; Poison centres: Collection of the annual

reports 1994, Analysis and synthesis, Final Report 31.8.96.

  1. Picchioni AL. Acute overdose of oral contraceptives. Am J Hosp

Pharm 1965; 22: 486.

 


    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.