View / Download pdf version of this article Key advisor: Dr Helen Roberts, Senior Lecturer, Department of Obstetrics and Gynaecology, Faculty of Medicine and Health Sciences, University of Auckland

Approximately 147,000 women in New Zealand take oral contraceptives. About 80% of these women take combined oral contraceptives (COC) containing oestrogen and a progestogen.1

This article offers guidance for managing situations when women who are currently using COCs:

  • Develop conditions which affect their suitability for COC use.
  • Require other medicines that interact with COCs.
  • Experience adverse effects.

A follow up visit is appropriate to measure blood pressure and assess any problems, three months after a first prescription of an oral contraceptive, and then at least yearly thereafter. Women should also be advised to return if any problems arise.2

Medical conditions that affect the suitability of COC use

The use of COCs must be carefully considered in certain medical conditions. The UK Medical Eligibility Criteria (UKMEC) for combined oral contraceptive use provides guidance on suitability of COCs in particular conditions (view tables here).2

Conditions that may require review of COC use

Women whose clinical condition changes while using hormonal contraception require assessment on an individual basis. It may be appropriate to discuss risks and benefits and offer alternative contraceptive methods that pose less risk.

COCs are contraindicated in migraine with aura
Combined oral contraceptives increase the risk of stroke in women who suffer from migraines with aura. COCs should therefore not be started by women of any age who suffer from migraine with aura. They should also be discontinued in women who develop migraine with aura whilst already on COC.3 Progestogen only or non hormonal methods can be considered for these women.3

COCs are best discontinued if migraine without aura develops
It is usually recommended that women who develop migraine without aura following initiation of COC should discontinue use, especially women over 35 years. Progestogen only or non hormonal methods can also be considered for these women.3

Pre-existing migraine without aura in women less than 35 years old is not a contraindication to COC initiation.

COCs increase the risk of venous thromboembolism
Combined oral contraceptive users have a higher risk of venous thromboembolism (VTE) than non-users (see table below).

COCs are contraindicated for women with a current or past history of VTE and best avoided for those at high risk. Risk factors include obesity, smoking, or a family history of VTE in a first degree relative younger than 45 years old.3 Progestogen only or non hormonal methods can be used.

COC use in heavy smokers substantially increases cardiovascular risk3
COCs can generally be used in women younger than 35 years who smoke, however their use is not advised in women over 35 years who smoke. Progestogen only or non hormonal methods can be used in women who smoke.

Progestogen Only Pills (POPs)

POPs available in New Zealand contain; levonorgestrel, norethisterone or desogestrel. POPs mainly work by their action on the cervical mucous, however Cerazette is different in that the mode of action is ovulation inhibition. They have less contraindications to use compared with COCs however they require much more rigid compliance and have to be taken at the same time every day (within three hours, or within 12 hours for Cerazette). Breakthrough bleeding or spotting is more common with POP use than with COCs. Androgenic side effects, such as acne, may be a problem for some women.5

Components of progestogen-only pills
Progestogen (micrograms) Brand names
Desogestrel 75 Cerazette
Levonorgestrel 30 Microlut
Norethisterone 350 Noriday 28 Day*
*Fully funded

Get a PDF of VTE, Table 2 and table 3

Risk of venous thromboembolism (VTE)3, 4
Circumstance Risk of VTE per 100,000 women Relative risk
Healthy non-pregnant women (not taking any oral contraceptive) About five cases per year Baseline
COC containing norethisterone (1st generation) or levonorgestrel (2nd generation) About 15 cases per year of use three-fold increase
COC containing gestodene or desogestrel (3rd generation) About 25 cases per year of use five-fold increase
Pregnancy About 60 cases per year 12-fold increase

COCs may increase the risk of MI or stroke in the presence of multiple cardiovascular risk factors
There is weak evidence that COCs increase the risk of myocardial infarction and ischaemic stroke, however the absolute risk is still low.3

In women with multiple cardiovascular risk factors (e.g. older age, smoking, diabetes, hypertension, obesity or a family history of cardiovascular disease before age 50) the risk may be increased further.

COCs are best avoided in these women, however progestogen only or non hormonal methods can be used.8

Important drug interactions

Ethinyloestradiol and progestogens are metabolised by liver enzymes. Induction of these enzymes by certain drugs may affect the plasma concentration of contraceptive hormones. Some anti-epileptics and antibiotics are examples of drugs that may reduce the concentration of hormonal contraceptives and decrease their efficacy. Table 1 provides a list of drugs that interact with oral contraceptives. The list is not comprehensive.

There are new recommendations concerning the interaction between oral contraceptives and antibiotics. See "News in brief", BPJ 36 (June, 2011).

Table 1: Interactions with oral contraceptives6, 7
Drug class Examples Effect Examples that do not affect OCs
Anti-epileptics
Carbamazepine
Oxcarbazepine
Phenytoin
Phenobarbital
Primidone
Topiramate
Induce liver enzymes resulting in a reduction in ethinyloestradiol and progestogen concentrations
Ethosuximide
Gabapentin
Lamotrigine
Levetiracetam
Valproate
Vigabatrin
Antibiotics
Rifampicin
Rifabutin
Induce liver enzymes resulting in a reduction in ethinyloestradiol and progestogen concentrations, breakthrough bleeding No alternatives
All other antibiotics narrow- and broadspectrum
Potential reduction in ethinyloestradiol concentration due to effect on gut flora

Practice points for oral contraceptive interactions

Liver enzyme inducing drugs:
COCs and POPs are both affected; alternative methods of contraception may be a better choice for women using enzyme inducers long-term.

For short-term use of enzyme inducers, women taking COCs should use a 50 microgram daily dose of ethinyloestradiol and use additional precautions for the duration of treatment and for four weeks afterwards.

Antibiotics:
The antibiotics listed in the table as liver enzyme inducers should be dealt with as above. Although other antibiotics are not liver enzyme inducers, they may temporarily decrease colonic bacteria and therefore inhibit the enterohepatic circulation of ethinyloestradiol.7 Progestogen is not affected.

Generally the evidence for this interaction is weak and often based on anecdotal reports, however because the consequences of an unwanted pregnancy can be serious the following advice is provided for all antibiotics:

Women on short courses (less than three weeks) of antibiotics should be advised to use additional precautions during the course and until seven consecutive active pills have been taken after antibiotics have been discontinued. This may require missing the inactive pills or the pill-free week.

It is thought that gut flora develop resistance to non-enzyme inducing antibacterials after three weeks of treatment and for this reason additional precautions are not required after this time.6

Minor adverse effects

Most COCs contain the same oestrogen (ethinyloestradiol) and for that reason the properties of individual products are based on the amount of ethinyloestradiol in the tablet along with the varying properties of the progestogen (Table 2).

The activity of various progestogens is largely based on animal experiments and how this applies to humans is largely unknown. The dose is often adjusted to make different progestogens approximately equivalent in terms of their activity and for these reasons there is some debate about whether different progestogens are better or worse in terms of side effects or clinical responses.9

There is limited clinical evidence to guide pill changes when women experience adverse effects on a particular pill; however there are some principles that may guide choice (Table 3). Often a change in COC type can help to improve some adverse effects as long as it does not increase the risk of more serious medical conditions. Many side effects are commonly experienced in the first three months and may subside after this time therefore it is best to try a particular pill for at least three cycles before switching.5, 9

Get a PDF of VTE, Table 2 and table 3

Table 2: Components of combined oral contraceptives (COC)3, 5, 11
Oestrogen level
Ethinyloestradiol (micrograms)
Progestogen
(micrograms)
Brand names
20 micrograms
Levonorgestrel 100 Loette
Microgynon 20 ED
Desogestrel 150 Mercilon 21
Mercilon 28
30 micrograms

Gestodene 75 Femodene 28
Minulet 28
Levonorgestrel 150 Levlen ED*
Microgynon 30
Microgynon 30 ED
Monofeme*
Nordette
Desogestrel 150 Marvelon 21
Marvelon 28
Drospirenone 3000 Yasmin
35 micrograms
Cyproterone 2000 Estelle 35 ED*
Diane-35 ED
Norethisterone 500 Norimin*
Norethisterone 1000 Brevinor 1/21*
Brevinor 1/28*
50 micrograms Levonorgestrel 125 Microgynon 50 ED*
Phasic
30/40/30

Levonorgestrel
50/75 /125
Trifeme 28*
Triphasil 28
Triquilar ED
Mestranol 50 micrograms Norethisterone 1000 Norinyl 1/28
* Fully funded
Mestranol is converted in the liver to ethinyloestradiol; 50 micrograms of mestranol is pharmacologically equivalent to 35 micrograms of ethinyloestradiol.8

Get a PDF of VTE, Table 2 and table 3

Table 3: Combined oral contraceptive adverse effects and potential solutions3, 5, 10
Adverse effect Action needed Pill Suggestions
Acne
Increase oestrogen
Reduce progestogen
or change to less androgenic progestogen
Marvelon
Femodene
Yasmin
Estelle 35 ED*
Mercilon
Amenorrhoea
Increase oestrogen
Decrease progestogen
Norimin*
Brevinor-1*
Breakthrough bleeding
  • Early to mid cycle

Increase oestrogen

Levlen*, Monofeme*, Microgynon 30
Marvelon
  • Late cycle
Increase progestogen or change type Femodene
Trifeme*, Triphasil, Triquilar
Breast soreness
Decrease oestrogen
Decrease progestogen
Loette, Microgynon 20
Mercilon
Depression, moodiness or irritability
Decrease progestogen Norimin*
Loette, Microgynon 20
Trifeme*, Triphasil, Triquilar
Headache in pill-free week Tri-cycle pills (skip two pill-free
weeks in every three months)
 
Menstrual cramps Increase progestogen or tri-cycle
pills
 
Nausea Decrease oestrogen Loette, Microgynon 20
Mercilon
Weight gain
Decrease oestrogen
Decrease progestogen
Loette, Microgynon 20
Mercilon
* Fully funded

Level of oestrogen affects side effect profile

COCs contain 20–50 micrograms of ethinyloestradiol; 20 micrograms being considered low-strength, 30–40 micrograms standard-strength and 50 micrograms high strength.

Generally, advice at present is to start with a standard dose pill and a first or second generation progestogen (lower VTE risk) e.g. Levlen, Monofeme or Norimin. These pills are fully funded and cost $3 for six months supply.

Pharmacy co-payments have increased; funding information may be incorrect. See www.health.govt.nz

GPs may favour using the lowest effective dose of ethinyloestradiol as it would theoretically carry a lower risk of adverse effects associated with oral contraceptive use such as thrombosis or myocardial infarction.

Authors of a Cochrane review compared lower- versus higher-dose oestrogen for contraception. While they could not detect differences in rare adverse effects or contraceptive effectiveness they found lower-dose oestrogen COCs resulted in higher rates of bleeding pattern disruptions and early trial discontinuation.10

High-strength preparations containing 50 micrograms of ethinyloestradiol are generally used only in situations where the bioavailability of ethinyloestradiol will be reduced, for example in women who are concomitantly taking enzyme-inducing drugs.2

Type of progestogen may affect side effect profile

A Cochrane review that compared various progestogens in COCs found that second and third generation progestogens were preferred to norethisterone (first generation) across all acceptability indices they measured including; effectiveness (pregnancy rates), discontinuation rates, reasons for discontinuation, cycle control, and side effects. It also found that gestodene has comparable contraceptive effectiveness to levonorgestrel and desogestrel and that drospirenone is similar to desogestrel.12

The newer progestogens, gestodene and desogestrel are associated with a slightly increased absolute risk of VTE compared with levonorgestrel or norethisterone. Cyproterone acetate has a higher risk and is not generally recommended unless the woman has androgenic features such as acne and hirsutism or polycystic ovary syndrome (see article).

Switching COCs

When switching COCs containing different progestogens, the new COC should be started the day after the last active pill has been taken from the previous COC. For 28 day packs, this will mean missing out the seven inactive pills. If a seven-day break is taken before starting the new brand then additional precautions will be required until seven active pills have been taken.

Summary

COCs are generally safe, however their use may need review in some situations. Medical conditions may arise where a COC is no longer suitable and is best discontinued or the experience of adverse effects may require a trial of a different COC. Drug interactions may affect COC efficacy and additional precautions may be required.

UK Medical Eligibility Criteria (UKMEC) for combined oral contraceptive use 2

UKMEC Category 1 – Unrestricted Use
Age – menarche to <40 years
Parity – nulliparous and parous
Breastfeeding – >6 months postpartum
Postpartum – >21 days if not breastfeeding
Post-abortion – immediately first and second trimester, and post-septic
Past ectopic pregnancy
History of pelvic surgery
Minor surgery without immobilisation
Varicose veins
Non-migrainous headaches – mild or severe
Epilepsy – and not using liver enzyme-inducers
Depressive disorders
Vaginal bleeding – unsuspicious irregular, heavy or prolonged
Endometriosis
Benign ovarian tumour
Severe dysmenorrhoea
Gestational trophoblastic neoplasia – when hCG is normal
Cervical ectropion
Breast disease – benign breast disease or a family history of breast cancer
Endometrial or ovarian cancer
Uterine fibroids – with or without distortion of the uterine cavity
PID – current; or past history of, with or without subsequent pregnancy
STI – current, vaginitis or increased risk of STI
HIV/AIDS – risk of HIV/AIDS, current HIV not using antiretroviral therapy
Schistosomiasis, pelvic and non-pelvic tuberculosis, malaria
Diabetes – history of gestational disease
Thyroid disorders
Viral hepatitis – carrier
Anaemias – thalassaemia, iron deficiency
Raynaud’s disease – primary without lupus anticoagulant
UKMEC Category 2 – Benefits generally outweigh risks
Age – ≥40 yearsa
Breastfeeding – between 6 weeks and 6 months postpartum and partially breastfeeding (medium to low)
Smoking
– aged <35 years, or aged ≥35 years and stopped smoking ≥1 year ago
Obesity – BMI ≥30–34 kg/m2
History of high blood pressure during pregnancy
Family history of VTE in a first-degree relative aged ≥45 years
Major surgery without prolonged immobilisation
Superficial thrombophlebitis
Known hyperlipidaemias – e.g. common hypercholesterolaemia or familial combined hyperlipidaemia
Valvular and congenital heart disease – uncomplicated
Migraine headaches – without aura in women aged <35 years
Vaginal bleeding – suspicious for serious condition before evaluation
CIN and cervical cancer
HIV/AIDS – current HIV using antiretroviral therapy, or current AIDS and using HAART
Diabetes – NIDDM and IDDM, non-vascular disease
Gallbladder disease – asymptomatic or treated with a cholecystectomy
History of cholestasis – pregnancy-related
Inflammatory bowel disease
Sickle cell disease
Raynaud’s disease
– secondary without lupus anticoagulant
Non-liver enzyme-inducing antibiotics
Highly active antiretroviral therapy (HAART)
UKMEC Category 3 – Risks generally outweigh benefitsb
Breastfeeding – between 6 weeks and 6 months postpartum and fully or almost fully breastfeeding
Postpartum – <21 days postpartum
Smoking – aged ≥35 years and smoking <15 cigarettes per day, or stopped smoking <1 year ago
Obesity – BMI 35–39 kg/m2
Cardiovascular disease – multiple risk factors for arterial cardiovascular disease
Hypertension – elevated blood pressure >140 to 159 mmHg systolic or >90 to 94mmHg diastolic
Family history of VTE in a first-degree relative aged <45 years

Immobility (unrelated to surgery) – e.g. wheelchair use, debilitating illness
Known hyperlipidaemias – e.g. familial
hypercholesterolaemia
Migraine headaches – without aura in women aged ≥35 years; or a past history of migraine with aura at any age
Breast disease – past history of breast cancer and no evidence of recurrence for 5 years; carriers of known gene mutations associated with breast cancer (e.g. BRCA1); undiagnosed mass
Diabetes – with nephropathy/ retinopathy/ neuropathy; or other vascular disease or diabetes of >20 years’ duration (category given will depend on disease severity)
Gallbladder disease – symptomatic medically treated or current
History of cholestasis – past COC-related
Cirrhosis – mild compensated disease
Drugs which induce liver enzymes – e.g. rifampicin, rifabutin, St John’s Wort, griseofulvin and certain anticonvulsants (i.e. phenytoin, carbamazepine, barbiturates, primidone, topiramate, oxcarbazepine)
UKMEC Category 4 – Unacceptable health risk and should not be used
Breastfeeding – <6 weeks postpartum
Smoking – aged ≥35 years and smoking ≥15 cigarettes per day
Obesity
– BMI ≥40 kg/m2
Cardiovascular disease – multiple risk factors for arterial cardiovascular disease
Hypertension – blood pressure ≥160 mmHg systolic and/ or ≥95 mmHg diastolic; or vascular disease
VTE – current (on anticoagulants) or past history
Major surgery with prolonged immobilisation
Known thrombogenic mutations
Current and history of ischaemic heart disease
Stroke
Valvular and congenital heart disease – complicated by pulmonary hypertension, atrial fibrillation, history of subacute bacterial endocarditis
Migraine headaches – with aura at any age
Gestational trophoblastic neoplasia – when hCG is abnormal
Breast disease – current breast cancer
Diabetes – with nephropathy, retinopathy, neuropathy or other vascular disease, or diabetes of >20 years’ duration (category given will depend on disease severity)
Viral hepatitis – active disease
Cirrhosis – severe decompensated disease
Liver tumours – benign and malignant
Raynaud’s disease – secondary with lupus anticoagulant and thus a tendency to thrombosis

a Age ≥40 years: women may use COC until age 50 years if there are no medical contraindications.
b Definition of UKMEC 3 – the risks generally outweigh the benefits but the method can be considered for use with clinical judgement and/ or specialist referral if other methods are unacceptable.
AIDS, acquired immune deficiency syndrome; BMI, body mass index; CIN, cervical intraepithelial neoplasia; HAART, highly active antiretroviral therapy; hCG, human chorionic gonadotrophin; HIV, human immunodeficiency virus; IDDM, insulin-dependent diabetes; NIDDM, non-insulin-dependent diabetes; PID, pelvic inflammatory disease; STI, sexually transmitted infection; TB, tuberculosis; VTE, venous thromboembolism.

Reference

Faculty of Sexual and Reproductive Health Care Clinical Effectiveness Unit. First prescription of combined oral contraceptive. Available from: www.fsrh.org. Accessed February 2008

References

  1. Pharmaceutical warehouse database. Available from: New Zealand Health Information Service.
  2. Faculty of Sexual and Reproductive Health Care Clinical Effectiveness Unit. First prescription of combined oral contraceptive. Available from: www.ffprhc.org.uk/. Accessed February 2008
  3. National Prescribing Service Newsletter. Hormonal contraceptives: tailoring for the individual. Available from: http://www.nps.org.au/resources/NPS_News/news54/news54.pdf. Accessed February 2008
  4. MeReC Bulletin. Contraception – current issues. Available from: http://www.npc.co.uk/ebt/merec.htm. Accessed February 2008.
  5. Shoup D, Kjos SL. The handbook of contraception: a guide for practical management. Totowa: Humana Press; 2006.
  6. Baxter K (ed), Stockley’s Drug Interactions. [online] London: Pharmaceutical Press. http://www.medicinescomplete.com/ Accessed February 2008.
  7. Faculty of Sexual and Reproductive Health Care Clinical Effectiveness Unit. Drug interactions with hormonal contraception. Available from: www.fsrh.org. Accessed February 2008
  8. Clinical Knowledge Summaries. Contraception. Available from: http://www.cks.library.nhs.uk/contraception/. Accessed February 2008.
  9. Speroff L, Darney PD. A clinical guide for contraception. London: Lippincott Williams and Wilkins; 2005.
  10. Gallo MF, Nanda K, Grimes DA, Schulz KF. 20 mcg versus >20 mcg estrogen combined oral contraceptives. Cochrane Database Syst Rev 2005; 2.
  11. Cerel-Suhl SL, Yeager BF. Update on oral contraceptive pills. Am Fam Physician 1999; 60 (7): 2073-84.
  12. Maitra N, Kulier R, Bloemenkamp KWM, et al. Progestogens in combined oral contraceptives for contraception. Cochrane Database Syst Rev 2004; 3.