ORAL CONTRACEPTIVES

































  • Considered 2nd and 3rd generation. Norgestimate is converted to norgestrel (half-life 38 hours) and norelgestromin (half-life 18 hours)
  • References [1,9,Package insert]
PROGESTINS GROUPED BY GENERATION
First generation Second generation Third generation
  • Dienogest
  • Ethynodiol Diacetate
  • Norethindrone
  • Norethindrone Acetate
  • Levonorgestrel
  • Norgestimate
  • Norgestrel
  • Desogestrel
  • Norgestimate
PROGESTINS GROUPED BY STRUCTURE
Testosterone-related Progesterone-related Spironolactone-related
  • Desogestrel (half-life 38 hours)
  • Dienogest (half-life 11 hours)
  • Ethynodiol Diacetate
  • Levonorgestrel (half-life 24-29 hours)
  • Norethindrone (half-life 8-9 hours)
  • Norethindrone Acetate (half-life 7-8 hours)
  • Norgestimate
  • Norgestrel (half-life 38 hours)
  • Medroxyprogesterone
  • Megestrol acetate
  • Drospirenone (half-life 30 hours)




Common side effects
Overview
  • Common side effects of OCPs are listed below
  • In general, well-done clinical trials comparing OCPs to placebo have found that there is no significant difference in the frequency of these complaints
  • Low dose estrogen pills (EE ≤0.020 mg) have been found to significantly increase the risk of irregular bleeding (spotting and breakthrough bleeding) [6,11,12]
Common side effects reported with OCP use include:
  • Irregular menstrual bleeding
  • Nausea
  • Headache / Migraine
  • Breast tenderness
  • Mood disorders
  • Decreased libido
Summary
  • While these complaints are common, in controlled trials, they do not appear to be significantly different than placebo
  • Low EE pills (EE ≤0.020 mg) do cause more irregular bleeding

Weight gain

Increase in blood pressure

Diabetes and glucose intolerance

High potassium (drospirenone)
Overview
  • Drospirenone is structurally related to the aldosterone antagonist spironolactone
  • Spironolactone blocks aldosterone receptors in the kidney and this can lead to elevated potassium levels (nephron diagram)
  • The manufacturers of drospirenone-containing OCPs warn that it may cause high potassium levels in women with kidney disease and in those who are taking medications that can raise potassium levels (aldosterone antagonists, ACE inhibitors, ARBs, ENaC inhibitors, etc.)
Clinical studies
  • A number of cohort studies and randomized trials have looked at the incidence of high potassium (hyperkalemia) among women taking drospirenone-containing OCPs
  • These studies have found that drospirenone does not increase the risk of high potassium when compared to other OCPs
  • Drospirenone also does not appear to increase the risk of high potassium when taken with other potassium-raising medications including spironolactone [17,29,30,69]
Summary
  • In general, hyperkalemia from drospirenone does not appear to be significant even when it is taken with other potassium-raising medications
  • Spironolactone is increasingly used in young women to treat acne. These women are often also taking drospirenone-containing OCPs. The American Academy of Dermatology states that spironolactone may be used safely with drospirenone-containing OCPs [69]

Liver adenomas

Photosensitivity



Venous thromboembolism (VTE)
Overview
  • Venous thromboembolism includes deep vein thrombosis and pulmonary embolism
  • It is well-documented that combined OCPs increase the risk of VTE. Progestin-only pills do not appear to increase the risk of VTE.
  • The risk of VTE is particularly high during the postpartum period (42 days after delivery). See postpartum below for recommendations on using OCPs during this period.
  • For perspective on the degree of risk, the incidence of VTE in the general female population is as follows:
    • Non-pregnant, non-OCP user: 1 - 5 blood clots per 10,000 women over the course of a year
    • OCP user: 3 - 9 blood clots per 10,000 women taking OCPs for a year
    • Pregnant female: 5 - 20 blood clots per 10,000 pregnant women over the course of a year
    • Postpartum (12 weeks after delivering baby): 40 - 65 blood clots per 10,000 postpartum women over the course of a year. The risk appears to be greatest during the first 6 postpartum weeks, then it decreases significantly. [17,18,58]
Drospirenone
  • Drospirenone has received much attention lately because it may confer a higher risk of blood clots when compared to other progestins
  • The FDA has reviewed the issue, and they released a statement that said drospirenone-containing OCPs may be associated with a higher risk of blood clots, but the evidence is not conclusive. FDA statement
  • Some observational studies have shown as much as a three-fold higher risk, while others have shown no increased risk
Three nested case-control studies compared incidence rates of VTE between different progestins and found the following:
  • A study from a US database found that women taking drospirenone OCPs had 2.3 the odds of developing a blood clot when compared to those taking levonorgestrel OCPs. The incidence rates of blood clots was 3 per 10,000 women taking drospirenone for a year, and 1.25 per 10,000 women taking levonorgestrel for a year. [21]
  • A study from a UK database found that women taking drospirenone OCPs had 3.3 the odds of developing a blood clot when compared to those taking levonorgestrel OCPs. The incidence rates of blood clots was 2.3 per 10,000 women taking drospirenone for a year, and 0.91 per 10,000 women taking levonorgestrel for a year. [22]
  • A study from two UK databases found that women taking drospirenone- and desogestrel-containing OCPs had significantly greater odds of developing a thromboembolism when compared to those taking levonorgestrel-containing OCPs.
  • The estimated number of extra cases of thromboembolism per year for each progestin when compared to unexposed women (aged 15 - 49 years) was as follows:
    • Levonorgestrel - 7 cases per 10,000 women treated
    • Desogestrel - 14 cases per 10,000 women treated
    • Drospirenone - 13 cases per 10,000 women treated [62]
Summary
  • All OCPs cause a slight increase in the risk for blood clots
  • The risk is still less than what is seen in pregnancy
  • There is some evidence that OCPs with drospirenone may have a slightly higher risk of blood clots than other progestins. The evidence is observational, and therefore, it cannot be considered conclusive.
  • Low EE (≤ 0.020 mg) pills may also have a lower risk of blood clots (see high vs low EE above)

Heart attack and stroke

Breast cancer

Cervical cancer

Fracture risk

Gallbladder disease
















Migraine headache
Overview
  • There is evidence that women with migraine headaches have an increased risk of stroke
  • The evidence appears to be even stronger for women who have migraine headaches with aura (auras typically involve visual changes that precede the migraine)
  • The overall risk of stroke in young women (< 45 years) is low: 5 - 10 strokes per 100,000 women over the course of a year
  • A history of any migraine headache appears to increase the risk slightly (odds ratio around 3)
  • A history of migraine headache with aura increases the risk slightly more (odds ratio around 6)
  • Because combined OCPs also increase the risk of stroke, some experts have recommended that they not be taken by women who have migraine headaches with aura [24]
Summary
  • In general, the following is true:
    • Women who have migraines with aura and other risk factors for stroke (age > 35 years, smokers, hypertension, strong family history of vascular disease, diabetics, high cholesterol, obesity) should not take combined OCPs
    • Women who have migraines without aura and are 35 years and older may want to avoid combined OCPs [24,25]

Obesity
OCP failure
  • Some studies have found that obese women have higher rates of OCP failure than normal weight women. Other studies have not found an association.
  • A randomized controlled trial that directly measured ovulation rates between normal weight women and obese women on OCPs found no significant difference between the two groups. [PubMed abstract]
  • There is no conclusive evidence that OCPs are less effective in obese women [33,34]
Blood clots
  • Obesity is a risk factor for blood clots
  • Because OCPs increase the risk of blood clots (see blood clots above), obese women may have a higher risk than average weight women for blood clots while taking OCPs

Postpartum (after childbirth)
Overview
  • After a woman delivers a baby, her risk of blood clots is elevated for up to 42 days with the highest risk occurring during the first 21 days
  • Because combined hormonal contraceptives (OCPs, patch, vaginal ring) increase the risk of blood clots, there is some controversy as to whether women should use these agents during the first 42 days after giving birth.
  • IUDs and progestin-only contraceptives (pills, Depo-Provera®, implants) are considered safe immediately after childbirth
  • The CDC published guidelines in 2016 for the use of combined hormonal contraceptives (OCPs with ≤ 35 mcg of EE, patch, vaginal ring) in postpartum women. The guidelines differ slightly for breastfeeding and nonbreastfeeding women and are summarized below.
CDC recommendations
  • CDC recommendations for women who are breastfeeding
    • First 30 days after delivery - all women should avoid combined hormonal contraceptives
    • Days 30 - 42 after delivery
      • Women with risk factors for blood clots (see below) - do not use combined hormonal contraceptives
      • Women without risk factors for blood clots - the advantages of combined hormonal contraceptives generally outweigh the risk
    • > 42 days after delivery - the advantages of combined hormonal contraceptives generally outweigh the risks in all appropriate patients
    • Breastfeeding and combined hormonal contraceptives - the CDC states that there is conflicting evidence about the effects of combined birth control methods on breast milk production. No consistent effects on infant growth or illness have been reported. Adverse health outcomes or manifestations of exogenous estrogen in infants exposed to CHCs through breast milk have not been demonstrated; however,studies have been inadequately designed to determine whether a risk for either serious or subtle long-term effects exists. [67]
  • CDC recommendations for women who are NOT breastfeeding
    • First 21 days after delivery - all women should avoid combined hormonal contraceptives
    • Days 21 - 42 after delivery
      • Women with risk factors for blood clots (see below) - do not use combined hormonal contraceptives
      • Women without risk factors for blood clots - the advantages of combined hormonal contraceptives generally outweigh the risk
    • > 42 days after delivery - combined hormonal contraceptives may be used in all appropriate patients [67]
  • Risk factors for blood clots include:

Hypertension

Liver disease

Kidney disease

Thyroid hormone

Fetal exposure to OCPs



Drug interactions

All OCPs
  • Acetaminophen (Tylenol®) - Acetaminophen may increase blood level of ethinyl estradiol. OCPs may decrease levels of acetaminophen.
  • Antibiotics - see antibiotics below
  • Anticonvulsants - see anticonvulsants below
  • Ascorbic acid (Vitamin C) - Studies have shown that ascorbic acid may increase blood levels of ethinyl estradiol
  • Atorvastatin (Lipitor®) - atorvastatin may increase blood levels of EE by approximately 20 - 25% [71]
  • Benzodiazepines (alprazolam, Xanax®, triazolam, temazepam, etc.) - OCPs have been shown to both increase and decrease blood levels of benzodiazepines [38]
  • Bile acid sequestrants (Welchol®, etc.) - Bile acid sequestrants can block the absorption of EE. In one study, colesevelam decreased the absorption of EE when EE was taken one hour before colesevelam. When EE was taken 4 hours before colesevelam, no interaction occurred. [PubMed abstract]
  • Cyclosporine - OCPs may increase blood levels of cyclosporine
  • CYP3A4 Inducers - CYP3A4 inducers can decrease blood levels of OCPs
  • CYP3A4 Inhibitors - CYP3A4 inhibitors can increase blood levels of OCPs. The significance of this effect is unknown. Patients taking CYP3A4 inhibitors with OCPs may want to take a low ethinyl estradiol pill (<0.030 mg).
  • GLP-1 analogs
    • GLP-1 analogs slow gastric emptying which can affect the absorption of OCPs
    • Manufacturers of exenatide and lixisenatide recommend that OCP dosing be spaced apart from their product's administration
    • OCPs should be taken 1 hour before exenatide (Byetta®, Bydureon®) is injected [55]
    • OCPs should be taken at least 1 hour before lixisenatide (Adlyxin®) administration or at least 11 hours after the last dose of lixisenatide [73]
  • Griseofulvin (Gris-Peg®) - Griseofulvin may decrease blood levels of OCPs
  • HIV/Hepatitis C medications - many of the protease inhibitors and NNRTIs used to treat HIV and hepatitis C are CYP3A4 inducers and inhibitors. These drugs may affect blood levels of OCPs
  • Morphine - OCPs may decrease blood levels of morphine
  • Pioglitazone (Actos®) - Pioglitazone is a CPY3A4 inducer. Pioglitazone may decrease OCP blood levels.
  • Pramlintide (Symlin®) - Pramlintide slows gastric emptying and may affect the absorption and effectiveness of OCPs
  • Prednisolone - OCPs may increase blood levels of prednisolone
  • Rosuvastatin (Crestor®) - rosuvastatin may increase blood levels of EE by approximately 20 - 25% [71]
  • Technivie® (ombitasvir, paritaprevir, and ritonavir) - OCPs with ethinyl estradiol should not be taken with the hepatitis C drug Technivie. ALT elevations > 5 - 20 ULN have been seen in some patients.
  • Theophylline (Theo-Dur®) - OCPs may increase blood levels of theophylline
  • Thyroid hormone - OCPs may cause an increase in blood levels of thyroid hormone and thyroid-binding globulin. The amount of active (free) thyroid hormone is generally unchanged. (See Thyroid Disease under precautions above)
  • Tizanidine (Zanaflex®) - OCPs may increase blood levels of tizanidine
  • Viekira-Pak™/Viekira XR™ (ombitasvir, paritaprevir, ritonavir, and dasabuvir) - OCPs with ethinyl estradiol should not be taken with the hepatitis C drug Viekira-Pak. ALT elevations > 5 - 20 ULN have been seen in some patients.
  • Voriconazole - OCPs may increase blood levels of voriconazole

Anticonvulsants
  • Today, anticonvulsants are used to treat a number of conditions including migraines, pain, and psychiatric conditions
  • Some anticonvulsants may theoretically decrease the effectiveness of OCPs because they induce CYP3A4 enzymes and therefore decrease blood levels of OCP hormones
  • Only one small study from 1979 that involved 82 women found an increased rate of pregnancy among users of anticonvulsants
  • In general, other forms of contraception (IUD, barrier) should be considered in women who are taking anticonvulsants that induce CYP3A4. This recommendation is based on very little evidence. Women taking OCPs with anticonvulsants that induce CYP3A4 still have very low pregnancy rates.
  • If OCPs are desirable while taking anticonvulsants that induce CYP3A4, then higher dose OCPs (Ethinyl Estradiol 0.035 - 0.050 mg) should be used (list of OCPs with 0.050 mg of EE)
  • Also of note, OCPs have been shown to decrease blood levels of lamotrigine (Lamictal®) by up to 50%. They may also decrease levels of valproic acid. When taken together, blood levels of lamotrigine and valproic acid should be monitored closely when stopping or starting OCPs [35,36,70]

Antibiotics
  • It has long been suspected that antibiotics may interact with OCPs leading to OCP failure and unintended pregnancies
  • Outside of rifampin (a CYP3A4 inducer), supporting evidence to this belief is weak or nonexistent
  • Studies evaluating the direct effect of antibiotics on blood levels of hormones have generally found that they do not significantly affect plasma levels of hormones. However, a small number of patients in these studies have shown large variations in hormone levels when taking antibiotics.
  • It is possible that a small population of patients are predisposed to some type of antibiotic-OCP interaction, the mechanism of which has not been elucidated
  • Because it is impossible at this time to identify these women, patients should use an additional form of birth control (condoms) while taking an antibiotic and for 1 week after they have finished the antibiotic
  • Women taking antibiotics for an extended period (ex. acne) may want to consider an alternative form of contraception [37,76]
  • Antibiotics known to interact with OCPs
    • Rifampin
  • Antibiotics that may interact with OCPs
    • Penicillins (ampicillin, amoxicillin, etc.)
    • Metronidazole (Flagyl®)
    • Tetracyclines (doxycycline, minocycline, etc.)