The P-I-E-N-O Parkinsn's List Drug Database
estrogen-progestin / LoestrinTM , Lo/OvralTM , ModiconTM , NelovaTM , NordetteTM , NorinylTM , NorlestrinTM , Ortho-CeptTM
ORAL CONTRACEPTIVE
Description: Combinations of a progesterone with an estrogen are used most commonly as oral contraceptives (i.e., the "pill"). Combination products confer better contraceptive protection than either agent administered as a single entity. Estrogen-progestin combinations can be used as a post-coital contraceptive but currently only OvralTM is approved for this use. These products are also used to regulate menstruation in patients with coagulopathies or heavy menstrual bleeding. In general, the estrogen-progestin products are available in four combinations: mestranol with norethrindrone; and ethinyl estradiol with either norethindrone acetate, norgestrel, or ethynodiol diacetate. Estrogen/progestin products were investigated for contraceptive use in the late 1950s. The first FDA approval was given in 1961; currently, at least 30 products are commercially available. A transdermal product is undergoing investigation for treatment of postmenopausal osteoporosis.
Mechanism of Action: The primary action of the combination of an estrogen with a progestin is to suppress the hypothalamic- pituitary system, preventing the secretion of follicle- stimulating hormone (FSH) and ultimately inhibiting maturation and release of the ovule. Long-term use also can directly affect the response of the ovaries to endogenous gonadotropins. In addition, viscosity of the cervical mucus increases with contraceptive use, preventing the penetration of the sperm. Estrogen is also responsible for a number of other metabolic changes such as alterations in hepatic carbohydrate and liver metabolism, changes in protein levels, and increases in sex hormones. Untoward effects, such as thrombosis, also are associated with estrogen use (see Adverse Reactions).
When oral contraception is discontinued, ovulation usually returns within three menstrual cycles but can take up to 6 months in some women.
Pharmacokinetics: Following oral administration, about 65% of the progestin and about 40% of the estrogen survive absorption and first pass through the liver. Both drugs are widely distributed and are strongly protein-bound, primarily to albumin and sex hormone-binding globulin (SHBG). Progestins are generally metabolized by reduction, followed by conjugation to the sulfate and glucuronate salts. Estrogens are metabolized in the GI mucosa during the absorption process and in the liver. Excretion of the inactive metabolites occurs via the urine and feces. Elimination half-life is approximately 5-14 hours for progestins and about 6-20 hours for estrogens.
CONTRAINDICATIONS/PRECAUTIONS: The relationship between contraceptive use and various cancers is controversial. Generally, the risk of cervical cancer is greatest in women who use oral contraceptives for more than 5 years. Combined results of many large studies have indicated that the use of oral contraceptives does not increase the risk or incidence of breast cancer in women 25-39 years of age. However, increased length of contraceptive use (i.e., >8 years); decreased number of pregnancies; and increasing age potentially increase the risk. Oral contraceptives can have a protective effect against endometrial and ovarian carcinomas. Continued studies are warranted due to some of the contradictory findings. Hormonal contraceptive agents are absolutely contraindicated in patients with breast carcinoma, uterine carcinoma, cervical carcinoma, or vaginal carcinoma.
Hormonal contraceptive agents are relatively contraindicated in women with endometriosis; menstrual irregularity including undiagnosed vaginal bleeding; uterine leiomyomata (fibroids), because the drug can cause the fibroids to increase in size; known or suspected pregnancy; or incomplete abortion.
Hormonal contraceptive agents have been associated with thromboembolic disease such as deep venous thrombosis (DVT). Because tobacco smoking increases the risk of this serious adverse event, estrogen-progestin contraceptives should be used cautiously, if at all, in smokers. Hormonal contraceptive agents are absolutely contraindicated in patients with a history of stroke, cerebrovascular disease, or thromboembolic disease.
Estrogen-progestin agents are relatively contraindicated in gallbladder disease and acute or intermittent porphyria. Because of their association with the development of cholestatic jaundice and hepatic neoplasms, hormonal contraceptive agents should be used cautiously in patients with any preexisting hepatic disease.
Because of their association with elevations in blood pressure, hormonal contraceptive agents should be used cautiously in patients with hypertension or coronary artery disease.
Estrogen-progestin agents are not recommended in patients with hypercalcemia associated with tumors or metabolic bone disease because estrogens influence the metabolism of calcium and phosphorus.
DRUG INTERACTIONS: Estrogens have reportedly potentiated the anti-inflammatory effects of hydrocortisone and delayed the clearance of prednisolone. Studies involving other corticosteroids have failed to show an interaction. Estrogens may decrease corticosteroid metabolism secondary to enzyme inhibition, compete at metabolism sites, or alter the protein binding of corticosteroids. Patients should be monitored for increased corticosteroid effects when estrogens are used in patients receiving either hydrocortisone or prednisolone.
Although several case reports suggested ampicillin reduced the efficacy of estrogen-progestin oral contraceptives, subsequent studies of this drug-drug interaction did not substantiate a pharmacokinetic interaction. It is possible, however, that significant ampicillin-induced diarrhea may impair the oral bioavailability of oral contraceptives in some patients. Since amoxicillin and bacampicillin theoretically produce less diarrhea than ampicillin, no interaction with oral contraceptives would be expected with these agents.
Rifampin, a potent hepatic enzyme inducer, increases the elimination of both estrogen and progestin. In addition, free hormone concentrations are decreased because rifampin increases estrogenic protein binding ability. It is estimated that 70% of women taking estrogen-containing oral contraceptives and rifampin experience menstrual abnormalities, and 6% become pregnant. Like other anti-infectives, rifampin indirectly inhibits the enterohepatic recirculation of estrogen through disruption of GI flora growth and this may also be a contributory factor. Concurrent administration of other hepatic enzyme inducers with estrogen-containing oral contraceptives, including barbiturates, carbamazepine, griseofulvin, phenytoin and primidone, may produce similar results.
Anti-infectives which disrupt the normal GI flora, including chloramphenicol, neomycin, nitrofurantoin, penicillin V, sulfonamides, and tetracyclines, may potentially decrease the effectiveness of estrogen. Normally, GI bacteria hydrolyze estrogen conjugates that are eliminated via the bile. This hydrolyzation allows enterohepatic recirculation of the active estrogenic component to occur. A decrease in enterohepatic recirculation could compromise the effectiveness of estrogen- containing oral contraceptives. These anti-infectives may also increase estrogen metabolism. The clinical significance of this interaction has not been established due to conflicting reports on its validity. However, patients should be made aware of this potential interaction.
Mineral oil can reduce absorption of oral contraceptives from the GI tract producing lower plasma levels of progestin and estrogen. This interaction is the result of simultaneous administration.
The effects of warfarin are generally decreased during concurrent use with estrogen-containing oral contraceptives because estrogens increase the production of clotting factors VII, VIII, IX, and X. Furthermore, estrogens promote platelet aggregation. Dosage adjustment of warfarin should be based on the prothrombin time or INR value.
The dosage of oral hypoglycemics or insulin may have to be increased when oral contraceptives are administered. Oral contraceptives may antagonize the hypoglycemic effects of the diabetic agents by impairing glucose tolerance.
Estrogen-containing oral contraceptives appear to decrease the effectiveness of clofibrate through increasing the glucuronide conjugation of the active form of clofibrate. Through a similar mechanism, estrogen-containing oral contraceptives may increase the clearance of benzodiazepines that undergo glucuronide conjugation such as lorazepam, temazepam and oxazepam. Conversely, estrogen-containing oral contraceptives may inhibit the clearance of benzodiazepines which undergo oxidation such as diazepam and chlordiazepoxide. Other benzodiazepines which undergo oxidation and could potentially interact include alprazolam, clorazepate, flurazepam, and halazepam.
Serum concentrations of theophylline may be increased during concurrent administration with oral contraceptives. This interaction occurs from the inhibition of theophylline oxidation in the liver. The resulting increased half-life and decreased clearance may necessitate a decrease in theophylline dosage. Similarly, the oxidative metabolism of tricyclic antidepressants may be decreased by oral contraceptives resulting in increased serum concentrations. Current evidence indicates that this interaction may be related to the estrogen dosage, with larger doses causing a more significant interaction.
Estrogens interfere with the therapeutic effect of tamoxifen, since the mechanism of tamoxifen is to antagonize estrogen receptors.
A few reports of increased cyclosporine levels and cyclosporine toxicity have been documented following concurrent administration of oral contraceptives. This interaction is likely the result of decreased cyclosporine metabolism. Patients taking these medications concurrently should have cyclosporine levels evaluated regularly.
Concurrent administration of troleandomycin and estrogen- containing oral contraceptives may decrease the metabolism of the latter, causing alterations in bilirubin and bile acid secretion. Cholestatic jaundice has occurred in some patients. Although both agents have caused jaundice independently, concurrent use is not recommended.
Estrogens interact with hepatotoxic medications, particularly dantrolene, by increasing the risk of hepatotoxicity. Women over 35 years and patients with a history of liver disease are especially at risk.
A multiple-dose, placebo-controlled, randomized two-way crossover study investigated the use of lansoprazole with a low-dose oral contraceptive containing ethinylestradiol and levonorgestrel. The bioavailability of oral contraceptives was not affected by lansoprazole.D
ADVERSE REACTIONS: The relationship between hormonal contraceptive use and various cancers is controversial. Generally, the risk of cervical cancer is greatest in women who use oral contraceptives for more than 5 years. Combined results of many large studies have indicated that the use of oral contraceptives does not increase the risk or incidence of breast carcinoma in women 25-39 years of age. However, increased length of contraceptive use (i.e., >8 years); decreased number of pregnancies; and increasing age potentially increase the risk. Oral contraceptives can have a protective effect against endometrial and ovarian carcinomas. Continued studies are warranted due to some of the contradictory findings. Hormonal contraceptive agents are absolutely contraindicated in breast carcinoma, uterine carcinoma, cervical carcinoma, or vaginal carcinoma.
Thromboembolic and thrombotic disorders are more common in oral contraceptive users than in non-users. The relative risk of superficial venous thrombosis is 3 times higher in users versus non-users. The risk is approximately 3 times greater for the development of deep venous thrombosis and pulmonary embolism. The risk for women with predisposing conditions for venous thromboembolic disease is 4 times greater. The relative risk of thromboitc stroke is 10 times greater and hemorrhagic stroke is 2 times greater in users versus non-users.
Ocular disorders can occur during therapy with hormonal contraceptive agents. These can include optic neuritis, diplopia, loss of vision, or retinal thrombosis. Hormonal contraceptive agents should be discontinued in patients developing any unexplained visual disturbance.
Changes in vaginal bleeding often occur after initiation of hormonal contraceptive therapy. Breakthrough bleeding and spotting are common during the first 3 months of use. When the bleeding occurs cyclically, the time of the cycle can indicate which component (i.e., estrogen or progestin) requires readjustment. Amenorrhea can occur during or after treatment with oral contraceptives.
Cardiovascular adverse reactions are associated with hormonal contraceptive therapy. Hypertension can occur within a few months of initiating therapy and the prevalence increases with duration of use and patient age. There appears to be some correlation of hypertension with the progesterone concentration. Close monitoring of blood pressures is recommended for patients at risk for hypertension; blood pressures usually return to normal after discontinuation of therapy. Hormonal contraceptive therapy is considered a risk factor for myocardial infarction (MI). Smoking is an additive risk to hormonal contraceptive therapy, increasing the relative risk of MI by five-fold. There is a 10-12 fold increase in risk of MI in patients who use hormonal contraceptive therapy and smoke compared to females who do not smoke or use therapy. Other reactions include fluid retention and edema.
Other breast changes that can occur during therapy with hormonal contraceptive agents include breast discharge, breast pain or mastalgia, galactorrhea, and breast enlargement.
Mood or personality changes occur commonly in women taking hormonal contraceptive agents. These changes include mental depression, anxiety, libido decrease, frustration, anger, or other emotional outbursts.
The relationship of headache, specifically migraine headache, and the administration of hormonal contraceptive agents is not clearly defined. A number of changes can occur when a woman initiates oral contraceptive therapy and include 1) migraines can appear for the first time, 2) a change in frequency, severity and duration of migraine headaches may be seen, or 3) an improvement or decrease in the occurrence of migraine headaches. When initiating therapy an individual's headache pattern should be observed and if migraines worsen consider discontinuing therapy.
Minor adverse GI reactions are uncommon during therapy with hormonal contraceptive agents. Nevertheless, abdominal pain can indicate cholelithiasis or cholecystitis, hepatitis, hepatoma, peliosis hepatitis, or pancreatitis. Hormonal contraceptive agents should be discontinued in any patient developing jaundice or severe abdominal pain.
Adverse skin manifestations during therapy with hormonal contraceptive agents can include a benign skin rash or chloasma gravidarum. Photosensitivity can be experienced with oral contraceptive use and protective clothing and sunscreens should be employed when exposed to sunlight or UV light. Other dermatologic reaction are infrequent and include maculopapular rash, acneiform rash, urticaria, erythema nodosum, and alopecia.
Vaginal discharge or vaginal irritation due to candidiasis or vaginitis can occur during therapy with hormonal contraceptive agents.
The following adverse reactions often subside after the first few months and require medical attention only if prolonged or bothersome: abdominal pain or cramps, anorexia or appetite stimulation, nausea/vomiting, fluid retention or edema with weight gain, azotemia, breast enlargement, and fatigue.
PATIENT INFORMATION:
What do estrogen; progestin tablets do?
Estrogen-progestin products (BreviconTM , DemulenTM 1/35-28, ModiconTM 28, NorinylTM 1+35 28, Ortho-NovumTM 1/35-28, etc.) are effective as oral contraceptives (birth control pills or "the pill"). These products combine natural or synthetic estrogens and progestins, similar to the natural sex hormones (estrogen and progesterone) produced in a woman's body. They can prevent ovulation and pregnancy. In general, a combination of estrogen and progestin works better than a single-ingredient product. Estrogen/progestin tablets can also help regulate heavy menstrual flow. There are more than 30 combination products available in the United States, in four different combinations.
What should my doctor, dentist, or pharmacist know before I take estrogen/progestin?
They need to know if you have any of these conditions:
How should I take this medicine?
Take estrogen/progestin pills by mouth. Before you start taking these pills decide what is a suitable time of day and always take them at the same time of day and in the order directed. Swallow the pills with a drink of water. Take with food to reduce stomach upset. Establish a pattern of taking your pills at the same time each day; do not take more often than directed. All products contain a 21-day supply of pills containing the active ingredients. Some products contain an additional 7 pills containing iron or inactive ingredients to be taken during the week of menstruation; this reduces the chance of missing the first day of the next cycle. Most products are to be started on the fifth day of your period, while others are to be started on the first Sunday after you start your period or on the first day of your period. Before starting this medication, read the package insert provided by your pharmacist, and make certain you understand the instructions.
Special precautions for use in children:
This medicine is not for children.
What if I miss a dose?
Try not to miss a dose, but if you do, proceed as follows: 21-day schedule: If you miss one dose, take it as soon as you remember and then take the next pill at the regular time as usual. You may feel slight nausea on the day you take the missed pill and your regular pill. If you miss two doses (days) in a row, throw away the missed pills and return to the regular schedule. To prevent pregnancy use a second method of contraception until the end of the cycle in addition to taking the pills. Missing a pill can cause spotting or light bleeding. Make sure that no more than 7 days pass at the end of the 21 day cycle, before you start your next pack of pills.
28-day schedule: Follow the same directions as above for the first 21 days of the schedule. If you miss 1 of the last 7 pills, you can either double the dose or skip it, but it is important to start the next month's cycle on the scheduled day.
Keep an extra month's supply available to ensure that you will not miss the first day of the next cycle.
What other medicines can interact with estrogen/progestin?
Tell your doctor or pharmacist: about all other medicines you are taking, including non-prescription medicines; if you are a frequent user of drinks with caffeine or alcohol; if you smoke; or if you use illegal drugs. These may affect the way your medicine works. Check before stopping or starting any of your medicines.
What side effects may I notice from taking estrogen/progestin?
Serious side effects with estrogen/progestin include:
Call your doctor as soon as you can if you get any of these side effects.
Minor side effects with estrogen/progestin include:
Let your doctor know about these side effects if they do not go away or if they annoy you.
What do I need to watch for while I take estrogen/progestin?
Visit your doctor for regular checks on your progress. You should have a complete check-up every 6 to 12 months. If you have any unusual bleeding contact your doctor for advice. If you miss a period the possibility of pregnancy must be considered, see your doctor as soon as you can.
Use an additional method of contraception during the first cycle that you take these tablets.
If you stop taking these tablets and want to get pregnant, a return to normal ovulation can take some time. You may not return to normal ovulation and fertility for 3 to 6 months. Discuss this with your doctor.
Tobacco smoking increases the risk of getting a blood clot or having a stroke while you are taking estrogen/progestin, especially if you are more than 35 years old. You are strongly advised not to smoke.
If you wear contact lenses and notice visual changes, or if the lenses begin to feel uncomfortable, consult your eye doctor.
You may get a vaginal yeast infection. If you have never had a yeast infection before, see your doctor to confirm the problem. If you have had yeast infections in the past and are comfortable with self-medicating the problem, get and use a nonprescription medication for 7 days to treat the yeast infection.
If you are going to have elective surgery, you should stop taking your contraceptive pills one month beforehand.
Check with your doctor if you develop a spotty darkening of the skin while you are taking estrogen/progestin.
Taking contraceptive pills does not protect you against HIV infection (AIDS) or other sexually transmitted diseases.
Where can I keep my medicine?
Keep out of the reach of children in a container that small children cannot open.
Store at room temperature between 15 and 30C (59 and 86F). Keep container tightly closed. Throw away any unused medicine after the expiration date.
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