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Monophasic ContraceptivesTriphasic Contraceptives
Combined hormonal contraceptive agents are contraindicated in patients with a current or past history of stroke, cerebrovascular disease, coronary artery disease, coronary thrombosis, myocardial infarction, thrombophlebitis, thromboembolism or thromboembolic disease, or valvular heart disease with complications. Hormonal combined oral contraceptives (COCs) have been associated with thromboembolism such as deep venous thrombosis (DVT). COCs are also generally contraindicated in women who have thrombogenic valvular or thrombogenic rhythm diseases of the heart (e.g., subacute bacterial endocarditis with valvular disease, or atrial fibrillation), or a known inherited or acquired hypercoagulopathies (e.g., protein S deficiency, protein C deficiency, Factor V Leiden, prothrombin G20210A mutation, antithrombin deficiency, antiphospholipid antibodies). Because tobacco smoking increases the risk of thromboembolism, DVT, myocardial infarction, stroke and other thromboembolic disease, patients receiving COCs are strongly advised not to smoke. Risk is especially high for female smokers over 35 years of age or those who smoke 15 or more cigarettes per day. Therefore, COCs are generally considered contraindicated in women over the age of 35 years who are tobacco smokers. A positive relationship between estrogen dosage and thromboembolic disease has been demonstrated, and oral products containing 50-mcg ethinyl estradiol should not be used unless medically indicated. In addition, certain progestins may increase thromboembolic risk. The overall risk of venous thromboembolism in women using COCs has been estimated to be 3 to 9 per 10,000 woman-years. Preliminary data from a large, prospective cohort safety study suggests that the risk is greatest during the first 6 months after initially starting COC therapy or restarting (following a break from therapy 4 weeks or more) with the same or different combination product. The risk of arterial thromboses, such as stroke and myocardial infarction, is especially increased in women with other risk factors for these events. Pre-existing high blood pressure, kidney disease, hypercholesterolemia, hyperlipidemia, morbid obesity, or patients with diabetes with vascular disease may also increase risk. After a COC is discontinued, the risk of thromboembolic disease due to oral contraceptives gradually disappears. Because of their association with elevations in blood pressure, COCs should be used cautiously in patients with mild to moderate hypertension or kidney disease; use is contraindicated in patients with uncontrolled or severe hypertension or hypertension with vascular disease. An increase in blood pressure has been reported in women taking COCs, and this increase is more likely in older women and with extended duration of use. The incidence of hypertension increases with increasing concentration of progestin. Blood pressure should be monitored closely in individuals with high blood pressure; discontinue ethinyl estradiol; norethindrone acetate; ferrous fumarate if blood pressure rises significantly. COCs may also cause fluid retention, and patients predisposed to complications from edema, such as those with cardiac or renal disease, should be closely monitored.
Combined oral contraceptive (COC) containing a synthetic estrogen and norethindrone acetate, a progestin with moderate androgenic and slight estrogenic activityFerrous fumarate tablets provide a small amount of iron supplement during menses but no significant therapeutic valueUsed for routine contraception in adolescent and adult premenopausal females; some products are additionally approved for acne treatment in these populationsAll COCs contain a boxed warning regarding the increased risk for thromboembolism in women who smoke
Blisovi 24 Fe, Blisovi Fe, Estrostep Fe, Gildess 24 Fe, Gildess Fe 1.5/30, Gildess Fe 1/20, Junel Fe 1.5/30, Junel Fe 1/20, Junel Fe 24, Larin Fe, Lo Loestrin Fe, Loestrin 24 Fe, Loestrin FE 1.5/30, Loestrin FE 1/20, Lomedia 24 Fe, Melodetta, Mibelas 24 Fe, Microgestin 24 Fe, Microgestin Fe 1.5/30, Microgestin Fe 1/20, Minastrin, Tarina Fe 1/20, Taytulla, Tilia Fe, Tri-Legest Fe
Blisovi 24 Fe/Blisovi Fe/Estrostep Fe/Ethinyl Estradiol, Norethindrone;Ferrous Fumarate/Ferrous Fumarate;Norethindrone Acetate, Ethinyl Estradiol/Gildess 24 Fe/Gildess Fe 1.5/30/Gildess Fe 1/20/Junel Fe 1.5/30/Junel Fe 1/20/Junel Fe 24/Larin Fe/Lo Loestrin Fe/Loestrin 24 Fe/Loestrin FE 1.5/30/Loestrin FE 1/20/Lomedia 24 Fe/Microgestin 24 Fe/Microgestin Fe 1.5/30/Microgestin Fe 1/20/Tarina Fe 1/20/Tilia Fe/Tri-Legest Fe Oral Tab: 10-75-1-10mcg, 75-1-0.02mg, 75-1-0.02-0.03-0.035mg, 75-1.5-0.03mgEthinyl Estradiol, Norethindrone;Ferrous Fumarate/Ferrous Fumarate;Norethindrone Acetate, Ethinyl Estradiol/Melodetta/Mibelas 24 Fe/Minastrin Oral Tab Chew: 75-1-20mcgTaytulla Oral Cap: 75-1-20mcg
1 active hormone tablet (containing either 0.02 mg ethinyl estradiol; 1 mg norethindrone acetate or alternatively, 0.03 mg ethinyl estradiol; 1.5 mg norethindrone acetate) PO once daily for 21 days, followed by 1 iron tablet (75 mg ferrous fumarate) PO once daily for 7 days. Pills should be taken in the order directed on the blister pack. The cycle should be repeated every 28 days. Administration of most combination OCs begins on the first Sunday after or on which bleeding has started. However, some clinicians and manufacturers suggest that administration begin on day 1 of the menstrual cycle to decrease the risk of early ovulation. If administration begins on day 1, spotting and breakthrough bleeding may be more common during the initial dosage cycle.
1 active hormone tablet (0.02 mg ethinyl estradiol; 1 mg norethindrone acetate) PO once daily for 24 days, followed by 1 iron tablet (75 mg ferrous fumarate) PO once daily for 4 days. Pills should be taken in the order directed on the blister pack. The cycle should be repeated every 28 days. Administration can begin on the first Sunday after or on which bleeding has started or the first day of bleeding. When switching from a 21-day combination hormonal contraceptive regimen, the patient should wait 7 days after her last tablet, patch, or ring before starting Loestrin 24 Fe. When switching from a 28-day combination OC regimen, the patient should begin Loestrin 24 Fe on the day after the last tablet. If a patient is taking an oral progestin-only regimen, the patient can switch to Loestrin 24 Fe at any time; she should start taking the Loestrin 24 Fe tablets the day after her last progestin-only tablet. If switching from an implant or an injection, the patient should start Loestrin 24 Fe on the day the implant is removed or the day the next injection would have been administered.
1 active hormone chewable tablet (0.02 mg ethinyl estradiol; 1 mg norethindrone acetate) PO once daily for 24 days, followed by 1 iron chewable tablet (75 mg ferrous fumarate) PO once daily for 4 days. Pills should be taken in the order directed on the blister pack. The cycle should be repeated every 28 days. Patients should start the blister pack on the first Sunday after or on which bleeding has started, or alternatively, on day 1 of the menstrual cycle (1st day of menstruation). When switching from another oral contraceptive, patients should start taking this product on the same day that a new pack of the previous oral contraceptive would have been started.
1 active hormone capsule (0.02 mg ethinyl estradiol; 1 mg norethindrone acetate) PO once daily for 24 days, followed by 1 iron capsule (75 mg ferrous fumarate) PO once daily for 4 days. Capsules should be taken in the order directed on the blister pack. The cycle should be repeated every 28 days. Patients should start the blister pack on the first Sunday after or on which bleeding has started, or alternatively, on day 1 of the menstrual cycle (1st day of menstruation). When switching from another oral contraceptive, patients should start taking this product on the same day that a new pack of the previous oral contraceptive would have been started.
Phase 1: 1 active hormone tablet (0.02 mg ethinyl estradiol; 1 mg norethindrone acetate) PO once daily for 5 days. Phase 2: 1 active hormone tablet (0.03 mg ethinyl estradiol; 1 mg norethindrone acetate) PO once daily for 7 days. Phase 3: 1 active hormone tablet (0.035 mg ethinyl estradiol; 1 mg norethindrone acetate) PO once daily for 9 days, followed by 1 iron tablet (75 mg ferrous fumarate) PO once daily for 7 days. Pills should be taken in the order directed on the blister pack. The cycle should be repeated every 28 days. Administration of most combination oral contraceptives begins on the first Sunday after or on which bleeding has started. Estrostep products are recommended to be administered according to this Sunday-start regimen.
Phase 1: 1 active hormone tablet (0.01 mg ethinyl estradiol; 1 mg norethindrone acetate) PO once daily for 24 days. Phase 2: 1 active hormone tablet (0.01 mg ethinyl estradiol) PO once daily for 2 days. Phase 3: 1 iron tablet (75 mg ferrous fumarate) PO once daily for 2 days. Pills should be taken in the order directed on the blister pack. The cycle should be repeated every 28 days. Patients should start the blister pack on the first day of menstrual bleeding. When switching from another oral contraceptive, patients should start taking Lo Loestrin Fe tablets on the same day that a new pack of the previous oral contraceptive would have been started.
Follow dose as for routine contraception. Improvement may not be noticeable for 2—4 months. Prolonged treatment may be needed to control condition.
Follow dose as for routine contraception. Treatment for 6—12 months may be required; OCs have limited utility when the underlying cause of the condition is not related to a hypoestrogenic or hyperandrogenic state.
Follow dose as for routine contraception; alternatively, the active tablets can be given continuously. Combined hormonal contraceptives can reduce endometriosis-associated dyspareunia, dysmenorrhea, and non-menstrual pelvic pain. Treatment for 6—9 months may be needed to induce endometrial atrophy and reduce symptoms.
†Indicates off-label use
1 tablet/day PO.
Not indicated in prepubescent females.
Hormonal contraceptives are contraindicated for use in the presence of active liver disease or markedly impaired liver function.
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
Oral contraceptive (OC) formulations:Tablets and soft gelatin capsules should be swallowed whole.Take at the same time each day to ensure maximum contraceptive efficacy. To minimize nausea, administer with or after the evening meal or at bedtime.Absorption may be incomplete in cases of severe vomiting or diarrhea. If these symptoms occur, additional contraceptive measures should be taken. If vomiting occurs within 3 to 4 hours after administration, this can be regarded as a missed dose.For multi-phasic products, explanation of tablet or capsule sequencing and different tablet or capsule colors may be needed.Contraceptive packs contain iron tablets or capsules. The iron tablets or capsules are included so that the daily dosage cycle can be continuous. This reduces the chance of missed doses. The iron-only doses are taken at the end of the cycle. OC administration instructions for patients:Instruct patient on risks and warnings associated with hormonal contraceptives.Missing pills can cause spotting or light bleeding.The length of time required for using a second method of contraception after drug initiation is slightly different for each manufacturer. In general, a second, non-hormonal form of contraception should be used until active ethinyl estradiol; norethindrone acetate; ferrous fumarate tablets have been taken for at least 7 consecutive days.Each manufacturer has slightly different recommendations for missed pills. Patients should be instructed to review the patient information leaflet that accompanies the prescription each time it is filled. General recommendations for missed OC doses:If one dose is missed, the patient should take it as soon as she remembers and then take the next pill at the regular time as usual. It may be necessary to take 2 tablets or capsules in one day. Some manufacturers recommend that a second method of non-hormonal contraception be used for at least 7 days after restarting the pills.If two doses in a row are missed, 2 tablets or capsules should be taken on both the day the missed doses are remembered and the following day. The regular schedule should then be continued. A second method of non-hormonal contraception should be used for at least 7 days after restarting the pills.If 3 or more doses in a row are missed, the patient should not take the missed pills. Recommendations for restarting the pills can be found in the patient information leaflet that accompanies the prescription each time it is filled. A second method of contraception should be used for at least 7 days after the pills are restarted.
Chewable oral contraceptive (OC) tablets (e.g., Minastrin24 Fe):The tablets may be chewed and swallowed or swallowed whole. Instruct patient to drink a full glass (8 ounces) of water immediately after swallowing the chewed tablet. Contraceptive pack contains 28 tablets. The first 24 pills contain active hormones; the last 4 tablets contain iron.
Blisovi 24 Fe:- Store below 86 degrees FBlisovi Fe:- Store below 86 degrees FEstrostep Fe:- Do not store outside the pouch provided- Protect from light- Store at or below 77 degrees FGildess 24 Fe:- Store below 86 degrees FGildess Fe 1.5/30:- Store below 86 degrees FGildess Fe 1/20:- Store below 86 degrees FJunel Fe 1.5/30:- Store below 86 degrees FJunel Fe 1/20:- Store below 86 degrees FJunel Fe 24:- Store below 86 degrees FLarin Fe:- Store below 86 degrees FLo Loestrin Fe:- Store at 77 degrees F; excursions permitted to 59-86 degrees FLo Minastrin Fe:- Store at 77 degrees F; excursions permitted to 59-86 degrees FLoestrin 24 Fe:- Store below 86 degrees FLoestrin FE 1.5/30:- Store below 86 degrees FLoestrin FE 1/20:- Store below 86 degrees FLomedia 24 Fe:- Store below 86 degrees FMelodetta:- Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees FMibelas 24 Fe:- Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees FMicrogestin 24 Fe:- Store below 86 degrees FMicrogestin Fe 1.5/30:- Store below 86 degrees FMicrogestin Fe 1/20:- Store below 86 degrees FMinastrin:- Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees FTarina Fe 1/20:- Store below 86 degrees FTaytulla:- Store at 77 degrees F; excursions permitted to 59-86 degrees FTilia Fe:- Do not store outside the pouch provided- Protect from light- Store at or below 77 degrees FTri-Legest Fe:- Do not store outside the pouch provided- Protect from light- Store at or below 77 degrees F
Estrogen-progestin combination therapy, including ethinyl estradiol; norethindrone acetate; ferrous fumarate, is contraindicated for use during pregnancy. Increased risk of a wide variety of fetal abnormalities, including modified development of sexual organs, cardiovascular anomalies, and limb defects, have been reported following the use of estrogens or synthetic progestins alone in pregnant women. With the exception of effects on sexual development, the majority of recent studies do not indicate a teratogenic effect of oral contraceptives when taken inadvertently during early pregnancy. In any patient in whom pregnancy is suspected, pregnancy should be ruled out before continuing oral contraceptive use. In addition, oral contraceptive use may change folate metabolism, and women who discontinue oral contraceptives to pursue pregnancy should preferably wait 3 months for folate concentrations to normalize if possible. Folate supplementation should be given once pregnant to reduce the incidence of neural tube defects.
Combined oral contraceptives (COCs) containing ethinyl estradiol; norethindrone acetate are contraindicated in patients with hepatic disease. Because of the association with cholestasis and hepatic neoplasms, estrogens are contraindicated in the presence of hepatocellular cancer, hepatic adenoma, other liver tumors (benign or malignant), or markedly impaired liver function (e.g., uncompensated cirrhosis). Do not use hormonal contraceptives in patients with a history of cholestatic jaundice/pruritus of pregnancy or jaundice from prior hormonal contraceptives; these conditions can recur with subsequent COC use. Discontinue use of ethinyl estradiol; norethindrone acetate; ferrous fumarate if jaundice develops during combined oral contraceptive use. Steroid hormones may be poorly metabolized in patients with liver impairment. Acute or chronic disturbances of liver function may necessitate the discontinuation of COC use until markers of liver function return to normal and COC causation has been excluded. Patients with hepatitis C who are being treated with ombitasvir/paritaprevir/ritonavir, with or without dasabuvir are also contraindicated to receive COCs. During clinical trials with the hepatitis C combination drug regimen that contains ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, ALT elevations greater than 5 times the upper limit of normal (ULN), including some cases greater than 20 times the ULN, were significantly more frequent in women using ethinyl estradiol-containing medications. Discontinue COCs prior to starting hepatitis C therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir; COCs can be restarted approximately 2 weeks following completion of treatment with the hepatitis C combination drug regimen. Hepatic adenomas are associated with COC use. An estimate of the attributable risk is 3.3 cases/100,000 COC users. Rupture of hepatic adenomas may cause death through intra-abdominal hemorrhage. Studies have shown an increased risk of developing hepatocellular carcinoma in long-term (more than 8 years) COC users. However, the attributable risk of liver cancers in COC users is less than 1 case per million users. In general, COCs should be used cautiously in patients with pre-existing gallbladder disease and acute or intermittent porphyria.
Both progestins and estrogens, like ethinyl estradiol (EE), appear to be excreted into breast milk. Manufacturers recommend avoidance of combined hormonal oral contraceptives (OCs) if possible until a mother has completely weaned her child. Small amounts of oral contraceptive steroids have been identified in the milk of nursing mothers and a few reports of effects on the infant exist, including jaundice and breast enlargement. Other experts often recommend avoidance of estrogen-containing hormonal contraceptives, in the first 21 days postpartum (or longer, if other risks for thromboembolism exist) due to maternal post-partum clot risks following obstetric delivery , and the potential for OCs to interfere with the establishment of lactation. It is generally accepted that estrogen-containing combined contraceptives may be used after this period in healthy women without other risk factors; general monitoring of the infant for effects such as appetite changes, breast changes and proper weight gain and growth should occur. Estrogens, including ethinyl estradiol, have been reported to interfere with milk production and duration of lactation in some women, particularly at doses of 30 mcg/day EE or more. One study found that lower dose oral combined contraceptives (e.g., 10 mcg/day EE) may not affect lactation. However, a systematic review concluded that the available evidence, even from randomized controlled trials, is limited and of poor quality; the authors concluded that properly designed and conducted trials are needed to make determinations on the appropriateness of hormonal contraception during lactation and the effects on the health and growth of the infant. However, in general, deleterious effects have not been noted in most infants. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA. Alternate contraceptive agents for consideration include non-hormonal contraceptive methods and also progestin-only contraceptives, such as medroxyprogesterone injection (e.g., Depo-Provera).
Although the effects appear to be minimal in most non-diabetic patients receiving hormone therapy with estrogen-progestin combinations, altered glucose tolerance secondary to decreased insulin sensitivity has been reported. Patients with hyperglycemia or diabetes mellitus should be observed for changes in glucose tolerance when initiating or discontinuing ethinyl estradiol; norethindrone acetate; ferrous fumarate therapy. Because of the increased potential for embolic risk, ethinyl estradiol; norethindrone acetate; ferrous fumarate is contraindicated in patients with diabetes with vascular involvement.
Estrogens generally have a favorable effect on blood lipids, and reduce LDL and increase HDL cholesterol concentrations. Progestins, however, may attenuate some of these effects by raising LDL and may make control of pre-existing hyperlipidemia more difficult. Serum triglycerides increase with estrogen administration. A small proportion of women may have persistent hypertriglyceridemia while using ethinyl estradiol; norethindrone acetate; ferrous fumarate. Patients with familial hyperlipoproteinemia may develop elevations in triglycerides while taking exogenous estrogens which may predispose them to pancreatitis; caution is warranted in these individuals.
Approximately 85% of patients diagnosed with systemic lupus erythematosus (SLE) are females, giving support to the notion that hormonal influences, especially estrogen, contribute to the pathophysiology of SLE. Accordingly, estrogen-progestin therapy has been reported to induce, unmask, and exacerbate lupus; case reports and other anecdotal data indicate that a temporal relationship between exogenous estrogen-progestin therapy and lupus flares exist. However, several retrospective studies dispute a relationship between estrogens causing or exacerbating lupus, and a large prospective, randomized clinical trial (SELENA) evaluating the safety of estrogen therapy has been completed and is being analyzed. Determining the risk of estrogen therapy in SLE patients is important as women with lupus benefit from estrogens; not only do they offer reliable birth control, but they also possibly protect patients requiring chronic corticosteroid therapy from bone fractures and osteoporosis. Women with hypercoagulable states are at increased risk of venous thromboembolism when taking estrogens; given the increased prevalence of hypercoagulable states in patients with SLE (in particular antiphospholipid antibodies and lupus anticoagulant), presence of a hypercoagulable state should be determined prior to initiation of estrogens in this population. Estrogens should be avoided in SLE patients with a history of venous or arterial thrombosis or the presence of a hypercoagulable state. If OCs are initiated in SLE patients without hypercoagulable states, low-dose estrogen contraceptives (i.e., 30—35 mcg of ethinyl estradiol or equivalent) should be used and consideration to a progestin-only contraceptive should be given. In addition, it may be prudent to avoid estrogen therapy in patients with unstable or severe SLE or a history of SLE exacerbation with estrogen therapy until more data regarding the use of estrogens in this population are available. The results of the SELENA trial should provide evidence regarding the use of estrogen therapy in this population.
Patients undergoing elective surgery of a type associated with an increased risk of thromboembolism should usually stop ethinyl estradiol; norethindrone acetate; ferrous fumarate at least 4 weeks prior and 2 weeks after surgery, dependent upon the continued potential for thromboembolic risk. Combination estrogen-progestin therapy should also be stopped during and after any prolonged immobilization.
Combination estrogen-progestin therapy is associated with elevations in blood pressure. Ethinyl estradiol; norethindrone acetate; ferrous fumarate is contraindicated in patients with severe hypertension. Use cautiously in patients with controlled hypertension or kidney disease. Blood pressure should be monitored closely in these individuals. Any significant increase in blood pressure while on estrogen-progestin therapy may require discontinuation of the medication. Estrogen-progestin therapy may also cause fluid retention, and patients predisposed to complications from edema, such as asthma, heart disease, renal disease, migraines, or seizure disorder, should be closely monitored. Ethinyl estradiol; norethindrone; ferrous fumarate is contraindicated in patient with headache, such as migraine that is accompanied by focal neurological symptoms, such as aura. Oral contraceptives may cause the onset or exacerbate a migraine or cause the development of headache with a new pattern which is recurrent, persistent, or severe. The cause of headache requires evaluation by a health care provider. Use hormonal contraceptives with caution in those patients with headaches.
Mood disorders, like depression, may be aggravated in women taking ethinyl estradiol; norethindrone acetate; ferrous fumarate. Women with a history of depression may need special monitoring. Low-dose oral contraceptive products may have minimal effect on depressive symptoms. If significant depression occurs, therapy should be discontinued.
Estrogens can increase the curvature of the cornea and may lead to intolerance of contact lenses. Consistent with potential thrombotic effects of oral contraceptives, there have been clinical case reports of retinal thrombosis or retinal vascular occlusion. Any change in vision or visual acuity should be examined by an ophthalmologist, and periodic eye examination is recommended in most patients during oral contraceptive use. Patients developing any unexplained visual disturbance require evaluation; if retinal vascular occlusion occurs, hormonal oral contraception should be discontinued. Long-term oral contraceptive use may play a potential role in the development of glaucoma. According to research presented at a meeting of the American Acadamy of Opthomology, the use of oral contraceptives for > 3 years, irrespective of formulation, was associated with a reported doubling of the incidence of glaucoma. Research data from the National Health and Nutrition Examination Survey (NHANES) included questionnaire responses administered by the Centers for Disease Control. Survey respondents (3406 women, >= 40 years of age) reported on oral contraceptive use between 2005 and 2008; participants completed the survey's vision and reproductive health questionnaire and underwent eye exams. Women reporting oral contraceptive use for > 3 years were 2.05 times as likely to also report a diagnosis of glaucoma. Although causality was not determined, experts caution patients and providers to be aware of this association and recommend glaucoma screening for patients with additional risk factors. Black patients, patients with a family history of glaucoma, and patients with a history of ocular hypertension or existing visual field defects represent groups with additional risk factors.
Ethinyl estradiol; norethindrone acetate; ferrous fumarate is contraindicated in patients with a history of, or known or suspected breast cancer, as breast cancer is a hormonally-sensitive tumor. All women taking combined oral contraceptives (COCs) should receive clinical breast examinations and perform monthly self-examinations as recommended by their health care professional based on patient age, known risk factors, and current standards of care. There is substantial evidence that use of COCs does not increase the incidence of breast cancer. Although some past studies have suggested that COCs might increase the incidence of breast cancer, more recent studies have not confirmed such findings. Several large, well designed observational studies have provided data regarding the risk of breast cancer with combined oral contraceptive (COC) use. From one large study published in 2017, the risk of breast cancer was higher among women who currently or recently used contemporary hormonal contraceptives than among women who had never used hormonal contraceptives, and this risk increased with longer durations of use; however, absolute increases in risk were small. The absolute risk of breast cancer associated with any hormonal contraceptive use was 13 per 100,000 women-years, which corresponds to 1 extra case of breast cancer for every 7,690 COC users in 1 year. Moreover, the same study data suggest that any increased risk of breast cancer usually disappears rapidly after an interruption in the use of COCs. There continues to be controversy regarding the risk of COC use in women with a family history of breast cancer (e.g., BRCA mutations). However, evidence does not suggest that the increased risk for breast cancer among women with either a family history of breast cancer or breast cancer susceptibility genes is modified by the use of COCs. Patients should be instructed to perform monthly self-breast examination and report any breast changes, lumps, or discharge to their health care professional. If breast cancer is suspected in a woman who is taking hormonal contraceptives, the contraceptive should be discontinued.
Ethinyl estradiol; norethindrone acetate; ferrous fumarate is not recommended in patients with hypercalcemia associated with tumors or metabolic bone disease because estrogens influence the metabolism of calcium and phosphorus. In particular, severe hypercalcemia may occur in patients with breast cancer with bone metastases. If hypercalcemia occurs, the drug should be discontinued and measures taken to reduce the serum calcium level. Estrogens should also be used with caution in individuals with severe hypocalcemia.
Ethinyl estradiol; norethindrone acetate; ferrous fumarate is contraindicated in the presence of cervical cancer or other estrogen-responsive tumors. Most cervical cancers are related to the presence of the human papillomavirus (HPV), but hormonal factors influence risk. In women taking COCs, studies have found an increased risk of cervical cancer compared with never-users. The risk appears to increase with duration of use and appears to decline when COCs are discontinued. Clinical surveillance of all women using COCs is important; all women receiving COC treatment should have an annual pelvic examination and other diagnostic or screening tests, such as cervical cytology, as clinically indicated or as generally recommended based on age, risk factors, and other individual needs.
In those women with known endometrial cancer or other estrogen-dependent tumors (e.g., vaginal cancer, uterine cancer, ovarian cancer), combined hormonal contraceptives are contraindicated, as such tumors are hormonally sensitive. Hormonal contraceptives are contraindicated in women with undiagnosed vaginal bleeding; evaluate such patients before combined hormonal contraceptive use to determine if a contraindication to use exists. The use of combined oral contraceptives (COCs) appears to have a protective effect against some cancers. In women using COCs, a meta-analysis of 10 studies indicates a significant trend in decreasing endometrial and ovarian cancer risk with increasing duration of COC use. The beneficial effects of COCs in this regard may persist for 15 years or more after COC use ceases.
Use ethinyl estradiol; norethindrone acetate; ferrous fumarate with caution in patients with thyroid disease, particularly hypothyroidism. Estrogens can increase thyroid-binding globulin (TBG) levels. Patients with normal thyroid function can compensate for the increased TBG by making more thyroid hormone, thus maintaining free T4 and T3 serum concentrations in the normal range. Patients dependent on thyroid hormone replacement therapy who are also receiving estrogens may require increased doses of their thyroid replacement therapy. These patients should have their thyroid function monitored in order to maintain their free thyroid hormone levels in an acceptable range.
Ethinyl estradiol; norethindrone acetate; ferrous fumarate does not protect against human immunodeficiency virus (HIV) infection or other sexually transmitted diseases. Conversely, patients with known HIV infection or acquired immunodeficiency syndrome (AIDS) should be aware that the use of this hormonal combination will not prevent the transmission of HIV or other diseases to their partner(s).
Preliminary studies have suggested that obesity may be a risk factor for OC (e.g., ethinyl estradiol; norethindrone acetate; ferrous fumarate) failure, particularly with the predominantly lower-dose (i.e., < 50 mcg/day) estrogen formulations available; more studies are needed. Also, pre-existing morbid obesity can be one factor that may increase cardiovascular or thromboembolic risks associated with combination hormonal contraceptive or estrogen use in selected individuals.
Chloasma may occasionally occur, especially in women with a history of chloasma gravidarum. Women with a tendency for chloasma should avoid sunlight (UV) exposure while taking ethinyl estradiol; norethindrone acetate; ferrous fumarate.
Cases of both anaphylactic reactions and angioedema have been reported in patients taking exogenous estrogens. Events have developed in minutes and have required emergency medical treatment. Ethinyl estradiol is generally contraindicated in patients who have a history of anaphylaxis or history of angioedema to the drug. In addition, exogenous estrogens may induce or exacerbate symptoms of angioedema, particularly in women with hereditary angioedema, which may be hormonally sensitive.
The safety and efficacy of ethinyl estradiol; norethindrone acetate; ferrous fumarate contraceptives have not been established in neonates, infants, or pre-menarchal female children. Ethinyl estradiol; norethindrone acetate; ferrous fumarate may be used in post-menarchal female children and adolescents. The safety and efficacy of oral contraceptive products have only been established in females of reproductive age. Safety and efficacy of ethinyl estradiol; norethindrone acetate; ferrous fumarate is expected to be the same for postpubertal children under the age of 16 and for users 16 years of age and older. Estrogens are not indicated in young children because estrogens promote epiphysial closure. Per the manufacturers, serious ill effects have not been reported following the acute ingestion of large oral doses of estrogen-progestin containing products by young children.
thrombosis / Delayed / 0-1.0thromboembolism / Delayed / 0-1.0pulmonary embolism / Delayed / 0-1.0myocardial infarction / Delayed / 0-1.0stroke / Early / 0-1.0intracranial bleeding / Delayed / 0-1.0visual impairment / Early / 0-1.0retinal thrombosis / Delayed / 0-1.0optic neuritis / Delayed / 0-1.0papilledema / Delayed / 0-1.0hepatoma / Delayed / 0-1.0pancreatitis / Delayed / 0-1.0porphyria / Delayed / 0-1.0suicidal ideation / Delayed / Incidence not knownerythema nodosum / Delayed / Incidence not knownerythema multiforme / Delayed / Incidence not knownanaphylactoid reactions / Rapid / Incidence not knownangioedema / Rapid / Incidence not knownbowel ischemia / Delayed / Incidence not knowncholecystitis / Delayed / Incidence not knownnew primary malignancy / Delayed / Incidence not knownlupus-like symptoms / Delayed / Incidence not known
vaginitis / Delayed / 1.0-10.0depression / Delayed / 1.0-10.0candidiasis / Delayed / 6.1-6.1galactorrhea / Delayed / 0-1.0cataracts / Delayed / 0-1.0hepatitis / Delayed / 0-1.0peliosis hepatis / Delayed / 0-1.0jaundice / Delayed / 0-1.0elevated hepatic enzymes / Delayed / 0-1.0lactation suppression / Early / Incidence not knownpalpitations / Early / Incidence not knownhypertension / Early / Incidence not knownfluid retention / Delayed / Incidence not knownsinus tachycardia / Rapid / Incidence not knownchest pain (unspecified) / Early / Incidence not knownedema / Delayed / Incidence not knownmigraine / Early / Incidence not knownperipheral edema / Delayed / Incidence not knowncholelithiasis / Delayed / Incidence not knowncolitis / Delayed / Incidence not knownhypertriglyceridemia / Delayed / Incidence not knownhyperlipidemia / Delayed / Incidence not knowncholestasis / Delayed / Incidence not knowncervical dysplasia / Delayed / Incidence not knowncystitis / Delayed / Incidence not known
amenorrhea / Delayed / 22.0-36.0breakthrough bleeding / Delayed / 24.0-35.0menorrhagia / Delayed / 1.0-10.0pelvic pain / Delayed / 1.0-10.0menstrual irregularity / Delayed / 1.0-10.0breast enlargement / Delayed / 1.0-10.0vaginal discharge / Delayed / 1.0-10.0leukorrhea / Delayed / 1.0-10.0vaginal irritation / Early / 1.0-10.0appetite stimulation / Delayed / 1.0-10.0libido decrease / Delayed / 1.0-10.0fatigue / Early / 1.0-10.0irritability / Delayed / 1.0-10.0libido increase / Delayed / 1.0-10.0anxiety / Delayed / 1.0-10.0asthenia / Delayed / 1.0-10.0emotional lability / Early / 1.0-10.0abdominal pain / Early / 1.0-10.0vomiting / Early / 1.0-10.0headache / Early / 6.3-6.3nausea / Early / 4.6-4.6dysmenorrhea / Delayed / 4.4-4.4mastalgia / Delayed / 3.4-3.4acne vulgaris / Delayed / 2.7-2.7weight gain / Delayed / 2.0-2.0breast discharge / Delayed / 0-1.0diplopia / Early / 0-1.0insomnia / Early / Incidence not knowndizziness / Early / Incidence not knownmalaise / Early / Incidence not knownmaculopapular rash / Early / Incidence not knownmelasma / Delayed / Incidence not knownhirsutism / Delayed / Incidence not knownrash / Early / Incidence not knownphotosensitivity / Delayed / Incidence not knownurticaria / Rapid / Incidence not knownalopecia / Delayed / Incidence not knownpruritus / Rapid / Incidence not knownanorexia / Delayed / Incidence not knownweight loss / Delayed / Incidence not knowndyspepsia / Early / Incidence not knowndiarrhea / Early / Incidence not knownarthralgia / Delayed / Incidence not knownback pain / Delayed / Incidence not knownmyalgia / Early / Incidence not knownmusculoskeletal pain / Early / Incidence not knowngingivitis / Delayed / Incidence not knownsinusitis / Delayed / Incidence not knownrhinitis / Early / Incidence not known
The primary action of the combination of an estrogen with a progestin is to suppress the hypothalamic-pituitary system, decreasing the secretion of gonadotropin-releasing hormone (GnRH). Progestins blunt luteinizing hormone (LH) release, and estrogens suppress follicle-stimulating hormone (FSH) from the anterior pituitary. Both estrogen and progestin ultimately inhibit maturation and release of the dominant ovule. In addition, viscosity of the cervical mucus increases with hormonal contraceptive use, which increases the difficulty of sperm entry into the uterus. Alteration in endometrial tissues also occurs, which reduces the likelihood of implantation of the fertilized ovum. The contraceptive effect is reversible. When traditional regimens of oral contraception are discontinued, ovulation usually returns within three menstrual cycles but can take up to 6 months in some women. Pituitary function and ovarian functions recover more quickly than endometrial activity, which can take up to 3 months to regain normal histology. Both estrogens and progestins are responsible for a number of other metabolic changes. The summary of these changes is dependent on the net actions of the estrogen and progestin combinations. Such total effects may only be clinically significant for some predisposed individuals. At the cellular level, estrogens and progestins diffuse into their target cells and interact with a protein receptor. Metabolic responses to estrogens and progestins require an interaction between DNA and the hormone-receptor complex. Target cells include the female reproductive tract, the mammary gland, the hypothalamus, and the pituitary. Estrogens increase the hepatic synthesis of sex hormone binding globulin (SHBG), thyroid-binding globulin (TBG), and other serum proteins. Estrogens generally have a favorable effect on blood lipids, and lack of estrogen is now recognized as a risk factor for myocardial infarction. Estrogens reduce LDL and increase HDL cholesterol concentrations. Serum triglycerides increase with estrogen administration. Folate metabolism and excretion is increased by estrogens and may lead to slight serum folate deficiency. Estrogens also enhance sodium and fluid retention. Progestins are classified according to their progestational, estrogenic and androgenic properties. Progestins can alter hepatic carbohydrate metabolism, increase insulin resistance, and have either little to slightly favorable effects on serum lipoproteins. Less androgenic progestins have only slight effects on carbohydrate metabolism. More androgenic progestins can aggravate acne. Serious adverse events, like thrombosis, have long been associated with the estrogen component of oral contraceptives but may be the result of both estrogen and progestin components. The mechanism for thrombosis may be associated with increased clotting factor production and/or decreases in anti-thrombin III. Minor side effects can be addressed by choosing formulations that take advantage of relative estrogen, progestin, and androgenic potencies.
Ethinyl estradiol; norethindrone acetate; ferrous fumarate is administered orally.Ethinyl estradiol: Ethinyl estradiol is widely distributed. Ethinyl estradiol is highly but non-specifically protein-bound to albumin. Ethinyl estradiol induces an increase in the serum concentrations of both sex hormone-binding globulin (SHBG) and corticosteroid binding globulin (CBG). Ethinyl estradiol is primarily metabolized in the liver via CYP3A4 to 2-hydroxy-ethinyl estradiol. Both ethinyl estradiol and its hydroxylated and methylated metabolites undergo glucuronide and sulfate conjugation. Estrogen conjugates can be hydrolyzed back to the active drug in the GI tract and then undergo entero-hepatic recycling. Excretion of estrogen-progestin steroids as inactive metabolites occurs via the urine and feces. Elimination half-life is approximately 26 hours for ethinyl estradiol at steady state. It is the prolonged biologic effects of the hormone that allows for once-daily administration.Norethindrone acetate: Norethindrone acetate is a prodrug that requires conversion to norethindrone via hydrolysis to become the active drug, norethindrone. Norethindrone is widely distributed. Norethindrone is strongly protein-bound, primarily to albumin and sex hormone-binding globulin (SHBG). Approximately 10% of norethindrone is metabolized by oxidative reduction, and the remainder via conjugation to the sulfate and glucuronate salts. No appreciable entero-hepatic recycling occurs. Interestingly, norethindrone is aromatized to a slight degree in tissues of the liver and ovary to ethinyl estradiol. This may be of clinical significance. Excretion of estrogen-progestin steroids as inactive metabolites occurs via the urine and feces. Elimination half-life is approximately 5 to 14 hours for norethindrone at steady state. It is the prolonged biologic effects of the hormone that allows for once-daily administration. Affected cytochrome P450 (CYP450) isoenzymes and drug transporters: CYP3A4, CYP2B6, CYP2C19, CYP2C9, P-glycoprotein (P-gp)Ethinyl Estradiol: In vitro and in vivo studies indicate that estrogens are partially metabolized by CYP3A4. Interactions with drugs that are inhibitors or inducers of CYP3A4 are possible. Ethinyl estradiol is a substrate of the drug transporter P-gp. While ethinyl estradiol is an in vitro inhibitor of CYP2B6, 2C19, and 3A4 and an in vitro substrate of 2C9, clinically significant drug interactions are not expected through these pathways.
ethinyl estradiol: Ethinyl estradiol is absorbed with maximum plasma concentrations generally occurring 1—2 hours post dose. Administration of food with the Lo Loestrin Fe tablet that contains only ethinyl estradiol decreased the maximum concentration of ethinyl estradiol by 31%; when the Lo Loestrin FE combination tablet was administered with food, the maximum concentration of ethinyl estradiol decreased by 23%. The extent of absorption for either tablet was not affected. Following oral administration in the third cycle of use as an oral contraceptive, 83% of ethinyl estradiol survives absorption and first pass through the liver. Estrogens are metabolized in the GI mucosa during absorption and in the liver. The major 1st-pass metabolite of ethinyl estradiol is its sulfate conjugate.norethindrone acetate: Norethindrone acetate is absorbed with maximum plasma concentrations generally occurring 1—2 hours post dose. Administration of the Lo Loestrin combination tablets with food did not affect the maximum concentration of norethindrone and increased the extent of absorption by 24%. Following oral administration in the third cycle of use as an oral contraceptive, 47—73% of norethindrone acetate survives absorption and first pass through the liver. Norethindrone acetate is completely and rapidly deacetylated to its active form, norethindrone, after oral administration.