CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`022501Orig1s000
`
`LABELING
`
`
`
`
`

`

`--------------------WARNINGS AND PRECAUTIONS---------------------
`•
`Vascular risks: Stop Lo Loestrin Fe if a thrombotic event occurs. Stop
`Lo Loestrin Fe at least 4 weeks before through 2 weeks after major
`surgery. Start Lo Loestrin Fe no earlier than 4 weeks after delivery, in
`women who are not breastfeeding. (5.1)
`Liver disease: Discontinue Lo Loestrin Fe if jaundice occurs. (5.3)
`High blood pressure: Do not prescribe Lo Loestrin Fe for women with
`uncontrolled hypertension or hypertension with vascular disease. (5.4)
`Carbohydrate and lipid metabolic effects: Monitor prediabetic and
`diabetic women taking Lo Loestrin Fe. Consider an alternative
`contraceptive method for women with uncontrolled dyslipidemia. (5.6)
`Headache: Evaluate significant change in headaches and discontinue Lo
`Loestrin Fe if indicated. (5.7)
`•
`Uterine bleeding: Evaluate irregular bleeding or amenorrhea. (5.8)
`------------------------ADVERSE REACTIONS------------------------------
`The most common adverse reactions (≥ 2%) are nausea/vomiting (7%),
`headache (7%), bleeding irregularities (5%), dysmenorrhea (4%), weight
`change (4%, breast tenderness (4%), acne (3%), abdominal pain (3%), anxiety
`(2%) and depression (2%). (6)
`To report SUSPECTED ADVERSE REACTIONS, contact Warner
`Chilcott at 1-800-521-8813 or FDA at 1-800-FDA-1088 or
`www.fda.gov/medwatch.
`----------------------------DRUG INTERACTIONS---------------------------
`•
`Drugs or herbal products that induce certain enzymes, including
`CYP3A4, may decrease the effectiveness of COCs or increase
`breakthrough bleeding. Counsel patients to use a back-up method or
`alternative method of contraception when enzyme inducers are used with
`COCs. (7.1)
`-------------------USE IN SPECIFIC POPULATIONS---------------------
`•
`Nursing mothers: Not recommended; can decrease milk production
`(8.3)
`See 17 for PATIENT COUNSELING INFORMATION and FDA-
`Approved Patient Labeling.
`
`
`
`
`
`
`
`
`
`Revised: 10/2010
`
`•
`•
`
`•
`
`•
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use Lo
`Loestrin Fe safely and effectively. See full prescribing information for Lo
`Loestrin Fe.
`LO LOESTRIN FE (norethindrone acetate and ethinyl estradiol tablets,
`ethinyl estradiol tablets and ferrous fumarate tablets)
`Initial U.S. Approval: 1968
`
`WARNING: CIGARETTE SMOKING AND SERIOUS
`CARDIOVASCULAR EVENTS
`See full prescribing information for complete boxed warning.
`• Women over 35 years old who smoke should not use Lo Loestrin Fe.
`(4)
`Cigarette smoking increases the risk of serious cardiovascular
`events from combination oral contraceptive (COC) use. (4)
`
`•
`
`•
`•
`
`-----------------------INDICATIONS AND USAGE--------------------------
`• Lo Loestrin Fe is an estrogen/progestin COC indicated for use by women
`to prevent pregnancy. (1)
`• The efficacy of Lo Loestrin Fe in women with a body mass index of
`> 35 kg/m2 has not been evaluated (1, 8.8).
`------------------DOSAGE AND ADMINISTRATION---------------------
`•
`Take one tablet by mouth at the same time every day for 28 days. (2.1)
`•
`Take tablets in the order directed on the blister pack. (2.1)
`-------------------DOSAGE FORM AND STRENGTH---------------------
`Lo Loestrin Fe consists of 28 tablets in the following order (3):
`•
`24 blue tablets (active), each containing 1 mg norethindrone acetate and
`10 mcg ethinyl estradiol
`2 white tablets (active), each containing 10 mcg ethinyl estradiol
`2 brown tablets (non-hormonal placebo), each containing 75 mg ferrous
`fumarate. The ferrous fumarate tablets do not serve any therapeutic
`purpose
`------------------------CONTRAINDICATIONS------------------------------
`•
`A high risk of arterial or venous thrombotic diseases (4)
`•
`Breast cancer or other estrogen- or progestin-sensitive cancer (4)
`•
`Liver tumors or liver disease (4)
`•
`Undiagnosed abnormal uterine bleeding (4)
`•
`Pregnancy (4)
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`WARNING: CIGARETTE SMOKING AND SERIOUS
`CARDIOVASCULAR EVENTS
`1
`INDICATIONS AND USAGE
`2 DOSAGE AND ADMINISTRATION
`2.1 How to Take Lo Loestrin Fe
`2.2 How to Start Lo Loestrin Fe
`2.3
`Switching from another Hormonal Method of Contraception
`2.4 Advice in Case of Gastrointestinal Disturbances
`2.5
`For additional patient instructions regarding missed pills
`2.6 Use after pregnancy, abortion or miscarriage
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`5.1 Thrombotic and Other Vascular Events
`5.2 Carcinoma of the Breasts and Cervix
`5.3 Liver Disease
`5.4 High Blood Pressure
`5.5 Gallbladder Disease
`5.6 Carbohydrate and Lipid Metabolic Effects
`5.7 Headache
`5.8 Bleeding Irregularities and Amenorrhea
`5.9 COC Use before or during Early Pregnancy
`5.10 Depression
`5.11
`Interference with Laboratory Tests
`5.12 Monitoring
`5.13 Other Conditions
`6 ADVERSE REACTIONS
`6.1 Clinical Trial Experience
`
`
`
`
`
`
`
`7.2
`
`7 DRUG INTERACTIONS
`7.1 Changes in Contraceptive Effectiveness Associated with Co-
`Administration of Other Products
`Increase in Plasma Levels of Ethinyl Estradiol Associated with Co-
`Administered Drugs
`7.3 Changes in Plasma Levels of Co-Administered Drugs
`8 USE IN SPECIFIC POPULATIONS
`8.1
`Pregnancy
`8.3 Nursing Mothers
`8.4
`Pediatric Use
`8.5 Geriatric Use
`8.6 Renal Impairment
`8.7 Hepatic Impairment
`8.8 Body Mass Index
`10 OVERDOSAGE
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.2 Pharmacodynamics
`12.3 Pharmacokinetics
`13 NONCLINICAL TOXICOLOGY
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`14 CLINICAL STUDIES
`16 HOW SUPPLIED/STORAGE AND HANDLING
`16.1 How Supplied
`16.2 Storage Conditions
`17 PATIENT COUNSELING INFORMATION
`
`*Sections or subsections omitted from the full prescribing information are not
`listed.
`
`

`

`FULL PRESCRIBING INFORMATION
`
`
`
`WARNING: CIGARETTE SMOKING AND SERIOUS
`CARDIOVASCULAR EVENTS
`Cigarette smoking increases the risk of serious cardiovascular events from combination
`oral contraceptive (COC) use. This risk increases with age, particularly in women over
`35 years of age, and with the number of cigarettes smoked. For this reason, COCs
`should not be used by women who are over 35 years of age and smoke. [See
`Contraindications (4).]
`
` 1
`
` 2
`
`
`INDICATIONS AND USAGE
`Lo Loestrin Fe is indicated for use by women to prevent pregnancy [see Clinical Studies
`(14)].
`
`The efficacy of Lo Loestrin Fe in women with a body mass index (BMI) of > 35 kg/m2 has
`not been evaluated.
`
` DOSAGE AND ADMINISTRATION
`2.1 How to Take Lo Loestrin Fe
`To achieve maximum contraceptive effectiveness, Lo Loestrin Fe must be taken exactly as
`directed. Take one tablet by mouth at the same time every day. Tablets must be taken in the
`order directed on the blister pack. Tablets should not be skipped or taken at intervals
`exceeding 24 hours. For patient instructions for missed pills, see FDA-Approved Patient
`Labeling. Lo Loestrin Fe tablets may be administered without regard to meals [see Clinical
`Pharmacology (12.3)].
`
`2.2 How to Start Lo Loestrin Fe
`Instruct the patient to begin taking Lo Loestrin Fe on Day 1 of her menstrual cycle (that is,
`the first day of her menstrual bleeding) [see FDA-Approved Patient Labeling]. One blue
`tablet should be taken daily for 24 consecutive days, followed by one white tablet daily for
`2 consecutive days, followed by one brown tablet daily for 2 consecutive days. Instruct the
`patient to use a non-hormonal contraceptive as back-up during the first 7 days if she starts
`taking Lo Loestrin Fe other than on the first day of her menstrual cycle.
`
`For postpartum women who do not breastfeed or after a second trimester abortion, Lo
`Loestrin Fe may be started no earlier than 4 weeks postpartum. Recommend use of a non-
`hormonal back-up method for the first 7 days. When COCs are used during the postpartum
`period, the increased risk of thromboembolic disease associated with the postpartum period
`must be considered [see Warnings and Precautions (5.1)]. The possibility of ovulation and
`conception before starting COCs should also be considered.
`Lo Loestrin Fe may be initiated immediately after a first-trimester abortion or miscarriage; if
`the patient starts Lo Loestrin Fe immediately, additional contraceptive measures are not
`needed.
`
`

`

`
`2.3 Switching from another Hormonal Method of Contraception
`If the patient is switching from a combination hormonal method such as:
`° Another pill
`° Vaginal ring
`° Patch
`Instruct her to take the first blue tablet on the day she would have taken her next COC
`pill. She should not continue taking the tablets from her previous birth control pack, and
`should not skip any days between packs. If she does not have a withdrawal bleed, rule out
`pregnancy before starting Lo Loestrin Fe.
`If she previously used a vaginal ring or transdermal patch, she should start using Lo
`Loestrin Fe on the day she would have resumed the previous product.
`
`•
`
`•
`
`•
`
`•
`
`
`If the patient is switching from a progestin-only method such as a:
`° Progestin-only pill
`° Implant
`° Intrauterine system
`° Injection
`Instruct her to take the first blue tablet on the day she would have taken her next
`progestin-only pill, or had her next injection or on the day of removal of her implant.
`If switching from an IUD, depending on the timing of removal, back-up contraception
`may be needed.
`
`
`2.4 Advice in Case of Gastrointestinal Disturbances
`If the patient vomits or has diarrhea (within 3 to 4 hours after she takes a blue or white pill),
`she should follow the instructions in the “What to Do if You Miss Pills” section [see FDA-
`Approved Patient Labeling].
`
` 3
`
` DOSAGE FORMS AND STRENGTHS
`Lo Loestrin Fe (norethindrone acetate and ethinyl estradiol tablets, ethinyl estradiol tablets
`and ferrous fumarate tablets) are available in blister packs.
`
`Each blister pack (28 tablets) contains in the following order:
`• 24 blue, round (active) tablets imprinted with “WC” on one side and “421” on the other
`and each containing 1 mg norethindrone acetate and 10 mcg ethinyl estradiol.
`• 2 white, hexagonal (active) tablets imprinted with “WC” on one side and “422” on the
`other and each containing 10 mcg ethinyl estradiol.
`• 2 brown, round (non-hormonal placebo) tablets imprinted with “WC” on one side and
`“624” on the other and each containing 75 mg ferrous fumarate. The ferrous fumarate
`tablets do not serve any therapeutic purpose.
`
`
`
`

`

`4 CONTRAINDICATIONS
`Do not prescribe Lo Loestrin Fe to women who are known to have the following conditions:
`• A high risk of arterial or venous thrombotic diseases. Examples include women who are
`known to:
`• Smoke, if over age 35 [see Boxed Warning and Warnings and Precautions (5.1)]
`• Have deep vein thrombosis or pulmonary embolism, now or in the past [see Warnings
`and Precautions (5.1)]
`• Have cerebrovascular disease [see Warnings and Precautions (5.1)]
`• Have coronary artery disease [see Warnings and Precautions (5.1)]
`• Have thrombogenic valvular or thrombogenic rhythm diseases of the heart (for
`example, subacute bacterial endocarditis with valvular disease, or atrial fibrillation)
`[see Warnings and Precautions (5.1)]
`• Have inherited or acquired hypercoagulopathies [see Warnings and Precautions
`(5.1)]
`• Have uncontrolled hypertension [see Warnings and Precautions (5.4)]
`• Have diabetes mellitus with vascular disease [see Warnings and Precautions (5.6)]
`• Have headaches with focal neurological symptoms or have migraine headaches with
`or without aura if over age 35 [see Warnings and Precautions (5.7)]
`• Breast cancer or other estrogen- or progestin-sensitive cancer, now or in the past [see
`Warnings and Precautions (5.2)]
`• Liver tumors, benign or malignant, or liver disease [see Warnings and Precautions (5.3)]
`• Undiagnosed abnormal uterine bleeding [see Warnings and Precautions (5.8)]
`• Pregnancy, because there is no reason to use COCs during pregnancy [see Warnings and
`Precautions (5.9) and Use in Specific Populations (8.1)]
`
` WARNINGS AND PRECAUTIONS
`5.1 Thrombotic and Other Vascular Events
`Stop Lo Loestrin Fe if an arterial or deep venous thrombotic event occurs. Although use of
`COCs increases the risk of venous thromboembolism, pregnancy increases the risk of venous
`thromboembolism as much or more than the use of COCs. The risk of venous
`thromboembolism in women using COCs is 3 to 9 per 10,000 woman-years. The risk is
`highest during the first year of use of a COC. Use of COCs also increases the risk of arterial
`thromboses such as strokes and myocardial infarctions, especially in women with other risk
`factors for these events. The risk of thromboembolic disease due to oral contraceptives
`gradually disappears after COC use is discontinued.
`
`If feasible, stop Lo Loestrin Fe at least 4 weeks before and through 2 weeks after major
`surgery or other surgeries known to have an elevated risk of thromboembolism.
`
`Start Lo Loestrin Fe no earlier than 4 weeks after delivery, in women who are not
`breastfeeding. The risk of postpartum thromboembolism decreases after the third postpartum
`week, whereas the risk of ovulation increases after the third postpartum week.
`
`
` 5
`
`

`

`COCs have been shown to increase both the relative and attributable risks of cerebrovascular
`events (thrombotic and hemorrhagic strokes), although, in general, the risk is greatest in older
`(> 35 years of age), hypertensive women who also smoke. COCs also increase the risk for
`stroke in women with underlying risk factors.
`
`Oral contraceptives must be used with caution in women with cardiovascular disease risk
`factors.
`
`Stop Lo Loestrin Fe if there is unexplained loss of vision, proptosis, diplopia, papilledema, or
`retinal vascular lesions. Evaluate for retinal vein thrombosis immediately.
`
`5.2 Carcinoma of the Breast and Cervix
`Women who currently have or have had breast cancer should not use Lo Loestrin Fe because
`breast cancer is a hormonally-sensitive tumor.
`
`There is substantial evidence that COCs do 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.
`
`Some studies suggest that COCs are associated with an increase in the risk of cervical cancer
`or intraepithelial neoplasia. However, there is controversy about the extent to which these
`findings may be due to differences in sexual behavior and other factors.
`
`5.3 Liver Disease
`Discontinue Lo Loestrin Fe if jaundice develops. Steroid hormones may be poorly
`metabolized in patients with impaired liver function. 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.
`
`Hepatic adenomas are associated with COC use. An estimate of the attributable risk is
`3.3 cases per 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
`(>8 years) COC users. However, the attributable risk of liver cancers in COC users is less
`than one case per million users.
`
`Oral contraceptive-related cholestasis may occur in women with a history of pregnancy-
`related cholestasis. Women with a history of COC-related cholestasis may have the
`condition recur with subsequent COC use.
`
`5.4 High Blood Pressure
`For women with well-controlled hypertension, monitor blood pressure and stop Lo Loestrin
`Fe if blood pressure rises significantly. Women with uncontrolled hypertension or
`hypertension with vascular disease should not use COCs.
`
`
`

`

`An increase in blood pressure has been reported in women taking COCs, and this increase is
`more likely in older women with extended duration of use. The incidence of hypertension
`increases with increasing concentrations of progestin.
`
`5.5 Gallbladder Disease
`Studies suggest a small increased relative risk of developing gallbladder disease among COC
`users.
`
`5.6 Carbohydrate and Lipid Metabolic Effects
`Carefully monitor prediabetic and diabetic women who are taking Lo Loestrin Fe. COCs
`may decrease glucose tolerance in a dose-related fashion.
`
`Consider alternative contraception for women with uncontrolled dyslipidemias. A small
`proportion of women will have adverse lipid changes while on COCs.
`
`Women with hypertriglyceridemia, or a family history thereof, may be at an increased risk of
`pancreatitis when using COCs.
`
`5.7 Headache
`If a woman taking Lo Loestrin Fe develops new headaches that are recurrent, persistent, or
`severe, evaluate the cause and discontinue Lo Loestrin Fe if indicated.
`
`An increase in frequency or severity of migraine during COC use (which may be prodromal
`of a cerebrovascular event) may be a reason for immediate discontinuation of the COC.
`
`5.8 Bleeding Irregularities and Amenorrhea
`Unscheduled (breakthrough or intracyclic) bleeding and spotting sometimes occur in patients
`on COCs, especially during the first three months of use. If bleeding persists or occurs after
`previously regular cycles, check for causes such as pregnancy or malignancy. If pathology
`and pregnancy are excluded, bleeding irregularities may resolve over time or with a change
`to a different COC.
`
`The clinical trial that evaluated the efficacy of Lo Loestrin Fe also assessed unscheduled
`bleeding and/or spotting. The participants in this 12-month clinical trial (N=1,582 who had
`at least one post-treatment evaluation) completed over 15,000 cycles of exposure.
`
` A
`
` total of 1,257 women (85.9%) experienced unscheduled bleeding and/or spotting at some
`time during Cycles 2-13 of this study. The incidence of unscheduled bleeding and/or
`spotting was highest during Cycle 2 (53%) and lowest at Cycle 13 (36%). Among these
`women, the mean number of days of unscheduled bleeding and/or spotting during a 28-day
`cycle ranged from 1.8 to 3.2 days.
`
`Scheduled (withdrawal) bleeding and/or spotting remained fairly constant over the one year
`study, with an average of less than 2 days per cycle.
`
`
`

`

`Women who are not pregnant and use Lo Loestrin Fe may experience amenorrhea (absence
`of scheduled and unscheduled bleeding/spotting). In the clinical trial with Lo Loestrin Fe,
`the incidence of amenorrhea increased from 32% in Cycle 1 to 49% by Cycle 13. If
`scheduled (withdrawal) bleeding does not occur, consider the possibility of pregnancy. If the
`patient has not adhered to the prescribed dosing schedule (missed one or more active tablets
`or started taking them on a day later than she should have), consider the possibility of
`pregnancy at the time of the first missed period and take appropriate diagnostic measures. If
`the patient has adhered to the prescribed regimen and misses two consecutive periods, rule
`out pregnancy.
`
`Some women may experience amenorrhea or oligomenorrhea after stopping COCs,
`especially when such a condition was preexistent.
`
`5.9 COC Use before or during Early Pregnancy
`Extensive epidemiologic studies have revealed no increased risk of birth defects in women
`who have used oral contraceptives prior to pregnancy. Studies also do not suggest a
`teratogenic effect, particularly in so far as cardiac anomalies and limb reduction defects are
`concerned, when oral contraceptives are taken inadvertently during early pregnancy. Lo
`Loestrin Fe use should be discontinued if pregnancy is confirmed.
`
`Administration of oral contraceptives to induce withdrawal bleeding should not be used as a
`test for pregnancy [see Use in Specific Populations (8.1)].
`
`5.10 Depression
`Women with a history of depression should be carefully observed and Lo Loestrin Fe
`discontinued if depression recurs to a serious degree.
`
`5.11 Interference with Laboratory Tests
`The use of COCs may change the results of some laboratory tests, such as coagulation
`factors, lipids, glucose tolerance, and binding proteins. Women on thyroid hormone
`replacement therapy may need increased doses of thyroid hormone because serum
`concentrations of thyroid binding globulin increase with use of COCs.
`
`5.12 Monitoring
`A woman who is taking COCs should have a yearly visit with her healthcare provider for a
`blood pressure check and for other indicated healthcare.
`
`5.13 Other Conditions
`In women with hereditary angioedema, exogenous estrogens may induce or exacerbate
`symptoms of angioedema. Chloasma may occasionally occur, especially in women with a
`history of chloasma gravidarum. Women with a tendency to chloasma should avoid
`exposure to the sun or ultraviolet radiation while taking COCs.
`
`
`

`

`6 ADVERSE REACTIONS
`The following serious adverse reactions with the use of COCs are discussed elsewhere in the
`labeling:
`• Serious cardiovascular events and smoking [see Boxed Warning and Warnings and
`Precautions (5.1)]
`• Vascular events [see Warnings and Precautions (5.1)]
`• Liver disease [see Warnings and Precautions (5.3)]
`
`Adverse reactions commonly reported by COC users are:
`• Irregular uterine bleeding
`• Nausea
`• Breast tenderness
`• Headache
`
`6.1 Clinical Trial Experience
`Because clinical trials are conducted under widely varying conditions, adverse reaction rates
`observed in the clinical trials of a drug cannot be directly compared to the rates in the clinical
`trials of another drug and may not reflect the rates observed in practice.
`
` multicenter phase 3 clinical trial evaluated the safety and efficacy of Lo Loestrin Fe for
`pregnancy prevention. The study was a one year, open-label, single-arm, uncontrolled study.
`A total of 1,660 women aged 18 to 45 were enrolled and took at least one dose of Lo Loestrin
`Fe. [See Clinical Studies (14.1).]
`
`Common Adverse Reactions (≥ 2% of all Treated Subjects): The most common adverse
`reactions reported by at least 2% of the 1,660 women using Lo Loestrin Fe were the
`following in order of decreasing incidence: nausea/vomiting (7%), headache (7%), bleeding
`irregularities (including metrorrhagia, irregular menstruation, menorrhagia, vaginal
`hemorrhage and dysfunctional uterine bleeding) (5%), dysmenorrhea (4%), weight
`fluctuation (4%), breast tenderness (4%), acne (3%), abdominal pain (3%), anxiety (2%), and
`depression (2%).
`
`Adverse Reactions Leading to Study Discontinuation: 10.7% of the women discontinued
`from the clinical trial due to an adverse reaction. Adverse reactions occurring in ≥1% of
`subjects leading to discontinuation of treatment were in decreasing order: menstrual
`irregularities (including metrorrhagia, irregular menstruation, menorrhagia and vaginal
`hemorrhage) (4%), headache/migraine (1%), mood disorder (including mood swings,
`depression, anxiety) (1%), and weight fluctuation (1%).
`
`Serious Adverse Reactions: deep vein thrombosis, ovarian vein thrombosis, cholecystitis
`
` A
`
` 7
`
` DRUG INTERACTIONS
`No drug-drug interaction studies were conducted with Lo Loestrin Fe.
`
`
`

`

`7.1 Changes in Contraceptive Effectiveness Associated with Co-Administration of
`Other Products
`If a woman on hormonal contraceptives takes a drug or herbal product that induces enzymes,
`including CYP3A4, that metabolize contraceptive hormones, counsel her to use additional
`contraception or a different method of contraception. Drugs or herbal products that induce
`such enzymes may decrease the plasma concentrations of contraceptive hormones, and may
`decrease the effectiveness of hormonal contraceptives or increase breakthrough bleeding.
`Some drugs or herbal products that may decrease the effectiveness of hormonal
`contraceptives include:
`• barbiturates
`• bosentan
`• carbamazepine
`• felbamate
`• griseofulvin
`• oxcarbazepine
`• phenytoin
`• rifampin
`• St. John’s wort
`• topiramate
`
`
`HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors: Significant
`changes (increase or decrease) in the plasma levels of the estrogen and progestin have been
`noted in some cases of co-administration of HIV protease inhibitors or of non-nucleoside
`reverse transcriptase inhibitors.
`
`Antibiotics: There have been reports of pregnancy while taking hormonal contraceptives and
`antibiotics, but clinical pharmacokinetic studies have not shown consistent effects of
`antibiotics on plasma concentrations of synthetic steroids.
`
`Consult the labeling of all concurrently-used drugs to obtain further information about
`interactions with hormonal contraceptives or the potential for enzyme alterations.
`
`7.2
`
`Increase in Plasma Levels of Ethinyl Estradiol Associated with Co-Administered
`Drugs
`Co-administration of atorvastatin and certain COCs containing ethinyl estradiol increase
`AUC values for ethinyl estradiol by approximately 20%. Ascorbic acid and acetaminophen
`may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. CYP3A4
`inhibitors such as itraconazole or ketoconazole may increase plasma hormone levels.
`
`7.3 Changes in Plasma Levels of Co-Administered Drugs
`COCs containing some synthetic estrogens (e.g., ethinyl estradiol) may inhibit the
`metabolism of other compounds. COCs have been shown to significantly decrease plasma
`concentrations of lamotrigine, likely due to induction of lamotrigine glucuronidation. This
`may reduce seizure control; therefore, dosage adjustments of lamotrigine may be necessary.
`Consult the labeling of the concurrently-used drug to obtain further information about
`interactions with COCs or the potential for enzyme alterations.
`
`

`

` 8
`
` USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`There is little or no increased risk of birth defects in women who inadvertently use COCs
`during early pregnancy. Epidemiologic studies and meta-analyses have not found an
`increased risk of genital or non-genital birth defects (including cardiac anomalies and limb
`reduction defects) following exposure to low dose COCs prior to conception or during early
`pregnancy.
`
`The administration of COCs to induce withdrawal bleeding should not be used as a test for
`pregnancy. COCs should not be used during pregnancy to treat threatened or habitual
`abortion.
`
`Women who do not breastfeed should not start COCs earlier than 4 weeks postpartum.
`
`Nursing Mothers
`8.3
`When possible, advise the nursing mother to use other forms of contraception until she has
`weaned her child. Estrogen-containing OCs can reduce milk production in breastfeeding
`mothers. This is less likely to occur once breastfeeding is well-established; however, it can
`occur at any time in some women. Small amounts of oral contraceptive steroids and/or
`metabolites are present in breast milk.
`
`Pediatric Use
`8.4
`Safety and efficacy of Lo Loestrin Fe have been established in women of reproductive age.
`Safety and efficacy are expected to be the same in postpubertal adolescents under the age of
`18 years as for users 18 years and older. Use of this product before menarche is not indicated.
`
`8.5 Geriatric Use
`Lo Loestrin Fe has not been studied in postmenopausal women and is not indicated in this
`population.
`
`Renal Impairment
`8.6
`The pharmacokinetics of Lo Loestrin Fe has not been studied in subjects with renal
`impairment.
`
`8.7 Hepatic Impairment
`No studies have been conducted to evaluate the effect of hepatic impairment on the
`disposition of Lo Loestrin Fe. However, steroid hormones may be poorly metabolized in
`patients with impaired liver function. 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. [See Contraindications (4) and Warnings and
`Precautions (5.3).]
`
`8.8 Body Mass Index
`The safety and efficacy of Lo Loestrin Fe in women with a body mass index (BMI)
`> 35 kg/m2 has not been evaluated. [See Clinical Studies (14).]
`
`

`

`
`10 OVERDOSAGE
`There have been no reports of serious ill effects from overdose of oral contraceptives,
`including ingestion by children. Overdosage may cause withdrawal bleeding in females and
`nausea.
`
`11 DESCRIPTION
`Lo Loestrin Fe (norethindrone acetate and ethinyl estradiol tablets, ethinyl estradiol tablets
`and ferrous fumarate tablets) provides an oral contraceptive regimen consisting of 24 blue
`active tablets and 2 white active tablets that contain the active ingredients specified for each
`tablet below, followed by 2 non-hormonal placebo tablets:
`
`
` •
`
` 24 blue, round tablets each containing 1 mg norethindrone acetate and 10 mcg ethinyl
`estradiol
`
` •
`
` •
`
` 2 white, hexagonal tablets each containing 10 mcg ethinyl estradiol
`
` 2 brown, round tablets each containing 75 mg ferrous fumarate
`
`
`Each blue tablet also contains the inactive ingredients mannitol, microcrystalline cellulose,
`FD&C Blue No. 1 Aluminum Lake, sodium starch glycolate, magnesium stearate, povidone,
`vitamin E and lactose monohydrate.
`
`Each white tablet also contains the inactive ingredients mannitol, microcrystalline cellulose,
`sodium starch glycolate, magnesium stearate, povidone, vitamin E and lactose monohydrate.
`
`Each brown tablet contains ferrous fumarate, mannitol, povidone, microcrystalline cellulose,
`sodium starch glycolate, magnesium stearate, sucralose and spearmint flavor. The ferrous
`fumarate tablets do not serve any therapeutic purpose. Ferrous fumarate tablets are not USP
`for dissolution and assay.
`
`The empirical formula of ethinyl estradiol is C20H24O2 and the structural formula is:
`
`
`OH
`CH3
`
`C
`
`CH
`
`H
`
`H
`
`H
`
`OH
`
`The chemical name of ethinyl estradiol is [19-Norpregna-1,3,5(10)-trien-20-yne-3,17-diol,
`(17α)-].
`
`
`

`

`The empirical formula of norethindrone acetate is C22H28O3 and the structural formula is:
`
`
`O
`CCH3
`CH
`C
`
`OCH3
`
`H
`
`H
`
`H
`
`H
`
`O
`
`The chemical name of norethindrone acetate is [19-Norpregn-4-en-20-yn-3-one, 17-
`(acetyloxy)-, (17α)-].
`
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`COCs lower the risk of becoming pregnant primarily by suppressing ovulation. Other
`possible mechanisms may include cervical mucus changes that inhibit sperm penetration and
`endometrial changes that reduce the likelihood of implantation.
`
`12.2 Pharmacodynamics
`No specific pharmacodynamic studies were conducted with Lo Loestrin Fe.
`
`12.3 Pharmacokinetics
`Absorption
`Norethindrone acetate is deacetylated to norethindrone after oral administration, and the
`disposition of norethindrone acetate is indistinguishable from that of orally administered
`norethindrone. Norethindrone acetate and ethinyl estradiol are absorbed from Lo Loestrin Fe,
`with maximum plasma concentrations of norethindrone and ethinyl estradiol generally
`occurring 1 to 2 hours postdose. Both are subject to first-pass metabolism after oral dosing,
`resulting in an absolute bioavailability of approximately 64% for norethindrone and 55% for
`ethinyl estradiol.
`The rate of norethindrone and ethinyl estradiol absorption from Lo Loestrin Fe tablets
`containing the combination of 1 mg norethindrone acetate and 10 mcg ethinyl estradiol is
`slower than that from a norethindrone suspension/ethinyl estradiol solution, but the extent of
`absorption is equivalent.
`Ethinyl estradiol bioavailability from Lo Loestrin Fe tablets containing 10 mcg ethinyl
`estradiol alone is equivalent to that from an ethinyl estradiol solution.
`The plasma norethindrone and ethinyl estradiol pharmacokinetic profiles and serum sex
`hormone binding globulin (SHBG) concentrations following multiple-dose administration of
`Lo Loestrin Fe were characterized in 15 healthy female volunteers. The mean plasma
`concentrations are shown below (Figures 1 and 2), and pharmacokinetic parameters are
`found in Table 1.
`Ethinyl estradiol and norethindrone Cmax values increase by a factor of 1.4 and 1.9,
`respectively, following 24 days administration of Lo Loestrin Fe combination tablets as
`
`

`

`compared to single-dose administration. Ethinyl estradiol and norethindrone AUC0–24h
`values increase by a factor of 1.6 and 2.5, respectively, following 24 days administration of
`Lo Loestrin Fe combination tablets as compared to single-dose administration.
`Norethindrone concentrations more than double by Day 24 due to both accumulation and
`increased SHBG concentration. Steady state with respect to ethinyl estradiol and
`norethindrone is reached by Day 5 and Day 13, respectively.
`
`Figure 1. Mean (± SD) plasma ethinyl est