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)
`
`•
`
`•
`•
`•
`
`•
`•
`
`•
`
`•
`
`-----------------------RECENT MAJOR CHANGES--------------------------
`Dosage and Administration, Missed Doses (2.4)
`
` 10/2021
`Contraindications, Pregnancy (4)
`
` Removed 10/2021
`Warnings and Precautions (5.2)
`
` 04/2022
`-----------------------INDICATIONS AND USAGE--------------------------
`• Lo Loestrin Fe is a combination of norethindrone acetate, a progestin, and
`ethinyl estradiol, an estrogen, 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 (4)
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`WARNING: CIGARETTE SMOKING AND SERIOUS
`CARDIOVASCULAR EVENTS
`1
`INDICATIONS AND USAGE
`2
`DOSAGE AND ADMINISTRATION
`How to Take Lo Loestrin Fe
`How to Start Lo Loestrin Fe
`Switching from another Hormonal Method of Contraception
`Missed Doses
`Advice in Case of Gastrointestinal Disturbances
`DOSAGE FORMS AND STRENGTHS
`CONTRAINDICATIONS
`WARNINGS AND PRECAUTIONS
`Thrombotic and Other Vascular Events
`Malignant Neoplasms
`Liver Disease
`Risk of Liver Enzyme Elevations with Concomitant Hepatitis C
`Treatment
`High Blood Pressure
`Gallbladder Disease
`Carbohydrate and Lipid Metabolic Effects
`Headache
`Bleeding Irregularities and Amenorrhea
`COC Use before or during Early Pregnancy
`Depression
`Interference with Laboratory Tests
`Monitoring
`Other Conditions
`ADVERSE REACTIONS
`Clinical Trial Experience
`Postmarketing Experience
`
`•
`•
`
`
`
`3
`4
`5
`
`6
`
`2.1
`2.2
`2.3
`2.4
`2.5
`
`5.1
`5.2
`5.3
`5.4
`5.5
`5.6
`5.7
`5.8
`5.9
`5.10
`5.11
`5.12
`5.13
`5.14
`6.1
`6.2
`
`Reference ID: 4976225
`
`7
`
`8
`
`Liver tumors or liver disease (4)
`Undiagnosed abnormal uterine bleeding (4)
`Co-administration with Hepatitis C drug combinations containing
`ombitavir/paritaprevir/ritonavir, with or without dasabuvir (4)
`
`
`--------------------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. (5.5)
`Carbohydrate and lipid metabolic effects: Monitor prediabetic and
`diabetic women taking Lo Loestrin Fe. Consider an alternative
`contraceptive method for women with uncontrolled dyslipidemia (5.7)
`Headache: Evaluate significant change in headaches and discontinue Lo
`Loestrin Fe if indicated (5.8)
`Uterine bleeding: Evaluate irregular bleeding or amenorrhea (5.9)
`•
`------------------------ADVERSE REACTIONS------------------------------
`The most common adverse reactions (≥ 2 percent) are nausea/vomiting (7
`percent), headache (7 percent), bleeding irregularities (5 percent),
`dysmenorrhea (4 percent), weight change (4 percent), breast tenderness (4
`percent), acne (3 percent), abdominal pain (3 percent), anxiety (2 percent) and
`depression (2 percent) (6)
`To report SUSPECTED ADVERSE REACTIONS, contact Allergan at 1-
`800-678-1605 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---------------------
`Lactation: Not recommended; Lo Loestrin Fe can decrease milk
`•
`production (8.2)
`See 17 for PATIENT COUNSELING INFORMATION and FDA-
`Approved Patient Labeling.
`
`
`
`
`
`
`Revised: 04/2022
`
`
`DRUG INTERACTIONS
`7.1
`Changes in Contraceptive Effectiveness Associated with Co-
`Administration of Other Products
`7.2
`Increase in Plasma Levels of Ethinyl Estradiol Associated with
`Co-Administered Drugs
`7.3
`Concomitant Use with HCV Combination Therapy – Liver
`Enzyme Elevation
`Changes in Plasma Levels of Co-Administered Drugs
`7.4
`USE IN SPECIFIC POPULATIONS
`Pregnancy
`8.1
`Lactation
`8.2
`Pediatric Use
`8.4
`Geriatric Use
`8.5
`Renal Impairment
`8.6
`Hepatic Impairment
`8.7
`Body Mass Index
`8.8
`OVERDOSAGE
`10
`DESCRIPTION
`11
`CLINICAL PHARMACOLOGY
`12
`Mechanism of Action
`12.1
`Pharmacodynamics
`12.2
`Pharmacokinetics
`12.3
`NONCLINICAL TOXICOLOGY
`13
`Carcinogenesis, Mutagenesis, Impairment of Fertility
`13.1
`CLINICAL STUDIES
`14
`HOW SUPPLIED/STORAGE AND HANDLING
`16
`How Supplied
`16.1
`Storage Conditions
`16.2
`PATIENT COUNSELING INFORMATION
`17
`*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)].
`
`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.
`
` 1
`
` 2
`
` 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. 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). 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.
`
`Reference ID: 4976225
`
`

`

`
`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 Missed Doses
`Table 1: Instructions for Missed Lo Loestrin Fe Tablets in a Monthly Dosing Regimen
`
`• If one blue tablet is missed
`
`• If two consecutive blue tablets are missed
`in Week 1 or Week 2
`
`• If two consecutive tablets (blue or white)
`are missed in Week 3 or Week 4
`
`Take the tablet as soon as possible, even if
`two tablets are taken in one day. Continue
`taking one tablet a day until the pack is
`finished.
`
`Take the two missed tablets as soon as
`possible, and the next two tablets the next
`day. Continue taking the remaining tablets,
`one tablet a day until the pack is finished.
`Use additional non-hormonal
`contraception (such as condoms and
`spermicide) for 7 consecutive days after
`missing tablets.
`
`Throw out the rest of the pack and start a new
`pack the same day. A withdrawal bleed may
`not occur.
`Use additional non-hormonal
`contraception (such as condoms and
`
`Reference ID: 4976225
`
`

`

`• If three or more consecutive tablets (blue
`or white) are missed at any time
`
`• If either of the brown tablets in Week 4 are
`missed
`
`spermicide) for 7 consecutive days after
`missing tablets.
`
`Throw out the rest of the pack and start a new
`pack that same day. A withdrawal bleeding
`may not occur.
`Use additional non-hormonal
`contraception (such as condoms and
`spermicide) for 7 consecutive days after
`missing tablets.
`
`Throw out the tablet you missed. Start a new
`pack on the same day a new pack is usually
`started.
`
`
`
`2.5 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 Missed Doses [see Dosage and Administration (2.4)].
`
` 3
`
` DOSAGE FORMS AND STRENGTHS
`Lo Loestrin Fe (norethindrone acetate and ethinyl estradiol tablets, ethinyl estradiol tablets
`and ferrous fumarate tablets) is 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
`Lo Loestrin Fe is contraindicated in females who are known to have or develop 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)]
`
`Reference ID: 4976225
`
`

`

`• 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)]
`• Current diagnosis of, or history of, breast cancer, which may be hormone-sensitive [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 (5.9)]
`• Use of Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with
`or without dasabuvir, due to the potential for ALT elevations [see Warnings and
`Precautions (5.4)].
`
` 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.
`
`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
`
`Reference ID: 4976225
`
`

`

`
`
`5.2 Malignant Neoplasms
`
`Breast Cancer
`Lo Loestrin Fe is contraindicated in females who currently have or have had breast
`cancer because breast cancer may be hormonally sensitive [see Contraindications (4)].
`
`Epidemiology studies have not found a consistent association between use of combined
`oral contraceptives (COCs) and breast cancer risk. Studies do not show an association
`between ever (current or past) use of COCs and risk of breast cancer. However, some
`studies report a small increase in the risk of breast cancer among current or recent
`users (<6 months since last use) and current users with longer duration of COC use [see
`Adverse Reactions (6.2)].
`
`Cervical Cancer
`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 Risk of Liver Enzyme Elevations with Concomitant Hepatitis C Treatment
`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, such as COCs. Discontinue Lo Loestrin Fe prior to starting therapy with the
`combination drug regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir
`
`Reference ID: 4976225
`
`

`

`[see Contraindications (4)]. Lo Loestrin Fe can be restarted approximately 2 weeks
`following completion of treatment with the Hepatitis C combination drug regimen.
`
`5.5 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.
`
`5.6 Gallbladder Disease
`Studies suggest a small increased relative risk of developing gallbladder disease among COC
`users.
`
`5.7 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.
`
`5.8 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.
`
`5.9 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.
`
` total of 1,257 women (85.9 percent) experienced unscheduled bleeding and/or spotting at
`some time during Cycles 2 to 13 of this study. The incidence of unscheduled bleeding and/or
`
` A
`
`Reference ID: 4976225
`
`

`

`spotting was highest during Cycle 2 (53 percent) and lowest at Cycle 13 (36 percent). 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 percent in Cycle 1 to 49 percent 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.
`
`5.10 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)].
`
`5.11 Depression
`Women with a history of depression should be carefully observed and Lo Loestrin Fe
`discontinued if depression recurs to a serious degree.
`
`5.12 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.
`
`5.13 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.
`
`
`Reference ID: 4976225
`
`

`

`5.14 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.
`
` 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.
`
` 6
`
` A
`
` 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)].
`
`Common Adverse Reactions (≥ 2 percent of all Treated Subjects): The most common
`adverse reactions reported by at least 2 percent of the 1,660 women using Lo Loestrin Fe
`were the following in order of decreasing incidence: nausea/vomiting (7 percent), headache
`(7 percent), bleeding irregularities (including metrorrhagia, irregular menstruation,
`menorrhagia, vaginal hemorrhage and dysfunctional uterine bleeding) (5 percent),
`dysmenorrhea (4 percent), weight fluctuation (4 percent), breast tenderness (4 percent), acne
`(3 percent), abdominal pain (3 percent), anxiety (2 percent), and depression (2 percent).
`
`Adverse Reactions Leading to Study Discontinuation: 10.7 percent of the women
`discontinued from the clinical trial due to an adverse reaction. Adverse reactions occurring in
`≥1 percent of subjects leading to discontinuation of treatment were in decreasing order:
`menstrual irregularities (including metrorrhagia, irregular menstruation, menorrhagia and
`vaginal hemorrhage) (4 percent), headache/migraine (1 percent), mood disorder (including
`mood swings, depression, anxiety) (1 percent), and weight fluctuation (1 percent).
`
`
`Reference ID: 4976225
`
`

`

`Serious Adverse Reactions: deep vein thrombosis, ovarian vein thrombosis, cholecystitis.
`
`6.2 Postmarketing Experience
`Five studies that compared breast cancer risk between ever-users (current or past use)
`of COCs and never-users of COCs reported no association between ever use of COCs
`and breast cancer risk, with effect estimates ranging from 0.90 - 1.12 (Figure 1).
`
`Three studies compared breast cancer risk between current or recent COC users (<6
`months since last use) and never users of COCs (Figure 1). One of these studies
`reported no association between breast cancer risk and COC use. The other two
`studies found an increased relative risk of 1.19 - 1.33 with current or recent use. Both of
`these studies found an increased risk of breast cancer with current use of longer
`duration, with relative risks ranging from 1.03 with less than one year of COC use to
`approximately 1.4 with more than 8-10 years of COC use.
`
`Figure 1.
`
`RR = relative risk; OR = odds ratio; HR = hazard ratio. “ever COC” are females with current or past COC use;
`“never COC use” are females that never used COCs.
`
`
`
` 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
`
`Reference ID: 4976225
`
`

`

`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 percent. 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 Concomitant Use with HCV Combination Therapy – Liver Enzyme Elevation
`Do not co-administer Lo Loestrin Fe with HCV drug combinations containing ombitasvir/
`paritaprevir/ritonavir, with or without dasabuvir, due to potential for ALT elevations
`[see Warnings and Precautions (5.4)].
`
`7.4 Changes in Plasma Levels of Co-Administered Drugs
`COCs containing some synthetic estrogens (for example, 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.
`
`Reference ID: 4976225
`
`

`

` 8
`
` USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`Risk Summary
`There is no use for contraception in pregnancy; therefore, Lo Loestrin Fe should be
`discontinued during pregnancy. Epidemiologic studies and meta-analyses have not found an
`increased risk of genital or nongenital birth defects (including cardiac anomalies and limb
`reduction defects) following exposure to combined hormonal contraceptives (CHCs) before
`conception or during early pregnancy.
`In the U.S. general population, the estimated background risk of major birth defects and
`miscarriage in clinically recognized pregnancies is 2 to 4 percent and 15 to 20 percent,
`respectively.
`
`Data
`Human Data
`Epidemiologic studies and meta-analyses have not found an increased risk of genital or
`nongenital birth defects (including cardiac anomalies and limb-reduction defects) following
`exposure to CHCs before conception or during early pregnancy.
`
`Lactation
`8.2
`Risk Summary
`Contraceptive hormones and/or metabolites are present in human milk. CHCs can reduce
`milk production in breastfeeding females. This reduction can occur at any time but is less
`likely to occur once breastfeeding is well-established. When possible, advise the nursing
`female to use other methods of contraception until she discontinues breastfeeding. [See also
`Dosage and Administration (2.2).] The developmental and health benefits of breastfeeding
`should be considered along with the mother’s clinical need for Lo Loestrin Fe and any
`potential adverse effects on the breastfed child from Lo Loestrin Fe or from the underlying
`maternal condition.
`
`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.
`
`8.6 Renal Impairment
`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