`
`
`
` 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--------------------------
`Contraindications (4)
`08/2017
`
`
`
`
`
`
`08/2017
`Warnings (5.4)
`
`
`
`
`
`-----------------------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)
`
`•
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`WARNING: CIGARETTE SMOKING AND SERIOUS
`
`CARDIOVASCULAR EVENTS
`
`
`INDICATIONS AND USAGE
`1
`
`
`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
`
`
`
`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 Risk of Liver Enzyme Elevations with Concomitant Hepatitis C
`
`Treatment
`
`
`
`5.5 High Blood Pressure
`
`
`5.6 Gallbladder Disease
`
`
`
`
`5.7 Carbohydrate and Lipid Metabolic Effects
`
`
`5.8 Headache
`
`
`
`5.9 Bleeding Irregularities and Amenorrhea
`
`
`
`5.10 COC Use before or during Early Pregnancy
`
`
`5.11 Depression
`
`
`5.12
`Interference with Laboratory Tests
`
`
`5.13 Monitoring
`
`
`5.14 Other Conditions
`
`
`6 ADVERSE REACTIONS
`
`
`
`6.1 Clinical Trial Experience
`
`
`
`•
`
`•
`
`
`
`
`
`Reference ID: 4136752
`
`
`•
`
`•
`
`•
`
`
`•
`
`•
`
`
`•
`
`
`•
`
`
`
`Undiagnosed abnormal uterine bleeding (4)
`
`
`Pregnancy (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
`800-433-8871 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: 08/2017
`
`
`
`
`
`
`
`
`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)].
`
`
`INDICATIONS AND USAGE
`1
`
`
`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.
`
`
`
`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. 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.
`
`Reference ID: 4136752
`
`
`
`
`
`
`
`
`
`
`
`
`•
`
`
`•
`
` 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) 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.
`
`
`
`
`Reference ID: 4136752
`
`
`
`
` 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 (5.5)]
`
`
`
`
`• Have diabetes mellitus with vascular disease [see Warnings and Precautions (5.7)]
`
`
`
`
`
`
`
`
`• Have headaches with focal neurological symptoms or have migraine headaches with
`
`
`
`or without aura if over age 35 [see Warnings and Precautions (5.8)]
`
`
`
`• 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 (5.9)]
`
`
`
`• Pregnancy, because there is no reason to use COCs during pregnancy [see Warnings and
`
`
`
`Precautions (5.10) and Use in Specific Populations (8.1)]
`
`
`• 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)].
`
`
`
`5 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.
`
`
`
`
`Reference ID: 4136752
`
`
`
`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.
`
`
`
`5.2 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.
`
`
`
`
`Reference ID: 4136752
`
`
`
`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
`
`
`[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.
`
`
`Reference ID: 4136752
`
`
`
`
`
`
`
`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 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
`
`
`
`
`
`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.
`
`
`
`Reference ID: 4136752
`
`
`
`
`
`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.
`
`
`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.
`
`
`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.
`
`
`
`
`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 (14.1)].
`
`
`
`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
`
`
`
`
`Reference ID: 4136752
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` ≥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).
`
`
`
`
`
`
`
`
`
`
`
`Serious Adverse Reactions: deep vein thrombosis, ovarian vein thrombosis, cholecystitis.
`
`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.
`
`
`
`Reference ID: 4136752
`
`
`
`
`
`
`
`
`
`
`
`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.
`
`
`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.
`
`
`
`8.4
`Pediatric Use
`
`
`
`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.
`
`
`
`
`
`
`
`Reference ID: 4136752
`
`
`
`
`
`
`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 ble