`•
`
`•
`
`•
`
`•
`
`•
`
`•
`
`
`
`
`
`Breast cancer or other estrogen- or progestin-sensitive cancer (4)
`
`
`
`Liver tumors or liver disease (4)
`
`
`Undiagnosed abnormal uterine bleeding (4)
`
`
`Pregnancy (4)
`
`
`
`
`
`
`Hypersensitivity to any ingredients in Lo Minastrin Fe (4)
` Co-administration with Hepatitis C drug combinations containing
`
` ombitasvir/paritaprevir/ritonavir, with or without dasabuvir (4)
`
`
`
`
`
`------------------------WARNINGS AND PRECAUTIONS----------------------­
`
`Vascular risks: Stop Lo Minastrin Fe if a thrombotic event occurs. Stop
`
`
`
`
`•
`at least 4 weeks before through 2 weeks after major surgery. Start no
`
`
`
`
`earlier than 4 weeks after delivery in women who are not breastfeeding
`
`
`(5.1)
`
`Liver disease: Discontinue if jaundice occurs (5.2)
`
`
`
`
`
`High blood pressure: If used in women with well-controlled
`
`
`
`
`hypertension, monitor blood pressure and stop Lo Minastrin Fe if blood
`
`pressure rises significantly (5.4)
`
`
`Carbohydrate and lipid metabolic effects: Monitor prediabetic and
`
`
`diabetic women taking Lo Minastrin Fe. Consider an alternative
`
`contraceptive method for women with uncontrolled dyslipidemia (5.6)
`
`
`
`
`Headache: Evaluate significant change in headaches and discontinue if
`
`indicated (5.7)
`
`
`
`
`Uterine bleeding: Evaluate irregular bleeding or amenorrhea (5.8)
`
`
`•
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`-------------------------------ADVERSE REACTIONS-----------------------------­
`
`
`
`
`
`
`The most common adverse reactions (≥ 2%) in clinical trials were
`nausea/vomiting, headache, bleeding irregularities, dysmenorrhea, weight
`
`
`
`change, breast tenderness, acne, abdominal pain, anxiety and depression (6.1)
`
`
`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----------------------­
`
`
`
`
`Nursing mothers: Not recommended; can decrease milk production (8.3)
`
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA-
`
`
`approved patient labeling.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Revised: 08/2017
`
` HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`
` These highlights do not include all the information needed to use LO
` MINASTRIN™ FE safely and effectively. See full prescribing
`
`
`
`
`
`
`
`
`information for LO MINASTRIN FE.
`
`
`LO MINASTRIN FE (norethindrone acetate and ethinyl estradiol tablets,
`
`
`
`ethinyl estradiol tablets and ferrous fumarate tablets), for oral use
`
`
`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 Minastrin
`
`
`
`
`
`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 (5.3)
`
`
`
`
`
`---------------------------INDICATIONS AND USAGE---------------------------­
`
`• Lo Minastrin Fe is an estrogen/progestin COC indicated for use by
`
`
`
`
`
`
`women to prevent pregnancy (1)
`
`
`• The efficacy in women with a body mass index of more than 35 kg/m2
`
`
`
`
`
`
`
`
`
`
`
`has not been evaluated (1, 8.8)
`
`
`
`
`
`
`-----------------------DOSAGE AND ADMINISTRATION----------------------­
`
`
`
`
`
`One blue tablet daily chewed and swallowed taken at the same time
`
`•
`
`
`
`
`
`every day for 24 days. Follow with 8 ounces of water (2.1)
`
`
`
`
`One white tablet daily swallowed taken at the same time every day for 2
`
`
`days (2.1)
`
`
`One brown tablet daily swallowed taken at the same time every day for 2
`
`
`days (2.1)
`
`
`Take tablets in the order directed on the blister pack (2.1)
`
`
`
`Tablets may be administered without regard to meals (2.1)
`
`
`•
`
`
`•
`
`
`•
`
`•
`
`
`----------------------DOSAGE FORMS AND STRENGTHS--------------------­
`
`
`
`Lo Minastrin Fe consists of 28 tablets in the following order (3):
`
`
`
`
`
`24 blue, mint-flavored, chewable 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 which does not serve any therapeutic purpose
`
`
`•
`
`•
`
`
`
`
`------------------------------CONTRAINDICATIONS------------------------------­
`
`
`
`
`A high risk of arterial or venous thrombotic diseases (4)
`
`•
`
`
`
`
`
`Reference ID: 4136736
`
`

`

`
` 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 Minastrin Fe
`
`
`
`
`
`2.2 How to Start Lo Minastrin 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 Thromboembolic Disorders and Other Vascular Problems
`
`
`
`
`
`
`5.2 Liver Disease
`
`
`
`5.3 Risk of Liver Enzyme Elevations with Concomitant Hepatitis C
`
`
`
`
`Treatment
`
`
`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 Carcinoma of the Breast and Cervix
`
`
`
`5.12 Effect on Binding Globulins
`
`
`
`
`5.13 Monitoring
`
`
`
`5.14 Hereditary Angioedema
`
`
`
`5.15 Chloasma
`
`
`
`6 ADVERSE REACTIONS
`
`
`6.1 Clinical Trial Experience
`
`
`
`
`
`
`
`
`
`
`
`
`Postmarketing Experience
`
`6.2
`
`
`7 DRUG INTERACTIONS
`
`
`7.1 Effects of Other Drugs on Combined Oral Contraceptives
`
`
`
`
`
`7.2 Effects of Combined Oral Contraceptives on Other Drugs
`
`
`
`7.3 Concomitant Use with HCV Combination Therapy – Liver
`
`
`
`
`
`Enzyme Elevation
`
`
`Interference with Laboratory Tests
`
`7.4
`
`
`
`8 USE IN SPECIFIC POPULATIONS
`
`
`8.1
`Pregnancy
`
`
`
`8.3 Nursing Mothers
`
`
`
`
`8.4
`Pediatric Use
`
`
`
`8.5 Geriatric Use
`
`
`
`8.6 Hepatic Impairment
`
`
`
`8.7 Renal 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.
`
`Reference ID: 4136736
`
`

`

`
`
` 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 Minastrin Fe is indicated for use by females of reproductive age to prevent pregnancy
`
`
`
`
`
`[see Clinical Studies (14)].
`
`
`The efficacy of Lo Minastrin Fe in women with a body mass index (BMI) of more than 35
`
`
`
`
`
` kg/m2 has not been evaluated.
`
`
`
`
`2 DOSAGE AND ADMINISTRATION
`
`
`2.1 How to Take Lo Minastrin Fe
`
`
`
`
`To achieve maximum contraceptive effectiveness, Lo Minastrin Fe must be taken exactly as
`
`
`
`
`directed. Instruct patients to take one tablet by mouth at the same time every day. The blue
`
`
`
`
`
`tablet should be chewed and swallowed. The patient should drink a full glass (8 ounces) of
`
`
`water immediately after chewing and swallowing the blue tablet. The white tablet and the
`
`
`
`
`
`
`
`brown tablet are swallowed. 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 tablets [see FDA-approved patient labeling]. Lo Minastrin Fe may be
`
`
`
`
`
`
`administered without regard to meals [see Clinical Pharmacology (12.3)].
`
`
`
`
`2.2 How to Start Lo Minastrin Fe
`
`
`
`
`
`Instruct the patient to begin taking Lo Minastrin 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 Minastrin 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
`
`Minastrin 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: 4136736
`
`

`

`
` Lo Minastrin Fe may be initiated immediately after a first-trimester abortion or miscarriage;
` if the patient starts Lo Minastrin 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 Minastrin Fe.
`
`
` If she previously used a vaginal ring or transdermal patch, she should start using Lo
`
` Minastrin 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
`
`
` • She may switch any day from a progestin-only pill; instruct her to take the first blue
`
`
`
`
`
`tablet on the day she would have taken her next progestin-only pill.
` If switching from an implant or injection, start the first blue tablet on the day her next
`
`
`
` injection would have been due 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
`
`
`
`tablet), she should follow the instructions in the “What to Do if You Miss Tablets” section
`
`
`[see FDA-approved patient labeling].
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`
`
`Lo Minastrin Fe is available in blister packs.
`
`
`
`
`Each blister pack contains 28 tablets in the following order:
`
`
`
`• 24 blue, round, chewable, mint-flavored (active) tablets imprinted with “WC” on one side
`
`
`
`
`and “537” 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: 4136736
`
`

`

`
`
`4 CONTRAINDICATIONS
`
`
`
`
`
`Do not prescribe Lo Minastrin 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
`
`
`
`aura [see Warnings and Precautions (5.7)]
`
`
`
`o Women over age 35 with any migraine headaches [see Warnings and Precautions
`
`
`
`
`(5.7)]
`
`• Liver tumors, benign or malignant, or liver disease [see Warnings and Precautions (5.2)]
`
`
`
`
`• 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)]
`
`
`• Breast cancer or other estrogen- or progestin-sensitive cancer, now or in the past [see
`
`
`
`
`Warnings and Precautions (5.11)]
`
`• Hypersensitivity to any ingredients in Lo Minastrin Fe
`
`
`
`• 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 (5.3)]
`
`
`
`5 WARNINGS AND PRECAUTIONS
`
`
`5.1 Thromboembolic Disorders and Other Vascular Problems
`
`
`
`
`Stop Lo Minastrin Fe if an arterial or deep venous thrombotic event (VTE) occurs. Stop Lo
`
`
`
`
`Minastrin Fe if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal
`
`
`vascular lesions. Evaluate for retinal vein thrombosis immediately.
`
`
`If feasible, stop Lo Minastrin Fe at least 4 weeks before and through 2 weeks after major
`
`
`
`
`surgery or other surgeries known to have an elevated risk of VTE.
`
`
`
`Reference ID: 4136736
`
`

`

`
`
` Start Lo Minastrin Fe no earlier than 4 weeks after delivery, in women who are not
`
`
`breastfeeding. The risk of postpartum VTE decreases after the third postpartum week,
`whereas the risk of ovulation increases after the third postpartum week.
`
`
` The use of COCs increases the risk of VTE. However, pregnancy increases the risk of VTE
`
`
`
`
`
`
`
` as much or more than the use of COCs. The risk of VTE in women using COCs is 3 to 9 per
` 10,000 woman-years. The risk of VTE is highest during the first year of use of a COC. The
`
`
`
`
`
` risk of thromboembolic disease due to oral contraceptives gradually disappears after COC
`
`
` use is discontinued.
`
`
`
`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. 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
`
`
`
`(greater than 35 years of age), hypertensive women who also smoke. COCs also increase the
`
`risk for stroke in women with underlying risk factors.
`
`
`
`Use COCs with caution in women with cardiovascular disease risk factors.
`
`
`5.2 Liver Disease
`
`
`
`Impaired Liver Function
`
`
`
`Do not use Lo Minastrin Fe in women with acute viral hepatitis or severe (decompressed)
`
`cirrhosis of the liver [see Contraindications (4)]. 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. Discontinue Lo Minastrin Fe if
`
`
`
`jaundice develops.
`
`
`Liver Tumors
`
`Lo Minastrin Fe is contraindicated in women with benign and malignant liver tumors [see
`
`
`
`Contraindications (4) ]. 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
`
`(greater than 8 years) COC users. However, the attributable risk of liver cancers in COC
`
`
`users is less than one case per million users.
`
`
`
`5.3 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 Minastrin Fe prior to starting therapy with the
`
`
`
`combination drug regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir
`
`
`
`
`Reference ID: 4136736
`
`

`

`
`
` [see Contraindications (4)]. Lo Minastrin Fe can be restarted approximately 2 weeks
`
`following completion of treatment with the Hepatitis C combination drug regimen.
`
`
`
`
`
`
` 5.4 High Blood Pressure
` Lo Minastrin Fe is contraindicated in women with uncontrolled hypertension or hypertension
`
`
` with vascular disease [see Contraindications (4)]. For women with well-controlled
`
`hypertension, monitor blood pressure and stop Lo Minastrin Fe if blood pressure rises
`
`
`
`significantly.
`
`
`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. Use of COCs may also worsen existing gallbladder disease.
`
`
`
`
`
`A past history of COC-related cholestasis predicts an increased risk with subsequent COC
`
`use. Women with a history of pregnancy-related cholestasis may be at an increased risk for
`
`
`COC-related cholestasis.
`
`
`5.6 Carbohydrate and Lipid Metabolic Effects
`
`
`Carefully monitor prediabetic and diabetic women who are taking Lo Minastrin 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 Minastrin Fe develops new headaches that are recurrent, persistent, or
`
`
`
`
`
`
`severe, evaluate the cause and discontinue Lo Minastrin Fe if indicated.
`
`
`
`
`
`Consider discontinuation of Lo Minastrin Fe in the case of an increased frequency or severity
`
`
`
`
`
`of migraine during COC use (which may be prodromal of a cerebrovascular event) [see
`
`
`Contraindications (4)].
`
`
`5.8 Bleeding Irregularities and Amenorrhea
`
`
`
`Unscheduled bleeding and Spotting
`
`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: 4136736
`
`

`

`
`
`Based on patient diaries from a clinical trial evaluating the safety and efficacy of a 28-day
`
`
`
`
`
`
`regimen consisting of norethindrone acetate 1 mg/ethinyl estradiol 10 mcg tablets for 24 days
`
`
`
`
`
`followed with ethinyl estradiol 10 mcg tablets for 2 days and ferrous fumarate tablets for 2
`
`
`days, 36-53% of women experienced unscheduled bleeding per cycle. 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. A total of 58 subjects out of 1,582 discontinued the study due to
`
`bleeding or spotting.
`
`
`Amenorrhea and Oligomenorrhea
`
`
`
`
`Women who are not pregnant and use Lo Minastrin Fe may experience amenorrhea. In the
`
`
`
`
`clinical trial with a 28-day regimen consisting of norethindrone acetate 1 mg/ethinyl estradiol
`
`
`
`
`
`
`10 mcg tablets for 24 days followed with ethinyl estradiol 10 mcg tablets for 2 days and
`
`
`
`
`ferrous fumarate tablets for 2 days, 31-49% of the women experienced amenorrhea in at least
`
`
`
`one cycle between Cycles 2 to 13.
`
`
`
`Some women may experience post-pill amenorrhea or oligomenorrhea, especially when such
`
`
`
`
`a condition was preexistent. 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.
`
`
`
`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.
`
`
`
`Discontinue Lo Minastrin Fe 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
`
`
`Carefully observe women with a history of depression and discontinue Lo Minastrin Fe if
`
`
`
`depression recurs to a serious degree.
`
`
`5.11 Carcinoma of the Breast and Cervix
`
`
`Lo Minastrin Fe is contraindicated in women who currently have or have had breast cancer
`
`
`because breast cancer is a hormonally-sensitive tumor [see Contraindications (4)].
`
`
`
`
`
`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.
`
`
`
`
`Reference ID: 4136736
`
`

`

`
`
`
`
`
`
` 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.
`
`
`
`
`5.12 Effect on Binding Globulins
`
`
`The estrogen component of COCs may raise the serum concentrations of thyroxine-binding
`
`
`globulin, sex hormone-binding globulin, and cortisol-binding globulin. The dose of
`
`
`
`replacement thyroid hormones or cortisol therapy may need to be increased.
`
`
`
` 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 Hereditary Angioedema
`
`
`
`In women with hereditary angioedema, exogenous estrogens may induce or exacerbate
`
`symptoms of angioedema.
`
`
`5.15 Chloasma
`
`
`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 Lo Minastrin Fe.
`
`
` 6 ADVERSE REACTIONS
`
`The following serious adverse reactions with the use of COCs are discussed elsewhere in the
`
` labeling:
` • Serious cardiovascular events and stroke [see Boxed Warning and Warnings and
`
`Precautions (5.1)]
`
`• Vascular events [see Warnings and Precautions (5.1)]
`
`
`
`
`• Liver disease [see Warnings and Precautions (5.2)]
`
`
`
`
`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.
`
`
`
`
`The data presented in Section 6.1 are from a clinical trial conducted with a 28-day regimen
`
`
`consisting of norethindrone acetate 1 mg/ethinyl estradiol 10 mcg tablets for 24 days
`
`
`
`
`
`
`followed with ethinyl estradiol 10 mcg tablets for 2 days and ferrous fumarate tablets for 2
`
`
`
`
`days. Lo Minastrin Fe is bioequivalent to this 28-day regimen.
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4136736
`
`

`

`
`
`
`
`
`A multicenter phase 3 clinical trial evaluated the safety and efficacy of the 28-day regimen
`
`
`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 the
`
`
`28-day regimen and 1,582 had at least one post-treatment evaluation [see Clinical Studies
`
`
`(14)].
`
`
`Common Adverse Reactions (Greater Than or Equal to 2% of all Treated Subjects): The
`
`
`
`
`most common adverse reactions reported by at least 2% of the 1,660 women using the 28-day
`
`
`
`
`regimen 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 greater than
`
`
`
`
`or equal to 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.
`
`
`
`6.2 Postmarketing Experience
`
`
`The following adverse reactions have been identified during post-approval use of a 28-day
`
`
`
`regimen consisting of norethindrone acetate 1 mg/ethinyl estradiol 10 mcg tablets for 24 days
`
`
`
`
`
`followed with ethinyl estradiol 10 mcg tablets for 2 days and ferrous fumarate tablets for 2
`
`
`
`days. Because these reactions are reported voluntarily from a population of uncertain size, it
`
`
`
`
`is not always possible to reliably estimate their frequency or evaluate a causal relationship to
`
`
`
`
`drug exposure.
`
`
`Adverse reactions are grouped into System Organ Classes.
`
`
`
`Vascular disorders: thrombosis/embolism (coronary artery, pulmonary, cerebral, deep vein)
`
`
`Immune system disorders: hypersensitivity reaction
`
`
`Skin and subcutaneous tissues: urticaria, rash, pruritis
`
`
`
`
`
`Gastrointestinal disorders: nausea, vomiting, abdominal pain/discomfort, diarrhea
`
`
`
`Nervous system disorders: headache, dizziness, migraine headache
`
`
`
`
`Psychiatric disorders: mood swings, depression, anxiety
`
`
`
`Reference ID: 4136736
`
`

`

`
`
`
`
` Respiratory, thoracic and mediastinal disorders: pulmonary embolism, dyspnea
`
`
`
`
`Reproductive system and breast disorders: breast enlargement, breast tenderness,
`dysmenorrhea, hypomenorrhea, menorrhagia, menstrual disorder, irregular menstruation,
`
` metrorrhagia
`
`
`7 DRUG INTERACTIONS
`
`
`Consult the labeling of the concurrently-used drug to obtain further information about
`
`interactions with COCs or the potential for enzyme alterations.
`
`
`No drug-drug interaction studies were conducted with Lo Minastrin Fe.
`
`
`7.1 Effects of Other Drugs on Combined Oral Contraceptives
`
`
`
`
`Substances decreasing the plasma concentrations of COCs and potentially diminishing the
`efficacy of COCs:
`
`
`Drugs or herbal products that induce certain enzymes, including cytochrome P450 3A4
`
`
`(CYP3A4), may decrease the plasma concentrations of COCs and potentially diminish the
`
`
`effectiveness of COCs or increase breakthrough bleeding. Some drugs or herbal products that
`
`
`may decrease the effectiveness of hormonal contraceptives include phenytoin, barbiturates,
`carbamazepine, bosentan, felbamate, griseofulvin, oxcarbazepine, rifampicin, topiramate,
`
`
`
`rifabutin, rufinamide, aprepitant and products containing St. John’s wort. Interactions
`
`
`
`between oral contraceptives and other drugs may lead to breakthrough bleeding and/or
`
`
`contraceptive failure. Counsel women to use an alternative method of contraception or a
`
`back-up method when enzyme inducers are used with COCs, and to continue back-up
`
`
`contraception for 28 days after discontinuing the enzyme inducer to ensure contraceptive
`
`reliability.
`
`
`Colesevelam: Colesevelam, a bile acid sequestrant, given together with a combination oral
`
`
`hormonal contraceptive, has been shown to significantly decrease the AUC of ethinyl
`
`
`estradiol. A drug interaction between the contraceptive and colesevelam was decreased when
`
`
`
`the two drug products were given 4 hours apart.
`
`
`Substances increasing the plasma concentrations of COCs:
`Co-administration of atorvastatin and certain COCs containing ethinyl estradiol increase
`
`
`AUC values for ethinyl estradiol by approximately 20-25%. Ascorbic acid and
`
`
`acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition
`
`of conjugation. CYP3A4 inhibitors such as itraconazole, voriconazole, fluconazole,
`
`
`
`grapefruit juice, or ketoconazole may increase plasma hormone concentrations.
`
`
`Human immunodeficiency virus (HIV)/ Hepatitis C Virus (HCV) protease inhibitors and
`
`non-nucleoside reverse transcriptase inhibitors:
`
`
`
`Significant changes in the plasma concentrations of the estrogen and/or progestin have been
`
`
`
`
`noted in some cases of co-administration with HIV protease inhibitors (decrease [for
`example, nelfinavir, ritonavir, darunavir/ritonavir, (fos)amprenavir/ritonavir,
`lopinavir/ritonavir, and tipranavir/ritonavir] or increase [for example, indinavir and
`
`atazanavir/ritonavir])/HCV protease inhibitors (decrease [for example, boceprevir and
`
`
`
`Reference ID: 4136736
`
`

`

`
`
`
`
` telaprevir]) or with non-nucleoside reverse transcriptase inhibitors (decrease [for example,
`
`
`
`nevirapine] or increase [for example, etravirine]).
`
`
`7.2 Effects of Combined Oral Contraceptives on Other D