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` HIGHLIGHTS OF PRESCRIBING INFORMATION
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` These highlights do not include all the information needed to use LO
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` MINASTRIN™ FE safely and effectively. See full prescribing
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` information for LO MINASTRIN FE.
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` LO MINASTRIN FE (norethindrone acetate and ethinyl estradiol tablets,
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` ethinyl estradiol tablets and ferrous fumarate tablets), for oral use
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` Initial U.S. Approval: 1968
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` WARNING: CIGARETTE SMOKING AND SERIOUS
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` CARDIOVASCULAR EVENTS
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` See full prescribing information for complete boxed warning.
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` Women over 35 years old who smoke should not use Lo Minastrin
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` Fe (4)
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` Cigarette smoking increases the risk of serious cardiovascular
` events from combination oral contraceptive (COC) use (4)
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` ---------------------------INDICATIONS AND USAGE----------------------------
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` Lo Minastrin Fe is an estrogen/progestin COC indicated for use by
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` women to prevent pregnancy (1)
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` The efficacy in women with a body mass index of more than 35 kg/m2
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` has not been evaluated (1, 8.8)
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` ------------------------WARNINGS AND PRECAUTIONS-----------------------
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` Vascular risks: Stop Lo Minastrin Fe if a thrombotic event occurs. Stop
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` at least 4 weeks before through 2 weeks after major surgery. Start no
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` earlier than 4 weeks after delivery in women who are not breastfeeding
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` (5.1)
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` Liver disease: Discontinue if jaundice occurs (5.2)
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` High blood pressure: If used in women with well-controlled
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` hypertension, monitor blood pressure and stop Lo Minastrin Fe if blood
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` pressure rises significantly (5.3)
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` Carbohydrate and lipid metabolic effects: Monitor prediabetic and
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` diabetic women taking Lo Minastrin Fe. Consider an alternative
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` contraceptive method for women with uncontrolled dyslipidemia (5.5)
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` Headache: Evaluate significant change in headaches and discontinue if
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` indicated (5.6)
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` Uterine bleeding: Evaluate irregular bleeding or amenorrhea (5.7)
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` Liver tumors or liver disease (4)
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` Undiagnosed abnormal uterine bleeding (4)
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` Pregnancy (4)
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` Hypersensitivity to any ingredients in Lo Minastrin Fe (4)
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` -----------------------DOSAGE AND ADMINISTRATION-----------------------
` One blue tablet daily chewed and swallowed taken at the same time
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` every day for 24 days. Follow with 8 ounces of water (2.1)
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` One white tablet daily swallowed taken at the same time every day for 2
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` days (2.1)
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` One brown tablet daily swallowed taken at the same time every day for 2
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` days (2.1)
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` Take tablets in the order directed on the blister pack (2.1)
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` Tablets may be administered without regard to meals (2.1)
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` ----------------------DOSAGE FORMS AND STRENGTHS---------------------
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` Lo Minastrin Fe consists of 28 tablets in the following order (3):
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` 24 blue, mint-flavored, chewable tablets (active), each containing 1 mg
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` norethindrone acetate and 10 mcg ethinyl estradiol
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` 2 white tablets (active), each containing 10 mcg ethinyl estradiol
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` 2 brown tablets (non-hormonal placebo) each containing 75 mg ferrous
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` fumarate which does not serve any therapeutic purpose
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`------------------------------CONTRAINDICATIONS-------------------------------
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` A high risk of arterial or venous thrombotic diseases (4)
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` Breast cancer or other estrogen- or progestin-sensitive cancer (4)
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` FULL PRESCRIBING INFORMATION: CONTENTS*
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` WARNING: CIGARETTE SMOKING AND SERIOUS
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` CARDIOVASCULAR EVENTS
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` INDICATIONS AND USAGE
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` 1
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` 2 DOSAGE AND ADMINISTRATION
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` 2.1 How to Take Lo Minastrin Fe
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` 2.2 How to Start Lo Minastrin Fe
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` 2.3
` Switching from another Hormonal Method of Contraception
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` 2.4 Advice in Case of Gastrointestinal Disturbances
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` 3 DOSAGE FORMS AND STRENGTHS
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` 4 CONTRAINDICATIONS
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` 5 WARNINGS AND PRECAUTIONS
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` 5.1 Thromboembolic Disorders and Other Vascular Problems
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` 5.2 Liver Disease
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` 5.3 High Blood Pressure
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` 5.4 Gallbladder Disease
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` 5.5 Carbohydrate and Lipid Metabolic Effects
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` 5.6 Headache
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` 5.7 Bleeding Irregularities and Amenorrhea
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` 5.8 COC Use before or during Early Pregnancy
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` 5.9 Depression
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` 5.10 Carcinoma of the Breasts and Cervix
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` 5.11 Effect on Binding Globulins
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` 5.12 Monitoring
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` 5.13 Hereditary Angioedema
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` 5.14 Chloasma
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` 6 ADVERSE REACTIONS
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` 6.1 Clinical Trial Experience
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`Reference ID: 4117448
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` -------------------------------ADVERSE REACTIONS------------------------------
` The most common adverse reactions (≥ 2%) in clinical trials were
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` nausea/vomiting, headache, bleeding irregularities, dysmenorrhea, weight
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` change, breast tenderness, acne, abdominal pain, anxiety and depression (6.1)
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` To report SUSPECTED ADVERSE REACTIONS, contact Warner
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` Chilcott at 1-800-521-8813 or FDA at 1-800-FDA-1088 or
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` www.fda.gov/medwatch.
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`------------------------------DRUG INTERACTIONS-------------------------------
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` Drugs or herbal products that induce certain enzymes, including CYP3A4,
` may decrease the effectiveness of COCs or increase breakthrough bleeding.
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` Counsel patients to use a back-up method or alternative method of
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` contraception when enzyme inducers are used with COCs (7.1)
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` ------------------------USE IN SPECIFIC POPULATIONS-----------------------
` Nursing mothers: Not recommended; can decrease milk production (8.3)
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` See 17 for PATIENT COUNSELING INFORMATION and FDA-
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` approved patient labeling.
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` Revised: 06/2017
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` 6.2
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` Postmarketing Experience
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` 7 DRUG INTERACTIONS
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` 7.1 Effects of Other Drugs on Combined Oral Contraceptives
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` 7.2 Effects of Combined Oral Contraceptives on Other Drugs
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` 7.3
` Interference with Laboratory Tests
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` 8 USE IN SPECIFIC POPULATIONS
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` Pregnancy
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` 8.1
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` 8.3 Nursing Mothers
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` 8.4
` Pediatric Use
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` 8.5 Geriatric Use
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` 8.6 Hepatic Impairment
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` 8.7 Renal Impairment
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` 8.8 Body Mass Index
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` 10 OVERDOSAGE
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` 11 DESCRIPTION
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` 12 CLINICAL PHARMACOLOGY
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` 12.1 Mechanism of Action
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` 12.2 Pharmacodynamics
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` 12.3 Pharmacokinetics
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` 13 NONCLINICAL TOXICOLOGY
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` 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
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` 14 CLINICAL STUDIES
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` 16 HOW SUPPLIED/STORAGE AND HANDLING
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` 16.1 How Supplied
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` 16.2 Storage Conditions
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` 17 PATIENT COUNSELING INFORMATION
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` *Sections or subsections omitted from the full prescribing information are not
`listed.
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` FULL PRESCRIBING INFORMATION
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`
`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
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`
`
` should not be used by women who are over 35 years of age and smoke [see
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`
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`
`
`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
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` kg/m2 has not been evaluated.
`
`
`
` 2 DOSAGE AND ADMINISTRATION
`
` 2.1 How to Take Lo Minastrin Fe
`
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` To achieve maximum contraceptive effectiveness, Lo Minastrin Fe must be taken exactly as
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` directed. Instruct patients to take one tablet by mouth at the same time every day. The blue
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` tablet should be chewed and swallowed. The patient should drink a full glass (8 ounces) of
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` water immediately after chewing and swallowing the blue tablet. The white tablet and the
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` brown tablet are swallowed. Tablets must be taken in the order directed on the blister pack.
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`Tablets should not be skipped or taken at intervals exceeding 24 hours. For patient
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`
`
` instructions for missed tablets [see FDA-approved patient labeling]. Lo Minastrin Fe may be
` administered without regard to meals [see Clinical Pharmacology (12.3)].
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`
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`
` 2.2 How to Start Lo Minastrin Fe
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` Instruct the patient to begin taking Lo Minastrin Fe on Day 1 of her menstrual cycle (that is,
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` the first day of her menstrual bleeding) [see FDA-approved patient labeling]. One blue tablet
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` should be taken daily for 24 consecutive days, followed by one white tablet daily for
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` 2 consecutive days, followed by one brown tablet daily for 2 consecutive days. Instruct the
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` patient to use a non-hormonal contraceptive as back-up during the first 7 days if she starts
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` taking Lo Minastrin Fe other than on the first day of her menstrual cycle.
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`For postpartum women who do not breastfeed or after a second trimester abortion, Lo
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` 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
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`period, the increased risk of thromboembolic disease associated with the postpartum period
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`Reference ID: 4117448
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` must be considered [see Warnings and Precautions (5.1)]. The possibility of ovulation and
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` conception before starting COCs should also be considered.
` Lo Minastrin Fe may be initiated immediately after a first-trimester abortion or miscarriage;
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` if the patient starts Lo Minastrin Fe immediately, additional contraceptive measures are not
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` needed.
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` 2.3 Switching from another Hormonal Method of Contraception
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` If the patient is switching from a combination hormonal method such as:
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` Another pill
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` Vaginal ring
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` Patch
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` Instruct her to take the first blue tablet on the day she would have taken her next COC
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`pill. She should not continue taking the tablets from her previous birth control pack, and
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` should not skip any days between packs. If she does not have a withdrawal bleed, rule out
` pregnancy before starting Lo Minastrin Fe.
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` If she previously used a vaginal ring or transdermal patch, she should start using Lo
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` Minastrin Fe on the day she would have resumed the previous product.
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` If the patient is switching from a progestin-only method such as a:
` Progestin-only pill
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` Implant
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` Intrauterine system
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` Injection
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` She may switch any day from a progestin-only pill; instruct her to take the first blue
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`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
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` 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
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`may be needed.
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` 2.4 Advice in Case of Gastrointestinal Disturbances
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` If the patient vomits or has diarrhea (within 3 to 4 hours after she takes a blue or white
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`tablet), she should follow the instructions in the “What to Do if You Miss Tablets” section
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` [see FDA-approved patient labeling].
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`
`
` 3 DOSAGE FORMS AND STRENGTHS
`
` Lo Minastrin Fe is available in blister packs.
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`
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` Each blister pack contains 28 tablets in the following order:
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` 24 blue, round, chewable, mint-flavored (active) tablets imprinted with “WC” on one side
`
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` and “537” on the other and each containing 1 mg norethindrone acetate and 10 mcg
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`
`
` ethinyl estradiol.
` 2 white, hexagonal (active) tablets imprinted with “WC” on one side and “422” on the
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`
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` other and each containing 10 mcg ethinyl estradiol.
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`
`
`Reference ID: 4117448
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`
`
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` 2 brown, round (non-hormonal placebo) tablets imprinted with “WC” on one side and
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` “624” on the other and each containing 75 mg ferrous fumarate. The ferrous fumarate
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` tablets do not serve any therapeutic purpose.
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`
`
` 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:
`
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`
`
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` 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
`
`
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`
`
` and Precautions (5.1)]
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` Have cerebrovascular disease [see Warnings and Precautions (5.1)]
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` Have coronary artery disease [see Warnings and Precautions (5.1)]
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`
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` Have thrombogenic valvular or thrombogenic rhythm diseases of the heart (for
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` example, subacute bacterial endocarditis with valvular disease, or atrial fibrillation)
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` [see Warnings and Precautions (5.1)]
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` Have inherited or acquired hypercoagulopathies [see Warnings and Precautions
`
`
` (5.1)]
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` Have uncontrolled hypertension [see Warnings and Precautions (5.3)]
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` Have diabetes mellitus with vascular disease [see Warnings and Precautions (5.5)]
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` Have headaches with focal neurological symptoms or have migraine headaches with
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` aura [see Warnings and Precautions (5.6)]
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` o Women over age 35 with any migraine headaches [see Warnings and Precautions
`
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`
` (5.6)]
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`
` Liver tumors, benign or malignant, or liver disease [see Warnings and Precautions (5.2)]
`
` Undiagnosed abnormal uterine bleeding [see Warnings and Precautions (5.7)]
`
`
`
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` Pregnancy, because there is no reason to use COCs during pregnancy [see Warnings and
`
`
`
`
`
` Precautions (5.8) 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 (5.10)]
`
` Hypersensitivity to any ingredients in Lo Minastrin Fe
`
`
`
` 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.
`
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` If feasible, stop Lo Minastrin Fe at least 4 weeks before and through 2 weeks after major
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` surgery or other surgeries known to have an elevated risk of VTE.
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`Reference ID: 4117448
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` Start Lo Minastrin Fe no earlier than 4 weeks after delivery, in women who are not
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`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 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.
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`
`Reference ID: 4117448
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`
`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.
`
`
` 5.4 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.
`
`
` 5.5 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.
`
`
` 5.6 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)].
`
`
` 5.7 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.
`
`
` 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.
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`
`Reference ID: 4117448
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`
` 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.
`
`
`
`
`
`
` 5.8 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)].
`
`
`
`
`
` 5.9 Depression
`
` Carefully observe women with a history of depression and discontinue Lo Minastrin Fe if
`
`
`depression recurs to a serious degree.
`
`
` 5.10 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.
`
`
`
`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.
`
`
`
`
` 5.11 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.
`
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`Reference ID: 4117448
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` 5.12 Monitoring
`
` A woman who is taking COCs should have a yearly visit with her healthcare provider for a
`
`
`
` blood pressure check and for other indicated healthcare.
`
`
` 5.13 Hereditary Angioedema
`
` In women with hereditary angioedema, exogenous estrogens may induce or exacerbate
`
`symptoms of angioedema.
`
`
`
` 5.14 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.
`
`
`
`
` 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
`
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`Reference ID: 4117448
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` 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
`
` 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.
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`Reference ID: 4117448
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` 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
`
`
` 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 Drugs
`
`
` COCs containing ethinyl estradiol may inhibit the metabolism of other compounds (for
`
`
`example, cyclosporine, prednisolone, theophylline, tizanidine, and voriconazole) and
`
` increase their plasma concentrations. COCs have been shown to decrease plasma
` concentrations of acetaminophen, clofibric acid, morphine, salicylic acid and temazepam. A
`
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`Reference ID: 4117448
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`
` significant decrease in the plasma concentration of lamotrigine has been shown, likely due to
`
`
`
`
`
` induction of lamotrigine glucuronidation. This may reduce seizure control; therefore, dosage
`
` adjustments of lamotrigine may be necessary.
`
` Women on thyroid hormone replacement therapy may need increased doses of thyroid
`
`
` hormone because serum concentration of thyroid-binding globulin increases with use of
`
`
`
` COCs [see Warnings and Precautions (5.11)].
`
`
` Interference with Laboratory Tests
`
`7.3
`
`
` The use of contraceptive steroids may influenc