FDA Label for Lo Loestrin Fe

Warning: Cigarette Smoking And Serious Cardiovascular Events

Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptive (COC) use. This risk increases with age, particularly in women over 35 years of age, and with the number of cigarettes smoked. For this reason, COCs should not be used by women who are over 35 years of age and smoke [see Contraindications (4)].

1       Indications And Usage

Lo Loestrin^® Fe is indicated for use by women to prevent pregnancy [see Clinical Studies (14)].  

The efficacy of Lo Loestrin Fe in women with a body mass index (BMI) of > 35 kg/m² has not been evaluated.

2.1       How To Take Lo Loestrin Fe

To achieve maximum contraceptive effectiveness, Lo Loestrin Fe must be taken exactly as directed. Take one tablet by mouth at the same time every day. Tablets must be taken in the order directed on the blister pack. Tablets should not be skipped or taken at intervals exceeding 24 hours. For patient instructions for missed pills, see FDA-Approved Patient Labeling. Lo Loestrin Fe tablets may be administered without regard to meals [see Clinical Pharmacology (12.3)].

2.2       How To Start Lo Loestrin Fe

Instruct the patient to begin taking Lo Loestrin Fe on Day 1 of her menstrual cycle (that is, the first day of her menstrual bleeding) [see FDA-Approved Patient Labeling]. One blue tablet should be taken daily for 24 consecutive days, followed by one white tablet daily for 2 consecutive days, followed by one brown tablet daily for 2 consecutive days. Instruct the patient to use a non-hormonal contraceptive as back-up during the first 7 days if she starts taking Lo Loestrin Fe other than on the first day of her menstrual cycle.

For postpartum women who do not breastfeed or after a second trimester abortion, Lo Loestrin Fe may be started no earlier than 4 weeks postpartum. Recommend use of a non-hormonal back-up method for the first 7 days. When COCs are used during the postpartum period, the increased risk of thromboembolic disease associated with the postpartum period must be considered [see Warnings and Precautions (5.1)]. The possibility of ovulation and conception before starting COCs should also be considered.

Lo Loestrin Fe may be initiated immediately after a first-trimester abortion or miscarriage; if the patient starts Lo Loestrin Fe immediately, additional contraceptive measures are not needed. 

2.3       Switching From Another Hormonal Method Of Contraception

If the patient is switching from a combination hormonal method such as:
○ Another pill
○ Vaginal ring
○ Patch

• Instruct her to take the first blue tablet on the day she would have taken her next COC pill. She should not continue taking the tablets from her previous birth control pack, and should not skip any days between packs. If she does not have a withdrawal bleed, rule out pregnancy before starting Lo Loestrin Fe.
  
• If she previously used a vaginal ring or transdermal patch, she should start using Lo Loestrin Fe on the day she would have resumed the previous product.

If the patient is switching from a progestin-only method such as a:
○ Progestin-only pill
○ Implant
○ Intrauterine system
○ Injection

• Instruct her to take the first blue tablet on the day she would have taken her next progestin-only pill, or had her next injection or on the day of removal of her implant.
  
• If switching from an IUD, depending on the timing of removal, back-up contraception may be needed.

2.4       Advice In Case Of Gastrointestinal Disturbances

If the patient vomits or has diarrhea (within 3 to 4 hours after she takes a blue or white pill), she should follow the instructions in the “What to Do if You Miss Pills” section [see FDA-Approved Patient Labeling].  

3       Dosage Forms And Strengths

Lo Loestrin Fe (norethindrone acetate and ethinyl estradiol tablets, ethinyl estradiol tablets and ferrous fumarate tablets) is available in blister packs.

Each blister pack (28 tablets) contains in the following order:

• 24 blue, round (active) tablets imprinted with “WC” on one side and “421” on the other and each containing 1 mg norethindrone acetate and 10 mcg ethinyl estradiol.
  
• 2 white, hexagonal (active) tablets imprinted with “WC” on one side and “422” on the other and each containing 10 mcg ethinyl estradiol.
  
• 2 brown, round (non-hormonal placebo) tablets imprinted with “WC” on one side and “624” on the other and each containing 75 mg ferrous fumarate. The ferrous fumarate tablets do not serve any therapeutic purpose. 

4       Contraindications

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)]. 

5.1       Thrombotic And Other Vascular Events

Stop Lo Loestrin Fe if an arterial or deep venous thrombotic event occurs. Although use of COCs increases the risk of venous thromboembolism, pregnancy increases the risk of venous thromboembolism as much or more than the use of COCs. The risk of venous thromboembolism in women using COCs is 3 to 9 per 10,000 woman-years. The risk is highest during the first year of use of a COC. Use of COCs also increases the risk of arterial thromboses such as strokes and myocardial infarctions, especially in women with other risk factors for these events. The risk of thromboembolic disease due to oral contraceptives gradually disappears after COC use is discontinued.

If feasible, stop Lo Loestrin Fe at least 4 weeks before and through 2 weeks after major surgery or other surgeries known to have an elevated risk of thromboembolism.

Start Lo Loestrin Fe no earlier than 4 weeks after delivery, in women who are not breastfeeding. The risk of postpartum thromboembolism decreases after the third postpartum week, whereas the risk of ovulation increases after the third postpartum week.

COCs have been shown to increase both the relative and attributable risks of cerebrovascular events (thrombotic and hemorrhagic strokes), although, in general, the risk is greatest in older (> 35 years of age), hypertensive women who also smoke. COCs also increase the risk for stroke in women with underlying risk factors.

Oral contraceptives must be used with caution in women with cardiovascular disease risk factors.

Stop Lo Loestrin Fe if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions. Evaluate for retinal vein thrombosis immediately.

5.2       Carcinoma Of The Breasts And Cervix

Women who currently have or have had breast cancer should not use Lo Loestrin Fe because breast cancer is a hormonally-sensitive tumor.

There is substantial evidence that COCs do not increase the incidence of breast cancer. Although some past studies have suggested that COCs might increase the incidence of breast cancer, more recent studies have not confirmed such findings.

Some studies suggest that COCs are associated with an increase in the risk of cervical cancer or intraepithelial neoplasia. However, there is controversy about the extent to which these findings may be due to differences in sexual behavior and other factors.

5.3       Liver Disease

Discontinue Lo Loestrin Fe if jaundice develops. Steroid hormones may be poorly metabolized in patients with impaired liver function. Acute or chronic disturbances of liver function may necessitate the discontinuation of COC use until markers of liver function return to normal and COC causation has been excluded.

Hepatic adenomas are associated with COC use. An estimate of the attributable risk is 3.3 cases per 100,000 COC users. Rupture of hepatic adenomas may cause death through intra-abdominal hemorrhage.

Studies have shown an increased risk of developing hepatocellular carcinoma in long-term (>8 years) COC users. However, the attributable risk of liver cancers in COC users is less than one case per million users.

Oral contraceptive-related cholestasis may occur in women with a history of pregnancy-related cholestasis. Women with a history of COC-related cholestasis may have the condition recur with subsequent COC use.

5.4       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.

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.

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 ≥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.

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.

8.1       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.

8.3       Nursing Mothers

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.

8.5       Geriatric Use

Lo Loestrin Fe has not been studied in postmenopausal women and is not indicated in this population.

8.6       Renal Impairment

The pharmacokinetics of Lo Loestrin Fe has not been studied in subjects with renal impairment. 

8.7       Hepatic Impairment

No studies have been conducted to evaluate the effect of hepatic impairment on the disposition of Lo Loestrin Fe. However, steroid hormones may be poorly metabolized in patients with impaired liver function. Acute or chronic disturbances of liver function may necessitate the discontinuation of COC use until markers of liver function return to normal and COC causation has been excluded [see Contraindications (4) and Warnings and Precautions (5.3)].

8.8       Body Mass Index

The safety and efficacy of Lo Loestrin Fe in women with a body mass index (BMI) > 35 kg/m² has not been evaluated [see Clinical Studies (14)]. 

10       Overdosage

There have been no reports of serious ill effects from overdose of oral contraceptives, including ingestion by children. Overdosage may cause withdrawal bleeding in females and nausea.

11       Description

Lo Loestrin Fe (norethindrone acetate and ethinyl estradiol tablets, ethinyl estradiol tablets and ferrous fumarate tablets) provides an oral contraceptive regimen consisting of 24 blue active tablets and 2 white active tablets that contain the active ingredients specified for each tablet below, followed by 2 non-hormonal placebo tablets:

• 24 blue, round tablets each containing 1 mg norethindrone acetate and 10 mcg ethinyl estradiol
  
• 2 white, hexagonal tablets each containing 10 mcg ethinyl estradiol
  
• 2 brown, round tablets each containing 75 mg ferrous fumarate

Each blue tablet also contains the inactive ingredients mannitol, microcrystalline cellulose, FD&C Blue No. 1 Aluminum Lake, sodium starch glycolate, magnesium stearate, povidone, vitamin E and lactose monohydrate.

Each white tablet also contains the inactive ingredients mannitol, microcrystalline cellulose, sodium starch glycolate, magnesium stearate, povidone, vitamin E and lactose monohydrate.

Each brown tablet contains ferrous fumarate, mannitol, povidone, microcrystalline cellulose, sodium starch glycolate, magnesium stearate, sucralose and spearmint flavor. The ferrous fumarate tablets do not serve any therapeutic purpose. Ferrous fumarate tablets are not USP for dissolution and assay.

The empirical formula of ethinyl estradiol is C₂₀H₂₄O₂ and the structural formula is:

     

The structural formula for ethinyl estradiol is [19-Norpregna-1,3,5(10)-trien-20-yne-3,17-diol, (17)-]. - lo loestrin fe 01

The chemical name of ethinyl estradiol is [19-Norpregna-1,3,5(10)-trien-20-yne-3,17-diol, (17α)-].

The empirical formula of norethindrone acetate is C₂₂H₂₈O₃ and the structural formula is:

     

The chemical name of norethindrone acetate is [19-Norpregn-4-en-20-yn-3-one, 17-(acetyloxy)-, (17α)-].

12.1       Mechanism Of Action

COCs lower the risk of becoming pregnant primarily by suppressing ovulation. Other possible mechanisms may include cervical mucus changes that inhibit sperm penetration and endometrial changes that reduce the likelihood of implantation.

12.2       Pharmacodynamics

No specific pharmacodynamic studies were conducted with Lo Loestrin Fe. 

12.3       Pharmacokinetics

Absorption

Norethindrone acetate is deacetylated to norethindrone after oral administration, and the disposition of norethindrone acetate is indistinguishable from that of orally administered norethindrone. Norethindrone acetate and ethinyl estradiol are absorbed from Lo Loestrin Fe, with maximum plasma concentrations of norethindrone and ethinyl estradiol generally occurring 1 to 2 hours postdose. Both are subject to first-pass metabolism after oral dosing, resulting in an absolute bioavailability of approximately 64 percent for norethindrone and 55 percent for ethinyl estradiol.

The rate of norethindrone and ethinyl estradiol absorption from Lo Loestrin Fe tablets containing the combination of 1 mg norethindrone acetate and 10 mcg ethinyl estradiol is slower than that from a norethindrone suspension/ethinyl estradiol solution, but the extent of absorption is equivalent.

Ethinyl estradiol bioavailability from Lo Loestrin Fe tablets containing 10 mcg ethinyl estradiol alone is equivalent to that from an ethinyl estradiol solution.

The plasma norethindrone and ethinyl estradiol pharmacokinetic profiles and serum sex hormone binding globulin (SHBG) concentrations following multiple-dose administration of Lo Loestrin Fe were characterized in 15 healthy female volunteers. The mean plasma concentrations are shown below (Figures 1 and 2), and pharmacokinetic parameters are found in Table 1.

Ethinyl estradiol and norethindrone C_max values increase by a factor of 1.4 and 1.9, respectively, following 24 days administration of Lo Loestrin Fe combination tablets as compared to single-dose administration. Ethinyl estradiol and norethindrone AUC_0–24h values increase by a factor of 1.6 and 2.5, respectively, following 24 days administration of Lo Loestrin Fe combination tablets as compared to single-dose administration. Norethindrone concentrations more than double by Day 24 due to both accumulation and increased SHBG concentration. Steady state with respect to ethinyl estradiol and norethindrone is reached by Day 5 and Day 13, respectively.

Figure 1. Mean (± SD) plasma ethinyl estradiol concentration versus time profiles following single- and multiple-dose oral administration of Lo Loestrin Fe to healthy female volunteers (n = 15) - lo loestrin fe 03

Food Effect:
Lo Loestrin Fe tablets may be administered without regard to meals.

Administration of food with a single-dose of a Lo Loestrin Fe combination tablet did not affect the maximum concentration of norethindrone and increased the extent of absorption by 24 percent; it decreased the maximum concentration of ethinyl estradiol by 23 percent and did not affect the extent of absorption. 

Administration of food with a single-dose of a Lo Loestrin Fe ethinyl estradiol alone tablet decreased the maximum concentration of ethinyl estradiol by 31 percent and did not affect the extent of absorption.

Distribution
Volume of distribution of norethindrone and ethinyl estradiol ranges from 2 to 4 L/kg. Plasma protein binding of both steroids is extensive (>95 percent); norethindrone binds to both albumin and SHBG, whereas ethinyl estradiol binds only to albumin. Although ethinyl estradiol does not bind to SHBG, it induces SHBG synthesis.

Metabolism
Norethindrone undergoes extensive biotransformation, primarily via reduction, followed by sulfate and glucuronide conjugation. The majority of metabolites in the circulation are sulfates, with glucuronides accounting for most of the urinary metabolites. A small amount of norethindrone acetate is metabolically converted to ethinyl estradiol.

Ethinyl estradiol is also extensively metabolized, both by oxidation and by conjugation with sulfate and glucuronide. Sulfates are the major circulating conjugates of ethinyl estradiol and glucuronides predominate in urine. The primary oxidative metabolite is 2-hydroxy ethinyl estradiol, formed by the CYP3A4 isoform of cytochrome P450. Part of the first-pass metabolism of ethinyl estradiol is believed to occur in gastrointestinal mucosa. Ethinyl estradiol may undergo enterohepatic circulation.

Excretion
Norethindrone and ethinyl estradiol are excreted in both urine and feces, primarily as metabolites. Plasma clearance values for norethindrone and ethinyl estradiol are similar (approximately 0.4 L/hr/kg). Elimination half-lives of norethindrone and ethinyl estradiol following administration of 1 mg norethindrone acetate/10 mcg ethinyl estradiol tablets are approximately 10 hours and 16 hours, respectively.

Specific populations
The pharmacokinetics of Lo Loestrin Fe in presence of renal or hepatic impairment has not been evaluated [see Use in Specific Populations (8.6) and (8.7)].

13.1       Carcinogenesis, Mutagenesis, Impairment Of Fertility

[See Warnings and Precautions (5.2, 5.3) and Use in Specific Populations (8.1).]

14       Clinical Studies

In a one year (thirteen 28-day cycles) multicenter open-label clinical trial, 1,270 women 18 to 35 years of age, were studied to assess the efficacy of Lo Loestrin Fe, completing the equivalent of 12,482 28-day evaluable cycles of exposure. The racial demographic of all enrolled women was: Caucasian (74.9 percent), African-American (11.8 percent), Hispanic (9.8 percent), Asian (1.3 percent), and Other (2.2 percent). Women with body mass index (BMI) greater than 35 mg/m² were excluded from the study. The weight range for those women treated was 89 to 260 lbs., with a mean weight of 150 lbs. Among the women in the trial, 51 percent had not used hormonal contraception immediately prior to enrolling in this study. Of treated women, 13.7 percent were lost to follow-up, 10.7 percent discontinued due to an adverse event, and 8.9 percent discontinued by withdrawing their consent.

The pregnancy rate (Pearl Index [PI]) in women 18 to 35 years of age was 2.92 pregnancies per 100 women-years of use (95 percent confidence interval 1.94 – 4.21), based on 28 pregnancies that occurred after the onset of treatment and extending through the 7 days following the last dose of Lo Loestrin Fe. Cycles in which conception did not occur, but which included the use of backup contraception, were not included in the calculation of the PI. The PI includes women who did not take the drug correctly.   

16.1       How Supplied

Lo Loestrin^® Fe (norethindrone acetate and ethinyl estradiol tablets, ethinyl estradiol tablets and ferrous fumarate tablets) is available in blister cards (dispensers) containing 28 tablets: 

NDC 0430-0420-14             Cartons of 5 blister cards (dispensers)

NDC 0430-0420-60             Cartons of 30 blister cards (dispensers)

Each blister card (28 tablets) contains in the following order:

• 24 blue, round tablets (active) imprinted with “WC” on one side and “421” on the other and each containing 1 mg norethindrone and 10 mcg ethinyl estradiol
  
• 2 white, hexagonal tablets (active) imprinted with “WC” on one side and “422” on the other and each containing 10 mcg ethinyl estradiol
  
• 2 brown, round tablets (non-hormonal placebo) imprinted with “WC” on one side and “624” on the other and each containing 75 mg ferrous fumarate

 

16.2       Storage Conditions

Store at 25° C (77° F); excursions permitted to 15 - 30° C (59 - 86° F) [see USP Controlled Room Temperature].

Keep this drug and all drugs out of the reach of children.

17       Patient Counseling Information

• Counsel patients that cigarette smoking increases the risk of serious cardiovascular events from COC use, and that women who are over 35 years old and smoke should not use COCs.
  
• Counsel patients that Lo Loestrin Fe does not protect against HIV infection (AIDS) and other sexually transmitted diseases.
  
• Counsel patients on the Warnings and Precautions associated with COCs.
  
• Counsel patients to take one tablet daily by mouth at the same time every day. Instruct patients what to do in the event pills are missed. See “What to Do if You Miss Pills” section in FDA-Approved Patient Labeling.
  
• Counsel patients to use a back-up or alternative method of contraception when enzyme inducers are used with Lo Loestrin Fe.
  
• Counsel patients who are breastfeeding or who desire to breastfeed that COCs may reduce breast milk production. This is less likely to occur if breastfeeding is well established.
  
• Counsel any patient who starts COCs postpartum, and who has not yet had a period, to use an additional method of contraception until she has taken a blue tablet for 7 consecutive days.
  
• Counsel patients that amenorrhea may occur. Rule out pregnancy in the event of amenorrhea in two or more consecutive cycles.