Lo Loestrin Fe

• Warner Chilcott (US), LLC

In the U.S.

• Lo Loestrin Fe
• Lo Minastrin Fe

Available Dosage Forms:

• Tablet
• Tablet, Chewable

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies on the relationship of age to the effects of norethindrone, ethinyl estradiol, and ferrous fumarate combination have not been performed in the pediatric population. However, pediatric-specific problems that would limit the usefulness of this medicine in teenagers are not expected. This medicine may be used for birth control in teenage females but should not be used before the start of menstruation.

Geriatric

Appropriate studies on the relationship of age to the effects of norethindrone, ethinyl estradiol, and ferrous fumarate combination have not been performed in the geriatric population. This medicine should not be used in elderly women.

Pregnancy

Breast Feeding

Studies suggest that this medication may alter milk production or composition. If an alternative to this medication is not prescribed, you should monitor the infant for side effects and adequate milk intake.

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

• Dasabuvir
• Ombitasvir
• Paritaprevir
• Ritonavir
• Tranexamic Acid

Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Anagrelide
• Aprepitant
• Boceprevir
• Bosentan
• Bupropion
• Carbamazepine
• Ceritinib
• Dabrafenib
• Darunavir
• Dexamethasone
• Dimercaprol
• Donepezil
• Eliglustat
• Eltrombopag
• Enzalutamide
• Fosphenytoin
• Griseofulvin
• Idelalisib
• Isotretinoin
• Lesinurad
• Lixisenatide
• Lumacaftor
• Mitotane
• Modafinil
• Oxcarbazepine
• Paclitaxel
• Paclitaxel Protein-Bound
• Phenytoin
• Piperaquine
• Pitolisant
• Prednisone
• Rifabutin
• Rifampin
• St John's Wort
• Sugammadex
• Theophylline
• Tizanidine
• Topiramate
• Ulipristal
• Valproic Acid

Using this medicine with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Alprazolam
• Amprenavir
• Atazanavir
• Bacampicillin
• Betamethasone
• Bexarotene
• Carbidopa
• Cefdinir
• Clarithromycin
• Colesevelam
• Cyclosporine
• Delafloxacin
• Delavirdine
• Demeclocycline
• Dolutegravir
• Doxycycline
• Efavirenz
• Eslicarbazepine Acetate
• Etoricoxib
• Fosamprenavir
• Fosaprepitant
• Gatifloxacin
• Ginseng
• Grepafloxacin
• Lamotrigine
• Levodopa
• Levofloxacin
• Levothyroxine
• Licorice
• Lomefloxacin
• Methyldopa
• Minocycline
• Moxifloxacin
• Mycophenolate Mofetil
• Mycophenolic Acid
• Nelfinavir
• Norfloxacin
• Ofloxacin
• Omeprazole
• Parecoxib
• Penicillamine
• Prednisolone
• Rifapentine
• Ritonavir
• Roflumilast
• Rosuvastatin
• Rufinamide
• Selegiline
• Telaprevir
• Temafloxacin
• Tetracycline
• Tipranavir
• Troglitazone
• Troleandomycin
• Trovafloxacin Mesylate
• Valdecoxib
• Voriconazole
• Warfarin
• Zinc

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following may cause an increased risk of certain side effects but may be unavoidable in some cases. If used together, your doctor may change the dose or how often you use this medicine, or give you special instructions about the use of food, alcohol, or tobacco.

• Caffeine
• Dairy Food
• Grapefruit Juice
• Phytic Acid Containing Food

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

• Abnormal or unusual vaginal bleeding or
• Blood clots (eg, deep vein thrombosis, pulmonary embolism), or history of or
• Breast cancer, active or history of or
• Diabetes with kidney, eye, nerve, or blood vessel damage or
• Heart attack, history of or
• Heart or blood vessel disease (eg, coronary artery disease, heart valve problems) or
• Heart rhythm problems (atrial fibrillation) or
• Hypertension (high blood pressure), poorly controlled or
• Liver disease, including tumors or cancer or
• Migraine headache, new or worse or a new kind of headache or
• Problems with circulation or blood clots, now or in the past or
• Stroke, history of—Should not be used in patients with these conditions.

• Angioedema (swelling of the face, tongue, or throat), inherited or
• Cervical cancer or intraepithelial neoplasia or
• Chloasma gravidarum (skin disorder during pregnancy), history of or
• Cholestasis (bile problem) during pregnancy, history of or
• Depression, history of or
• Diabetes or
• Dyslipidemia (high cholesterol or fats in the blood), uncontrolled or
• Gallbladder disease or
• Hypertension (high blood pressure)—Use with caution. May make these conditions worse.

• Tell all of your health care providers that you take this medicine. This includes your doctors, nurses, pharmacists, and dentists. This medicine may need to be stopped before certain types of surgery as your doctor has told you. If Lo Loestrin Fe is stopped, your doctor will tell you when to start taking this medicine again after your surgery or procedure.
• This medicine may raise the chance of blood clots, a stroke, or a heart attack. Talk with the doctor.
• Talk with your doctor if you will need to be still for long periods of time like long trips, bedrest after surgery, or illness. Not moving for long periods may raise your chance of blood clots.
• Some studies have shown the risk of breast cancer is raised in women taking birth control pills, especially at a younger age. This includes birth control pills that have drugs like this one in them. The risk was also linked to how long the birth control pills were taken. One study showed the risk of breast cancer was also raised in women who took birth control pills within the past 10 years. Talk with the doctor.
• If you have high blood sugar (diabetes), talk with your doctor. This medicine may raise blood sugar.
• Check your blood sugar as you have been told by your doctor.
• High blood pressure has happened with drugs like this one. Have your blood pressure checked as you have been told by your doctor.
• Have blood work checked as you have been told by the doctor. Talk with the doctor.
• Be sure to have regular breast exams and gynecology check-ups. Your doctor will tell you how often to have these. You will also need to do breast self-exams as your doctor has told you. Talk with your doctor.
• If you are allergic to tartrazine, talk with your doctor. Some products have tartrazine.
• If you drink grapefruit juice or eat grapefruit often, talk with your doctor.
• This medicine may affect certain lab tests. Tell all of your health care providers and lab workers that you take Lo Loestrin Fe.
• Certain drugs, herbal products, or health problems could cause this medicine to not work as well. Be sure your doctor knows about all of your drugs and health problems.
• This medicine does not stop the spread of diseases like HIV or hepatitis that are passed through blood or having sex. Do not have any kind of sex without using a latex or polyurethane condom. Do not share needles or other things like toothbrushes or razors. Talk with your doctor.
• This medicine may raise the chance of blood clots. The chance is highest during the first year of using Lo Loestrin Fe. The chance is also highest when starting to use hormone-based birth control again after not using it for 4 weeks or more. Talk with the doctor.
• If you are taking this medicine for pimples (acne), you need to be at least 15 years of age.
• If you have any signs of pregnancy or if you have a positive pregnancy test, call your doctor right away.

Use Lo Loestrin Fe (ethinyl estradiol, norethindrone, and ferrous fumarate) as ordered by your doctor. Read all information given to you. Follow all instructions closely.

• Follow how to use as you have been told by the doctor or read the package insert.
• Take this medicine at the same time of day.
• Take with or without food. Take with food if it causes an upset stomach.
• Do not skip doses, even if you do not have sex very often.
• If you throw up or have diarrhea, Lo Loestrin Fe may not work as well to prevent pregnancy. Use an extra form of birth control, like condoms, until you check with your doctor.
• If you miss 2 periods in a row, take a pregnancy test before starting a new cycle.

What do I do if I miss a dose?

• If a dose is missed, check the package insert or call the doctor to find out what to do. If using this medicine to prevent pregnancy, another form of birth control may need to be used for some time to prevent pregnancy.

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)]. 

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 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 Cmax 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 AUC0–24h 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)

Figure 2.       Mean (± SD) plasma norethindrone concentration versus time profiles following single- and multiple-dose oral administration of Lo Loestrin Fe to healthy female volunteers (n = 15)

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)].