Professional Information — Larin Fe 1/20

Indications and Usage

LARIN™ Fe 1/20 is indicated for the prevention of pregnancy in women who elect to use oral contraceptives as a method of contraception.

Oral contraceptives are highly effective. Table I lists the typical accidental pregnancy rates for users of combination oral contraceptives and other methods of contraception. The efficacy of these contraceptive methods, except sterilization, depends upon the reliability with which they are used. Correct and consistent use of methods can result in lower failure rates.

*The authors' best guess of the percentage of women expected to experience an accidental pregnancy among couples who initiate a method (not necessarily for the first time) and who use it consistently and correctly during the first year if they do not stop for any other reason.

**This term represents "typical" couples who initiate use of a method (not necessarily for the first time), who experience an accidental pregnancy during the first year if they do not stop use for any other reason.

***N/A--Data not available

Dosage and Administration

The tablet dispenser has been designed to make oral contraceptive dosing as easy and as convenient as possible. The tablets are arranged in four rows of seven tablets each, with the days of the week appearing on the tablet dispenser above the first row of tablets.

Note: Each tablet dispenser has been preprinted with the days of the week, starting with Sunday, to facilitate a Sunday-Start regimen. Six different day label stickers have been provided with the Detailed Patient & Brief Summary Patient Package Insert in order to accommodate a Day-1 Start regimen. If the patient is using the Day-1 Start regimen, she should place the self-adhesive day label sticker that corresponds to her starting day over the preprinted days.

Important: The patient should be instructed to use an additional method of protection until after the first week of administration in the initial cycle when utilizing the Sunday-Start regimen.

The possibility of ovulation and conception prior to initiation of use should be considered.

To achieve maximum contraceptive effectiveness, LARIN™ Fe 1/20 should be taken exactly as directed and at intervals not exceeding 24 hours.

LARIN™ Fe 1/20 provides a continuous administration regimen consisting of 21 pale yellow tablets of norethindrone acetate and ethinyl estradiol and 7 brown non-hormone containing tablets of ferrous fumarate. The ferrous fumarate tablets are present to facilitate ease of drug administration via a 28-day regimen and do not serve any therapeutic purpose. There is no need for the patient to count days between cycles because there are no "off-tablet days."

A.     Sunday-Start Regimen: The patient begins taking the first pale yellow tablet from the top row of the dispenser (labeled Sunday) on the first Sunday after menstrual flow begins. When the menstrual flow begins on Sunday, the first pale yellow tablet is taken on the same day. The patient takes one pale yellow tablet daily for 21 days. The last pale yellow tablet in the dispenser will be taken on a Saturday. Upon completion of all 21 pale yellow tablets, and without interruption, the patient takes one brown tablet daily for 7 days. Upon completion of this first course of tablets, the patient begins a second course of 28-day tablets, without interruption, the next day (Sunday), starting with the Sunday pale yellow tablet in the top row. Adhering to this regimen of one pale yellow tablet daily for 21 days, followed without interruption by one brown tablet daily for seven days, the patient will start all subsequent cycles on a Sunday.

B.      Day-1 Start Regimen: The first day of menstrual flow is Day 1. The patient places the self-adhesive day label sticker that corresponds to her starting day over the preprinted days on the tablet dispenser. She starts taking one pale yellow tablet daily, beginning with the first pale yellow tablet in the top row. After the last pale yellow tablet (at the end of the third row) has been taken, the patient will then take the brown tablets for a week (7 days). For all subsequent cycles, the patient begins a new 28 tablet regimen on the eighth day after taking her last pale yellow tablet, again starting with the first tablet in the top row after placing the appropriate day label sticker over the preprinted days on the tablet dispenser. Following this regimen of 21 pale yellow tablets and 7 brown tablets, the patient will start all subsequent cycles on the same day of the week as the first course.

Tablets should be taken regularly with a meal or at bedtime. It should be stressed that efficacy of medication depends on strict adherence to the dosage schedule.

Special Notes on Administration

Menstruation usually begins two or three days, but may begin as late as the fourth or fifth day, after the brown tablets have been started. In any event, the next course of tablets should be started without interruption. If spotting occurs while the patient is taking pale yellow tablets, continue medication without interruption.

If the patient forgets to take one or more pale yellow tablets, the following is suggested:

One tablet is missed

take tablet as soon as remembered

take next tablet at the regular time

Two consecutive tablets are missed (week 1 or week 2)

take two tablets as soon as remembered

take two tablets the next day

use another birth control method for seven days following the missed tablets

Two consecutive tablets are missed (week 3)

Sunday-Start  Regimen:

take one tablet daily until Sunday

discard remaining tablets

start new pack of tablets immediately (Sunday)

use another birth control method for seven days following the missed tablets

Day-1  Start  Regimen:

discard remaining tablets

start new pack of tablets that same day

use another birth control method for seven days following the missed tablets

Three (or more) consecutive tablets are missed

Sunday-Start  Regimen:

take one tablet daily until Sunday

discard remaining tablets

start new pack of tablets immediately (Sunday)

use another birth control method for seven days following the missed tablets

Day-1  Start  Regimen:

discard remaining tablets

start new pack of tablets that same day

use another birth control method for seven days following the missed tablets

The possibility of ovulation occurring increases with each successive day that scheduled pale yellow tablets are missed. While there is little likelihood of ovulation occurring if only one pale yellow tablet is missed, the possibility of spotting or bleeding is increased. This is particularly likely to occur if two or more consecutive pale yellow tablets are missed.

If the patient forgets to take any of the seven brown tablets in week four, those brown tablets that were missed are discarded and one brown tablet is taken each day until the pack is empty. A back-up birth control method is not required during this time. A new pack of tablets should be started no later than the eighth day after the last pale yellow tablet was taken.

In the rare case of bleeding which resembles menstruation, the patient should be advised to discontinue medication and then begin taking tablets from a new tablet dispenser on the next Sunday or the first day (Day-1), depending on her regimen. Persistent bleeding which is not controlled by this method indicates the need for reexamination of the patient, at which time nonfunctional causes should be considered.

Use of Oral Contraceptives in the Event of a Missed Menstrual Period:

1. If the patient has not adhered to the prescribed dosage regimen, the possibility of pregnancy should be considered after the first missed period and oral contraceptives should be withheld until pregnancy has been ruled out.

2. If the patient has adhered to the prescribed regimen and misses two consecutive periods, pregnancy should be ruled out before continuing the contraceptive regimen.

After several months on treatment, bleeding may be reduced to a point of virtual absence. This reduced flow may occur as a result of medication, in which event it is not indicative of pregnancy.

Contraindications

Oral contraceptives are contraindicated in women who currently have the following conditions:

• Thrombophlebitis or thromboembolic disorders
• A past history of deep vein thrombophlebitis or thromboembolic disorders
• Cerebral vascular or coronary artery disease
• Current diagnosis of, or history of, breast cancer, which may be hormone sensitive
• Carcinoma of the endometrium or other known or suspected estrogen-dependent neoplasia
• Undiagnosed abnormal genital bleeding
• Cholestatic jaundice of pregnancy or jaundice with prior pill use
• Hepatic adenomas or carcinomas
• Are receiving Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to the potential for ALT elevations (see WARNINGS, RISK OF LIVER ENZYME ELEVATIONS WITH CONCOMITANT HEPATITIS C TREATMENT ).

Adverse Reactions

An increased risk of the following serious adverse reactions has been associated with the use of oral contraceptives (see WARNINGS section):

• Thrombophlebitis
• Arterial thromboembolism
• Pulmonary embolism
• Myocardial infarction
• Cerebral hemorrhage
• Cerebral thrombosis
• Hypertension
• Gallbladder disease
• Hepatic adenomas or benign liver tumors

Post Marketing Experience

Five studies that compared breast cancer risk between ever-users (current or past use) of COCs and never-users of COCs reported no association between ever use of COCs and breast cancer risk, with effect estimates ranging from 0.90 - 1.12 (Figure 1) (70-74).

Three studies compared breast cancer risk between current or recent COC users (<6 months since last use) and never users of COCs (Figure 1) (70,73,75). One of these studies reported no association between breast cancer risk and COC use. The other two studies found an increased relative risk of 1.19 - 1.33 with current or recent use. Both of these studies found an increased risk of breast cancer with current use of longer duration, with relative risks ranging from 1.03 with less than one year of COC use to approximately 1.4 with more than 8-10 years of COC use.

FIGURE 1: RELEVANT STUDIES OF RISK OF BREAST CANCER WITH COMBINED ORAL CONTRACEPTIVES

RR = relative risk; OR = odds ratio; HR = hazard ratio. "ever COC" are females with current or past COC use; "never COC use" are females that never used COCs.

There is evidence of an association between the following conditions and the use of oral contraceptives, although additional confirmatory studies are needed:

• Mesenteric thrombosis
• Retinal thrombosis

The following adverse reactions have been reported in patients receiving oral contraceptives and are believed to be drug-related:

• Nausea
• Vomiting
• Gastrointestinal symptoms (such as abdominal cramps and bloating)
• Breakthrough bleeding
• Spotting
• Change in menstrual flow
• Amenorrhea
• Temporary infertility after discontinuation of treatment
• Edema
• Melasma which may persist
• Breast changes: tenderness, enlargement, secretion
• Change in weight (increase or decrease)
• Change in cervical erosion and secretion
• Diminution in lactation when given immediately postpartum
• Cholestatic jaundice
• Migraine
• Rash (allergic)
• Depression
• Reduced tolerance to carbohydrates
• Vaginal candidiasis
• Change in corneal curvature (steepening)
• Intolerance to contact lenses

The following adverse reactions have been reported in users of oral contraceptives and the association has been neither confirmed nor refuted:

• Pre-menstrual syndrome
• Cataracts
• Changes in appetite
• Cystitis-like syndrome
• Headache
• Nervousness
• Dizziness
• Hirsutism
• Loss of scalp hair
• Erythema multiforme
• Erythema nodosum
• Hemorrhagic eruption
• Vaginitis
• Porphyria
• Impaired renal function
• Hemolytic uremic syndrome
• Budd-Chiari syndrome
• Acne
• Changes in libido
• Colitis

Overdosage

Serious ill effects have not been reported following acute ingestion of large doses of oral contraceptives by young children. Overdosage may cause nausea, and withdrawal bleeding may occur in females.

Description

LARIN™ Fe 1/20 is a progestogen-estrogen combination.

LARIN™ Fe 1/20 provides a continuous dosage regimen consisting of 21 oral contraceptive tablets and seven ferrous fumarate tablets. The ferrous fumarate tablets are present to facilitate ease of drug administration via a 28-day regimen, are non-hormonal, and do not serve any therapeutic purpose.

Each pale yellow tablet contains norethindrone acetate (17 alpha-ethinyl-19-nortestosterone acetate), 1 mg; ethinyl estradiol (17 alpha-ethinyl-1,3,5(10)-estratriene-3,17 beta-diol), 20 mcg. Also contains polyvinyl alcohol, titanium dioxide, talc, macrogol/polyethylglycol  3350 NF, lecithin (soya), D&C Yellow No.10 Aluminum Lake, FD&C Blue No.2 Aluminum  Lake, FD&C Yellow No.6 Aluminum Lake, lactose, magnesium stearate and pregelatinized corn starch.

The structural formulas are as follows:

Each brown placebo tablet contains ferrous fumarate, polyvinyl alcohol, talc, macrogol/polyethyleneglycol 3350 NF, lecithin (soya), iron oxide black, iron oxide yellow,
microcrystalline cellulose, hydroxypropyl cellulose, magnesium stearate and crospovidone.
The ferrous fumarate tablets do not serve any therapeutic purpose.

Clinical Pharmacology

Combination oral contraceptives act by suppression of gonadotropins. Although the primary mechanism of this action is inhibition of ovulation, other alterations include changes in the cervical mucus (which increase the difficulty of sperm entry into the uterus) and the endometrium (which reduce the likelihood of implantation).

Pharmacokinetics

The pharmacokinetics of LARIN™ Fe 1/20 have not been characterized; however, the following pharmacokinetic information regarding norethindrone acetate and ethinyl estradiol is taken from the literature.

Absorption

Norethindrone acetate appears to be completely and rapidly deacetylated to norethindrone after oral administration, since the disposition of norethindrone acetate is indistinguishable from that of orally administered norethindrone (1). Norethindrone acetate and ethinyl estradiol are subject to first-pass metabolism after oral dosing, resulting in an absolute bioavailability of approximately 64% for norethindrone and 43% for ethinyl estradiol (1-3).

Distribution

Volume of distribution of norethindrone and ethinyl estradiol ranges from 2 to 4 L/kg (1-3). Plasma protein binding of both steroids is extensive (greater than 95%); norethindrone binds to both albumin and sex hormone binding globulin, whereas ethinyl estradiol binds only to albumin (4).

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 (5). 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 (6).

Excretion

Norethindrone and ethinyl estradiol are excreted in both urine and feces, primarily as metabolites (5, 6). Plasma clearance values for norethindrone and ethinyl estradiol are similar (approximately 0.4 L/hr/kg) (1-3).

Special Population

Race:

The effect of race on the disposition of LARIN™ Fe 1/20 has not been evaluated.

Renal  Insufficiency:

The effect of renal disease on the disposition of LARIN™ Fe 1/20 has not been evaluated. In premenopausal women with chronic renal failure undergoing peritoneal dialysis who received multiple doses of an oral contraceptive containing ethinyl estradiol and norethindrone, plasma ethinyl estradiol concentrations were higher and norethindrone concentrations were unchanged compared to concentrations in premenopausal women with normal renal function.

Hepatic  Insufficiency:

The effect of hepatic disease on the disposition of LARIN™ Fe 1/20 has not been evaluated. However, ethinyl estradiol and norethindrone may be poorly metabolized in patients with impaired liver function.

Drug-Drug  Interactions:

Numerous drug-drug interactions have been reported for oral contraceptives. A summary of these is found under PRECAUTIONS, Drug Interactions .

How Supplied / Storage and Handling

LARIN™ Fe 1/20 is available in dispensers (NDC 16714-406-01) each containing 21 pale yellow tablets and 7 brown tablets. Each pale yellow, biconvex, round tablet debossed with "L2" on one side contains 1mg of norethindrone acetate and 20 mcg of ethinyl estradiol.

Each brown, biconvex, round tablet debossed with "F" on one side and "N" on the other side contains 75 mg ferrous fumarate.

LARIN™ Fe 1/20 Tablets are available in the following configurations:

Carton of 1 NDC 16714-406-02

Carton of 3 NDC 16714-406-03

Carton of 6 NDC 16714-406-04

Store at 20 ˚ C to 25˚ C (68˚ F to 77 ˚ F) [See USP Controlled Room Temperature].

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (PATIENT PACKAGE INSERT BRIEF SUMMARY and DETAILED PATIENT PACKAGE INSERT).

• 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 (see BOXED WARNING and CONTRAINDICATIONS ).
• Counsel patients that the increased risk of venous thromboembolism compared to non-users of CHCs is greatest after initially starting a CHC or restarting (following a 4-week or greater interruption in intake) the same or a different CHC (see WARNINGS ).
• Counsel patients that this product does not protect against HIV-infection (AIDS) and other sexually transmitted infections.
• 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 DOSAGE AND ADMINISTRATION ).
• Counsel patients to use a back-up or alternative method of contraception when enzyme inducers are used with COCs (see PRECAUTIONS ).
• 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 (see PRECAUTIONS ).
• Counsel any patient who starts LARIN™ Fe 1/20 postpartum, and who has not yet had a period, to use an additional method of contraception until she has taken a pale yellow tablet for 7 consecutive days (see DOSAGE AND ADMINISTRATION ).
• Counsel patients that amenorrhea may occur. Pregnancy should be considered in the event of amenorrhea, and should be ruled out if amenorrhea is associated with symptoms of pregnancy, such as morning sickness or unusual breast tenderness (see WARNINGS).
• Counsel patients with a history of depression that depression may reoccur. Women should contact their healthcare provider if depression occurs (see WARNINGS ).