PRECAUTIONS SECTION.

PRECAUTIONS. 1. General.Patients should be counseled that oral contraceptives do not protect against transmission of HIV (AIDS) and other sexually transmitted diseases (STDs) such as Chlamydia, genital herpes, genital warts, gonorrhea, hepatitis B, and syphilis.2. Physical examination and followup.It is considered good medical practice for sexually active women using oral contraceptives to have annual history and physical examinations. The physical examination may be deferred until after initiation of oral contraceptives if requested by the woman and judged appropriate by the clinician.3. Carbohydrate and lipid metabolism.Some users may experience slight deterioration in glucose tolerance, with increases in plasma insulin, but women with diabetes mellitus who use progestin-only oral contraceptives do not generally experience changes in their insulin requirements. Nonetheless, prediabetic and diabetic women in particular should be carefully monitored while taking POPs.Lipid metabolism is occasionally affected in that HDL, HDL2, and apolipoprotein A-I and A-II may be decreased; hepatic lipase may be increased. There is no effect on total cholesterol, HDL3, LDL, or VLDL.4. Drug interactions.Change in contraceptive effectiveness associated with co-administration of other products:a. Anti-infective agents and anticonvulsants. Contraceptive effectiveness may be reduced when hormonal contraceptives are co-administered with antibiotics, anticonvulsants, and other drugs that increase the metabolism of contraceptive steroids. This could result in unintended pregnancy or breakthrough bleeding. Examples include rifampin, barbiturates, phenylbutazone, phenytoin, carbamazepine, felbamate, oxcarbazepine, topiramate, and griseofulvin.b. Anti-HIV protease inhibitors. Several of the anti-HIV protease inhibitors have been studied with co-administration of oral contraceptives; significant changes (increase and decrease) in the plasma levels of the estrogen and progestin have been noted in some cases. The safety and efficacy of OC products may be affected with the co-administration of anti-HIV protease inhibitors. Health care providers should refer to the label of the individual anti-HIV protease inhibitors for further drug-drug interaction information.c. Herbal products. Herbal products containing St. Johns Wort (hypericum perforatum) may induce hepatic enzymes (cytochrome P450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids. This may also result in breakthrough bleeding.5. Interactions with laboratory tests.The following endocrine tests may be affected by progestin-only oral contraceptive use:Sex hormone-binding globulin (SHBG) concentrations may be decreased.Thyroxine concentrations may be decreased, due to decrease in thyroid binding globulin (TBG). 6. Carcinogenesis.See WARNINGS section.7. Pregnancy.Many studies have found no effects on fetal development associated with long-term use of contraceptive doses of oral progestins. The few studies of infant growth and development that have been conducted have not demonstrated significant adverse effects. It is nonetheless prudent to rule out suspected pregnancy before initiating any hormonal contraceptive use.8. Nursing mothers.Small amounts of progestin pass into the breast milk, resulting in steroid levels in infant plasma of to 6% of the levels of maternal plasma.6 However, isolated postmarket cases of decreased milk production have been reported in POPs. Very rarely, adverse effects in the infant/child have been reported, including jaundice.9. Fertility following discontinuation.The limited available data indicate rapid return of normal ovulation and fertility following discontinuation of progestin-only oral contraceptives.10. Headache/Migraine.If you have headache or worsening migraine headache with new pattern that is recurrent, persistent, or severe, this requires discontinuation of oral contraceptives and evaluation of the cause.11. Gastrointestinal.Diarrhea and/or vomiting may reduce hormone absorption resulting in decreased serum concentrations.12. Pediatric use.Safety and efficacy of norethindrone have been established in women of reproductive age. Safety and efficacy are expected to be the same for postpubertal adolescents under the age of 16 and for users 16 years and older. Use of this product before menarche is not indicated.INFORMATION FOR THE PATIENT1. See PATIENT LABELING for detailed information. 2. Counseling issues. The following points should be discussed with prospective users before prescribing progestin-only oral contraceptives: The necessity of taking pills at the same time every day, including throughout all bleeding episodes.The need to use backup method such as condoms and spermicides for the next 48 hours whenever progestin-only oral contraceptive is taken or more hours late.The potential side effects of progestin-only oral contraceptives, particularly menstrual irregularities.The need to inform the clinician of prolonged episodes of bleeding, amenorrhea or severe abdominal pain. The importance of using barrier method in addition to progestin-only oral contraceptives if woman is at risk of contracting or transmitting STDs/HIV.. Sex hormone-binding globulin (SHBG) concentrations may be decreased.. Thyroxine concentrations may be decreased, due to decrease in thyroid binding globulin (TBG). The necessity of taking pills at the same time every day, including throughout all bleeding episodes.. The need to use backup method such as condoms and spermicides for the next 48 hours whenever progestin-only oral contraceptive is taken or more hours late.. The potential side effects of progestin-only oral contraceptives, particularly menstrual irregularities.. The need to inform the clinician of prolonged episodes of bleeding, amenorrhea or severe abdominal pain.. The importance of using barrier method in addition to progestin-only oral contraceptives if woman is at risk of contracting or transmitting STDs/HIV.

WARNINGS SECTION.

WARNINGS. Cigarette smoking greatly increases the possibility of suffering heart attacks and strokes. Women who use oral contraceptives are strongly advised not to smoke.NORLYROC tablets do not contain estrogen and, therefore, this insert does not discuss the serious health risks that have been associated with the estrogen component of combined oral contraceptives. The health care provider is referred to the prescribing information of combined oral contraceptives for discussion of those risks, including, but not limited to, an increased risk of serious cardiovascular disease in women who smoke, carcinoma of the breast and reproductive organs, hepatic neoplasia, and changes in carbohydrate and lipid metabolism. The relationship between progestin-only oral contraceptives and these risks have not been established and there are no studies definitely linking progestin-only pill (POP) use to an increased risk of heart attack or stroke.The physician should remain alert to the earliest manifestation of symptoms of any serious disease and discontinue oral contraceptive therapy when appropriate.1. Ectopic pregnancy. The incidence of ectopic pregnancies for progestin-only oral contraceptive users is per 1000 woman-years. Up to 10% of pregnancies reported in clinical studies of progestin-only oral contraceptive users are extrauterine. Although symptoms of ectopic pregnancy should be watched for, history of ectopic pregnancy need not be considered contraindication to use of this contraceptive method. Health providers should be alert to the possibility of an ectopic pregnancy in women who become pregnant or complain of lower abdominal pain while on progestin-only oral contraceptives.2. Delayed follicular atresia/Ovarian cysts. If follicular development occurs, atresia of the follicle is sometimes delayed, and the follicle may continue to grow beyond the size it would attain in normal cycle. Generally these enlarged follicles disappear spontaneously. Often they are asymptomatic; in some cases they are associated with mild abdominal pain. Rarely they may twist or rupture, requiring surgical intervention.3. Irregular genital bleeding. Irregular menstrual patterns are common among women using progestin-only oral contraceptives. If genital bleeding is suggestive of infection, malignancy or other abnormal conditions, such nonpharmacologic causes should be ruled out. If prolonged amenorrhea occurs, the possibility of pregnancy should be evaluated.4. Carcinoma of the breast and reproductive organs. Some epidemiologic studies of oral contraceptive users have reported an increased relative risk of developing breast cancer, particularly at younger age and apparently related to duration of use. These studies have predominantly involved combined oral contraceptives and there is insufficient data to determine whether the use of POPs similarly increase the risk. Women with breast cancer should not use oral contraceptives because the role of female hormone in breast cancer has not been fully determined.Some studies suggest that oral contraceptive use has been associated with an increase in the risk of cervical intraepithelial neoplasia in some populations of women. However, there continues to be controversy about the extent to which such findings may be due to differences in sexual behavior and other factors. There is insufficient data to determine whether the use of POPs increases the risk of developing cervical intraepithelial neoplasia.5. Hepatic neoplasia. Benign hepatic adenomas are associated with combined oral contraceptive use, although the incidence of benign tumors is rare in the United States. Rupture of benign, hepatic adenomas may cause death through intraabdominal hemorrhage. Studies from Britain and the U.S. have shown an increased risk of developing hepatocellular carcinoma in combined oral contraceptive users. However, these cancers are rare. There is insufficient data to determine whether POPs increase the risk of developing hepatic neoplasia.

CLINICAL PHARMACOLOGY SECTION.

CLINICAL PHARMACOLOGY. 1. Mode of Action. NORLYROC progestin-only oral contraceptives prevent conception by suppressing ovulation in approximately half of users, thickening the cervical mucus to inhibit sperm penetration, lowering the mid-cycle LH and FSH peaks, slowing the movement of the ovum through the fallopian tubes, and altering the endometrium.2. Pharmacokinetics.Absorption: Norethindrone is rapidly absorbed with maximum plasma concentrations occurring within to hours after norethindrone tablets administration (see Table 1). Norethindrone appears to be completely absorbed following oral administration; however, it is subject to first pass metabolism resulting in an absolute bioavailability of approximately 65%.Figure 1: Mean +- SD Norethindrone Plasma Concentrations Following Norethindrone Administration. Peak plasma concentrations occur approximately hour after administration (mean Tmax 1.2 hours). The mean (SD) Cmax was 4816.8 (1532.6) pg/mL and generally occurred within hour (mean) of tablet administration, ranging from 0.5 to hours. The mean (SD) Cavg was 885 (250) pg/mL, however, the mean concentration at 24 hrs was 130 (47) pg/mL.Table provides summary statistics of the pharmacokinetic parameters associated with single dose norethindrone administration.Table 1: Mean +- SD Pharmacokinetic Parameters Following Single Dose Administration of Norethindrone in 12 Healthy Female Subjects Under Fasting ConditionsPharmacokinetic ParameterNorethindrone 0.35 mgTmax (hr)1.2 +- 0.5Cmax (pg/mL)4817 +- 1533AUC(0-48) (pg.h/mL)21233 +- 6002t 1/2 (h)7.7 +- 0.5The food effect on the rate and extent of norethindrone absorption after norethindrone tablets administration has not been evaluated.Distribution: Following oral administration, norethindrone is 36% bound to sex hormone-binding globulin (SHBG) and 61% bound to albumin. Volume of distribution of norethindrone is approximately L/kg.Metabolism: Norethindrone undergoes extensive biotransformation, primarily via reduction, followed by sulfate and glucuronide conjugation; less than 5% of norethindrone dose is excreted unchanged; greater than 50% and 20 to 40% of dose is excreted in urine and feces, respectively. The majority of metabolites in the circulation are sulfate, with glucuronides accounting for most of the urinary metabolites.Excretion: Plasma clearance rate for norethindrone has been estimated to be approximately 600 L/day. Norethindrone is excreted in both urine and feces, primarily as metabolites. The mean terminal elimination half-life of norethindrone following single dose administration of norethindrone tablets is approximately hours.. figure.

INDICATIONS & USAGE SECTION.

INDICATIONS AND USAGE. Indications. Progestin-only oral contraceptives are indicated for the prevention of pregnancy.Efficacy. If used perfectly, the first-year failure rate for progestin-only oral contraceptives is 0.5%. However, the typical failure rate is estimated to be closer to 5%, due to late or omitted pills. The following table lists the pregnancy rates for users of all major methods of contraception.Table 2: Percentage of Women Experiencing an Unintended Pregnancy During the First Year of Typical Use and the First Year of Perfect Use of Contraception and the Percentage Continuing Use at the End of the First Year. United States.% of Women Experiencing an Unintended Pregnancy within the First Year of Use% of Women Continuing Use at One Year3 Method(1)Typical Use1 (2)Perfect Use2 (3)(4)Chance4 8585Spermicides5 26640Periodic abstinence2563Calendar9Ovulation Method3Sympto-Thermal6 2Post-Ovulation1Cap7 Parous Women402642Nulliparous Women20956SpongeParous Women402042Nulliparous Women20956Diaphragm7 20656Withdrawal194Condom8 Female (Reality)21556Male14361Pill571Progestin only0.5Combined0.1IUDsProgesterone T21.581Copper T380A0.80.678LNg 200.10.181Depo-Provera(R) 0.30.370Levonorgestrel Implants (Norplant(R))0.050.0588Female Sterilization0.50.5100Male Sterilization0.150.10100Emergency Contraceptive Pills: Treatment initiated within 72 hours after unprotected intercourse reduces the risk of pregnancy by at least 75%.9Lactational Amenorrhea Method: LAM is highly effective, temporary method of contraception.10Source: Trussell, J, Contraceptive Efficacy. In: Hatcher RA, Trussell J, Stewart F, Cates W, Stewart GK, Kowal D, Guest F, Contraceptive Technology: Seventeenth Revised Edition. New York NY: Irvington Publishers, 1998.1.Among typical couples who initiate use of method (not necessarily for the first time), the percentage who experience an accidental pregnancy during the first year if they do not stop use for any reason. 2.Among couples who initiate use of method (not necessarily for the first time), and who use it perfectly (both consistently and correctly), the percentage who experience an accidental pregnancy during the first year if they do not stop use for any other reason.3.Among couples attempting to avoid pregnancy, the percentage who continue to use method for one year.4.The percentage of women becoming pregnant noted in columns (2) and (3) are based on data from populations where contraception is not used and from women who cease using contraception in order to become pregnant. Among such populations, about 89% become pregnant within one year. This estimate was lowered slightly (to 85%) to represent the percentage that would become pregnant within one year among women now relying on reversible methods of contraception if they abandoned contraception altogether.5.Foams, creams, gels, vaginal suppositories, and vaginal film.6.Cervical mucus (ovulation) method supplemented by calendar in the pre-ovulatory and basal body temperature in the post-ovulatory phases.7.With spermicidal cream or jelly.8.Without spermicides.9.The treatment schedule is one dose within 72 hours after unprotected intercourse, and second dose 12 hours after the first dose. The Food and Drug Administration has declared the following brands of oral contraceptives to be safe and effective for emergency contraception: Ovral(R) (1 dose is white pills), Alesse(R) (1 dose is pink pills), Nordette(R) or Levlen(R) (1 dose is yellow pills).10.However, to maintain effective protection against pregnancy, another method of contraception must be used as soon as menstruation resumes, the frequency or duration of breastfeeds is reduced, bottle feeds are introduced, or the baby reaches months of age.. Indications. Progestin-only oral contraceptives are indicated for the prevention of pregnancy.. Efficacy. If used perfectly, the first-year failure rate for progestin-only oral contraceptives is 0.5%. However, the typical failure rate is estimated to be closer to 5%, due to late or omitted pills. The following table lists the pregnancy rates for users of all major methods of contraception.