ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The most common adverse reactions (>= 10%) in the clinical trial included menstrual changes (26%), nausea (23%), abdominal pain (18%), fatigue (17%), headache (17%), dizziness (11%) and breast tenderness (11%). (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Barr Laboratories at 1-800-330-1271 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trial Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. double-blind, controlled clinical trial in 1,955 evaluable women compared the efficacy and safety of Plan (one 0.75 mg tablet of levonorgestrel taken within 72 hours of unprotected intercourse, and one tablet taken 12 hours later) to the Yuzpe regimen (two tablets each containing 0.25 mg levonorgestrel and 0.05 mg ethinyl estradiol, taken within 72 hours of intercourse, and two tablets taken 12 hours later).The most common adverse events (>10%) in the clinical trial for women receiving Plan included menstrual changes (26%), nausea (23%), abdominal pain (18%), fatigue (17%), headache (17%), dizziness (11%), and breast tenderness (11%). Table lists those adverse events that were reported in >= 5% of Plan users.Table 1: Adverse Events in >= 5%of Women, by FrequencyPlan BLevonorgestrelN=977 (%)Nausea23.1 Abdominal Pain17.6Fatigue 16.9Headache 16.8Heavier Menstrual Bleeding 13.8Lighter Menstrual Bleeding 12.5Dizziness 11.2Breast Tenderness 10.7Vomiting5.6Diarrhea 5.0. 6.2 Postmarketing Experience. The following adverse reactions have been identified during post-approval use of Plan B. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure. Gastrointestinal DisordersAbdominal Pain, Nausea, VomitingGeneral Disorders and Administration Site ConditionsFatigueNervous System DisordersDizziness, HeadacheReproductive System and Breast DisordersDysmenorrhea, Irregular Menstruation, Oligomenorrhea, Pelvic Pain.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenicity: There is no evidence of increased risk of cancer with short-term use of progestins. There was no increase in tumorgenicity following administration of levonorgestrel to rats for years at approximately ug/day, to dogs for years at up to 0.125 mg/kg/day, or to rhesus monkeys for 10 years at up to 250 ug/kg/day. In another year dog study, administration of levonorgestrel at 0.5 mg/kg/day did increase the number of mammary adenomas in treated dogs compared to controls. There were no malignancies.Genotoxicity: Levonorgestrel was not found to be mutagenic or genotoxic in the Ames Assay, in vitro mammalian culture assays utilizing mouse lymphoma cells and Chinese hamster ovary cells, and in an in vivo micronucleus assay in mice. Fertility: There are no irreversible effects on fertility following cessation of exposures to levonorgestrel or progestins in general.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Emergency contraceptive pills are not effective if woman is already pregnant. Plan is believed to act as an emergency contraceptive principally by preventing ovulation or fertilization (by altering tubal transport of sperm and/or ova). In addition, it may inhibit implantation (by altering the endometrium). It is not effective once the process of implantation has begun.. 12.3 Pharmacokinetics. AbsorptionNo specific investigation of the absolute bioavailability of Plan in humans has been conducted. However, literature indicates that levonorgestrel is rapidly and completely absorbed after oral administration (bioavailability about 100%) and is not subject to first pass metabolism.After single dose of Plan (0.75 mg) administered to 16 women under fasting conditions, maximum serum concentrations of levonorgestrel were 14.1 7.7 ng/mL (mean SD) at an average of 1.6 0.7 hours.Table 2: Pharmacokinetic Parameter Values Following Single Dose Administration of Plan (Levonorgestrel) Tablets 0.75 mg to Healthy Female Volunteers under Fasting ConditionsMean (+- SD)Cmax (ng/mL)Tmax (h)CL(L/h)Vd (L)t 1/2 (h)AUCinf (ng/mL.h)Levonorgestrel14.1 (7.7)1.6 0.7)7.7 (2.7)260.024.4 (5.3)123.1 (50.1)Cmax maximum concentrationTmax time to maximum concentrationCL clearanceVd volume of distributiont1/2 elimination half lifeAUCinf area under the drug concentration curve from time to infinityEffect of Food: The effect of food on the rate and the extent of levonorgestrel absorption following single oral administration of Plan has not been evaluated. DistributionThe apparent volume of distribution of levonorgestrel is reported to be approximately 1.8 L/kg. It is about 97.5 to 99% protein-bound, principally to sex hormone binding globulin (SHBG) and, to lesser extent, serum albumin.MetabolismFollowing absorption, levonorgestrel is conjugated at the 17-OH position to form sulfate conjugates and, to lesser extent, glucuronide conjugates in plasma. Significant amounts of conjugated and unconjugated 3, 5-tetrahydrolevonorgestrel are also present in plasma, along with much smaller amounts of 3, 5-tetrahydrolevonorgestrel and 16hydroxylevonorgestrel. Levonorgestrel and its phase metabolites are excreted primarily as glucuronide conjugates. Metabolic clearance rates may differ among individuals by several-fold, and this may account in part for the wide variation observed in levonorgestrel concentrations among users. ExcretionAbout 45% of levonorgestrel and its metabolites are excreted in the urine and about 32% are excreted in feces, mostly as glucuronide conjugates.Specific Populations Pediatric: This product is not intended for use in the pediatric (pre-menarcheal) population, and pharmacokinetic data are not available for this population.Geriatric: This product is not intended for use in postmenopausal women and pharmacokinetic data are not available for this population.Race: No formal studies have evaluated the effect of race on pharmacokinetics of Plan B. However, clinical trials demonstrated higher pregnancy rate in Chinese women with both Plan and the Yuzpe regimen (another form of emergency contraception). The reason for this apparent increase in the pregnancy rate with emergency contraceptives in Chinese women is unknown [see USE IN SPECIFIC POPULATIONS (8.6)].Hepatic Impairment: No formal studies were conducted to evaluate the effect of hepatic disease on the disposition of Plan B. Renal Impairment: No formal studies were conducted to evaluate the effect of renal disease on the disposition of Plan B. Drug-Drug InteractionsNo formal drug-drug interaction studies were conducted with Plan [see DRUG INTERACTIONS (7)].

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. double-blind, randomized, multinational controlled clinical trial in 1,955 evaluable women (mean age 27) compared the efficacy and safety of Plan (one 0.75 mg tablet of levonorgestrel taken within 72 hours of unprotected intercourse, and one tablet taken 12 hours later) to the Yuzpe regimen (two tablets each containing 0.25 mg levonorgestrel and 0.05 mg ethinyl estradiol, taken within 72 hours of intercourse, and two additional tablets taken 12 hours later). After single act of intercourse occurring anytime during the menstrual cycle, the expected pregnancy rate of 8% (with no contraceptive use) was reduced to approximately 1% with Plan B.Emergency contraceptives are not as effective as routine hormonal contraception since their failure rate, while low based on single use, would accumulate over time with repeated use [see INDICATIONS AND USAGE (1)]. At the time of expected menses, approximately 74% of women using Plan had vaginal bleeding similar to their normal menses, 14% bled more than usual, and 12% bled less than usual. The majority of women (87%) had their next menstrual period at the expected time or within 7 days, while 13% had delay of more than days beyond the anticipated onset of menses.

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Drugs or herbal products that induce enzymes, including CYP3A4, that metabolize progestins may decrease the plasma concentrations of progestins, and may decrease the effectiveness of progestin-only pills. Some drugs or herbal products that may decrease the effectiveness of progestin-only pills include: barbiturates bosentan carbamazepine felbamate griseofulvinoxcarbazepine phenytoin rifampin St. Johns wort topiramate Significant changes (increase or decrease) in the plasma levels of the progestin have been noted in some cases of co-administration with HIV protease inhibitors or with non-nucleoside reverse transcriptase inhibitors. Consult the labeling of all concurrently used drugs to obtain further information about interactions with progestin-only pills or the potential for enzyme alterations. barbiturates bosentan carbamazepine felbamate griseofulvin. oxcarbazepine phenytoin rifampin St. Johns wort topiramate Drugs or herbal products that induce certain enzymes, such as CYP3A4, may decrease the effectiveness of progestin-only pills. (7).

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. Plan B(R) is progestin-only emergency contraceptive indicated for prevention of pregnancy following unprotected intercourse or known or suspected contraceptive failure. To obtain optimal efficacy, the first tablet should be taken as soon as possible within 72 hours of intercourse. The second tablet should be taken 12 hours later.Plan is available only by prescription for women younger than age 17 years, and available over the counter for women 17 years and older.Plan is not indicated for routine use as contraceptive.. Plan is progestin-only emergency contraceptive, indicated for prevention of pregnancy following unprotected intercourse or known or suspected contraceptive failure. Plan is available only by prescription for women younger than age 17 years, and available over the counter for women 17 years and older. Plan is not intended for routine use as contraceptive. (1).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. 17.1 Information for Patients. Take Plan as soon as possible and not more than 72 hours after unprotected intercourse or known or suspected contraceptive failure.If you vomit within two hours of taking either tablet, immediately contact your healthcare provider to discuss whether to take another tablet.Seek medical attention if you experience severe lower abdominal pain to weeks after taking Plan B, in order to be evaluated for an ectopic pregnancy.After taking Plan B, consider the possibility of pregnancy if your period is delayed more than one week beyond the date you expected your period. Do not use Plan as routine contraception.Plan is not effective in terminating an existing pregnancy.Plan does not protect against HIV-infection (AIDS) and other sexually transmitted diseases/infections.For women younger than age 17 years, Plan is available only by prescription.. Take Plan as soon as possible and not more than 72 hours after unprotected intercourse or known or suspected contraceptive failure.. If you vomit within two hours of taking either tablet, immediately contact your healthcare provider to discuss whether to take another tablet.. Seek medical attention if you experience severe lower abdominal pain to weeks after taking Plan B, in order to be evaluated for an ectopic pregnancy.. After taking Plan B, consider the possibility of pregnancy if your period is delayed more than one week beyond the date you expected your period. Do not use Plan as routine contraception.. Plan is not effective in terminating an existing pregnancy.. Plan does not protect against HIV-infection (AIDS) and other sexually transmitted diseases/infections.. For women younger than age 17 years, Plan is available only by prescription.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenicity: There is no evidence of increased risk of cancer with short-term use of progestins. There was no increase in tumorgenicity following administration of levonorgestrel to rats for years at approximately ug/day, to dogs for years at up to 0.125 mg/kg/day, or to rhesus monkeys for 10 years at up to 250 ug/kg/day. In another year dog study, administration of levonorgestrel at 0.5 mg/kg/day did increase the number of mammary adenomas in treated dogs compared to controls. There were no malignancies.Genotoxicity: Levonorgestrel was not found to be mutagenic or genotoxic in the Ames Assay, in vitro mammalian culture assays utilizing mouse lymphoma cells and Chinese hamster ovary cells, and in an in vivo micronucleus assay in mice. Fertility: There are no irreversible effects on fertility following cessation of exposures to levonorgestrel or progestins in general.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL. NDC 54868-4894-0Plan B(R) (LEVONORGESTREL)tablets 0.75 mgEmergency Contraceptive2 Levonorgestrel Tablets0.75 mg eachThe sooner you take the first tablet, the better Plan B(R) will workNot for regular birth control.Plan B(R) should be used only in emergencies.1 Take first tablet as soon as possible, within 72 hours (3 days) after unprotected sex.2 Take second tablet 12 hours after taking first tablet.TIME REMINDER Write on line below, the time the first tablet is taken. Take second tablet 12 hours laterAM/PM (circle one)Reduces the chance of pregnancy after unprotected sex (if regular birth control method fails or after sex without birth control).Rx only for women younger than age 17Take the first tablet as soon as possible within 72 hours (3 days) after unprotected sex. The sooner you take the first tablet, the better Plan B(R) will work. Take the second tablet 12 hours later.Drug FactsActive ingredient (in each tablet) PurposeLevonorgestrel 0.75mg......................Emergency contraceptiveUse reduces chance of pregnancy after unprotected sex (if contraceptive failed or if you did not use birth control)WarningsAllergy alert: Do not use if you have ever had an allergic reaction to levonorgestrelSexually transmitted diseases (STDs) alert: This product does not protect against HIV/AIDS or other STDsDo not use if you are already pregnant (because it will not work) for regular birth controlWhen using this product you may have menstrual changes nausea lower stomach (abdominal) pain tiredness headache dizziness breast pain vomitingKeep out of reach of children. In case of overdose, get medical help or contact Poison Control center right away.Directions women 17 years of age or older:take the first tablet as soon as possible within 72 hours (3 days) after unprotected sex. The sooner you take the first tablet, the better it will work. take the second tablet 12 hours after you take the first tabletif you vomit within hours of taking the medication, call ahealthcare professional to find out if you should repeat that doseprescription only for women younger than age 17. If youare younger than age 17, see healthcare professional. Other informationbefore using this product read the enclosed consumerinformation leaflet for complete directions and informationthis product is not recommended for regular birth control. It does not work as well as most other birth control methodsused correctly.this product works mainly by preventing ovulation (egg release). It may also prevent fertilization of released egg (joining of sperm and egg) or attachment of fertilized egg to the uterus (implantation).when used correctly every time you have sex, latex condoms greatly reduce, but do not eliminate, the risk of pregnancy and the risk of catching or spreading HIV, the virus that causes AIDS.See condom labeling for additional STD information. tablets are enclosed in blister seal. Do not use if the blisterseal is broken. store at 20-25C (68-77F)Inactive ingredientscolloidal silicon dioxide, corn starch, gelatin, lactose monohydrate, magnesium stearate, potato starch, talcQuestions or commentsFor more information or to speak to healthcare professional,call 1-800-330-1271, 24 hours day/7 days week.Visit our Web site at www.go2planb.com. if you are already pregnant (because it will not work). for regular birth control. menstrual changes. nausea. lower stomach (abdominal) pain. tiredness. headache. dizziness breast pain. vomiting. women 17 years of age or older:. take the first tablet as soon as possible within 72 hours (3 days) after unprotected sex. The sooner you take the first tablet, the better it will work.. take the second tablet 12 hours after you take the first tablet. if you vomit within hours of taking the medication, call ahealthcare professional to find out if you should repeat that dose. prescription only for women younger than age 17. If youare younger than age 17, see healthcare professional. before using this product read the enclosed consumerinformation leaflet for complete directions and information. this product is not recommended for regular birth control. It does not work as well as most other birth control methodsused correctly.. this product works mainly by preventing ovulation (egg release). It may also prevent fertilization of released egg (joining of sperm and egg) or attachment of fertilized egg to the uterus (implantation).. when used correctly every time you have sex, latex condoms greatly reduce, but do not eliminate, the risk of pregnancy and the risk of catching or spreading HIV, the virus that causes AIDS.See condom labeling for additional STD information.. tablets are enclosed in blister seal. Do not use if the blisterseal is broken. store at 20-25C (68-77F). Plan package label.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. AbsorptionNo specific investigation of the absolute bioavailability of Plan in humans has been conducted. However, literature indicates that levonorgestrel is rapidly and completely absorbed after oral administration (bioavailability about 100%) and is not subject to first pass metabolism.After single dose of Plan (0.75 mg) administered to 16 women under fasting conditions, maximum serum concentrations of levonorgestrel were 14.1 7.7 ng/mL (mean SD) at an average of 1.6 0.7 hours.Table 2: Pharmacokinetic Parameter Values Following Single Dose Administration of Plan (Levonorgestrel) Tablets 0.75 mg to Healthy Female Volunteers under Fasting ConditionsMean (+- SD)Cmax (ng/mL)Tmax (h)CL(L/h)Vd (L)t 1/2 (h)AUCinf (ng/mL.h)Levonorgestrel14.1 (7.7)1.6 0.7)7.7 (2.7)260.024.4 (5.3)123.1 (50.1)Cmax maximum concentrationTmax time to maximum concentrationCL clearanceVd volume of distributiont1/2 elimination half lifeAUCinf area under the drug concentration curve from time to infinityEffect of Food: The effect of food on the rate and the extent of levonorgestrel absorption following single oral administration of Plan has not been evaluated. DistributionThe apparent volume of distribution of levonorgestrel is reported to be approximately 1.8 L/kg. It is about 97.5 to 99% protein-bound, principally to sex hormone binding globulin (SHBG) and, to lesser extent, serum albumin.MetabolismFollowing absorption, levonorgestrel is conjugated at the 17-OH position to form sulfate conjugates and, to lesser extent, glucuronide conjugates in plasma. Significant amounts of conjugated and unconjugated 3, 5-tetrahydrolevonorgestrel are also present in plasma, along with much smaller amounts of 3, 5-tetrahydrolevonorgestrel and 16hydroxylevonorgestrel. Levonorgestrel and its phase metabolites are excreted primarily as glucuronide conjugates. Metabolic clearance rates may differ among individuals by several-fold, and this may account in part for the wide variation observed in levonorgestrel concentrations among users. ExcretionAbout 45% of levonorgestrel and its metabolites are excreted in the urine and about 32% are excreted in feces, mostly as glucuronide conjugates.Specific Populations Pediatric: This product is not intended for use in the pediatric (pre-menarcheal) population, and pharmacokinetic data are not available for this population.Geriatric: This product is not intended for use in postmenopausal women and pharmacokinetic data are not available for this population.Race: No formal studies have evaluated the effect of race on pharmacokinetics of Plan B. However, clinical trials demonstrated higher pregnancy rate in Chinese women with both Plan and the Yuzpe regimen (another form of emergency contraception). The reason for this apparent increase in the pregnancy rate with emergency contraceptives in Chinese women is unknown [see USE IN SPECIFIC POPULATIONS (8.6)].Hepatic Impairment: No formal studies were conducted to evaluate the effect of hepatic disease on the disposition of Plan B. Renal Impairment: No formal studies were conducted to evaluate the effect of renal disease on the disposition of Plan B. Drug-Drug InteractionsNo formal drug-drug interaction studies were conducted with Plan [see DRUG INTERACTIONS (7)].

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Nursing Mothers: Small amounts of progestin pass into the breast milk of nursing women taking progestin-only pills for long-term contraception, resulting in detectable steroid levels in infant plasma. (8.3)Plan is not intended for use in pediatric (premenarcheal) (8.4) or postmenopausal women (8.5).Clinical trials demonstrated higher pregnancy rate in the Chinese population. (8.6). Nursing Mothers: Small amounts of progestin pass into the breast milk of nursing women taking progestin-only pills for long-term contraception, resulting in detectable steroid levels in infant plasma. (8.3). Plan is not intended for use in pediatric (premenarcheal) (8.4) or postmenopausal women (8.5).. Clinical trials demonstrated higher pregnancy rate in the Chinese population. (8.6). 8.1 Pregnancy. Many studies have found no harmful 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 with progestin-only pills have not demonstrated significant adverse effects. 8.3 Nursing Mothers. In general, no adverse effects of progestin-only pills have been found on breastfeeding performance or on the health, growth or development of the infant. However, isolated post-marketing cases of decreased milk production have been reported. Small amounts of progestins pass into the breast milk of nursing mothers taking progestin-only pills for long-term contraception, resulting in detectable steroid levels in infant plasma. 8.4 Pediatric Use. Safety and efficacy of progestin-only pills for long-term contraception 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 Plan emergency contraception before menarche is not indicated. 8.5 Geriatric Use. This product is not intended for use in postmenopausal women.. 8.6 Race. No formal studies have evaluated the effect of race. However, clinical trials demonstrated higher pregnancy rate in Chinese women with both Plan and the Yuzpe regimen (another form of emergency contraception). The reason for this apparent increase in the pregnancy rate with emergency contraceptives in Chinese women is unknown.. 8.7 Hepatic Impairment No formal studies were conducted to evaluate the effect of hepatic disease on the disposition of Plan B.. 8.8 Renal Impairment. No formal studies were conducted to evaluate the effect of renal disease on the disposition of Plan B.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Ectopic Pregnancy: Women who become pregnant or complain of lower abdominal pain after taking Plan should be evaluated for ectopic pregnancy. (5.1) Plan is not effective in terminating an existing pregnancy. (5.2 Effect on menses: Plan may alter the next expected menses. If menses is delayed beyond week, pregnancy should be considered. (5.3)STI/HIV: Plan does not protect against STI/HIV. (5.4). Ectopic Pregnancy: Women who become pregnant or complain of lower abdominal pain after taking Plan should be evaluated for ectopic pregnancy. (5.1) Plan is not effective in terminating an existing pregnancy. (5.2 . Effect on menses: Plan may alter the next expected menses. If menses is delayed beyond week, pregnancy should be considered. (5.3). STI/HIV: Plan does not protect against STI/HIV. (5.4). 5.1 Ectopic Pregnancy. Ectopic pregnancies account for approximately 2% of all reported pregnancies. Up to 10% of pregnancies reported in clinical studies of routine use of progestin-only contraceptives are ectopic. history of ectopic pregnancy is not contraindication to use of this emergency contraceptive method. Healthcare providers, however, should consider the possibility of an ectopic pregnancy in women who become pregnant or complain of lower abdominal pain after taking Plan B. follow-up physical or pelvic examination is recommended if there is any doubt concerning the general health or pregnancy status of any woman after taking Plan B.. 5.2 Existing Pregnancy Plan is not effective in terminating an existing pregnancy.. 5.3 Effects on Menses. Some women may experience spotting few days after taking Plan B. Menstrual bleeding patterns are often irregular among women using progestin-only oral contraceptives and women using levonorgestrel for postcoital and emergency contraception. If there is delay in the onset of expected menses beyond week, consider the possibility of pregnancy.. 5.4 STI/HIV. Plan does not protect against HIV infection (AIDS) or other sexually transmitted infections (STIs).. 5.5 Physical Examination and Follow-up A physical examination is not required prior to prescribing Plan B. follow-up physical or pelvic examination is recommended if there is any doubt concerning the general health or pregnancy status of any woman after taking Plan B.. 5.6 Fertility Following Discontinuation. rapid return of fertility is likely following treatment with Plan for emergency contraception; therefore, routine contraception should be continued or initiated as soon as possible following use of Plan to ensure ongoing prevention of pregnancy.