of nursing women taking progestin-only pills for long-term contraception, resulting in detectable steroid levels in infant plasma. (8.3). •. Plan B One-Step is not
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_________________________________________________________________ _____________________________ ______________________________________________________________ _____________________________________ Page 1 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use Plan B One-Step safely and effectively. See full prescribing information for Plan B One-Step. Plan B One-Step (levonorgestrel) tablet, 1.5 mg, for oral use Initial U.S. Approval: 1982 ———-INDICATIONS AND USAGE————– Plan B One-Step is a progestin-only emergency contraceptive indicated for prevention of pregnancy following unpr otected intercourse or a known or suspected contraceptive failure. Plan B One-Step is available only by prescription for women younger than age 17 years, and available over the counter for women 17 years and older. Plan B One-Step is not intended for routine use as a contraceptive. (1) ——-DOSAGE AND ADMINISTRATION——– One tablet taken orally as soon as possible within 72 hours after unprotected intercourse. Efficacy is better if the ta blet is taken as soon as possible after unprotected intercourse. (2) ——-DOSAGE FORMS AND STRENGTHS—– 1.5 mg tablet (3) ———–CONTRAINDICATIONS—————– Known or suspected pregnancy (4) ——-WARNINGS AND PRECAUTIONS——— •Ectopic pregnancy: Women who become pregnant or complain of lower abdominal pain after taking Plan B One- Step should be evaluated for ectopic pregnancy. (5.1) •Plan B One-Step is not effec tive in terminating an existing pregnancy. (5.2) •Effect on menses: Plan B One-Step may alter the next expected menses. If menses is delayed beyond 1 week, pregnancy should be considered. (5.3) •STI/HIV: Plan B One-Step does not protect against STI/HIV. (5.4) —————-ADVERSE REACTIONS————– The most common adverse reactions ( 10%) in clinical trials included heavier menstrual bleeding (31%), nausea (14%), lower abdominal pain (13%), fatigue (13%), headache (10%), and dizziness (10%). (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Barr Laboratories at 1-800-330-1271 or FDA at 1-800-F 1088 or www.fda.gov/medwatch . —————-DRUG INTERACTIONS————– Drugs or herbal products that induce certain enzymes, such as CYP3A4, may decrease the effectiven ess of progestin-only pills. (7) ———–USE IN SPECIFIC POPULATIONS—– •Nursing Mothers: Small amounts of progestin pass into the breast milk of nursing women taking proges tin-only pills for long-term contraception, resulting in detectable steroid levels in infant plasma. (8.3) •Plan B One-Step is not intended fo r use in premenarcheal (8.4) or postmenopausal females (8.5). See 17 for PATIENT COUNSELING INFORMATION. Revised 7/2009 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Ectopic Pregnancy 5.2 Existing Pregnancy 5.3 Effect on Menses 5.4 STI/HIV 5.5 Physical Examination and Follow-up 5.6 Fertility Following Discontinuation 6 ADVERSE REACTIONS 6.1 Clinical Trial Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Race 8.7 Hepatic Impairment 8.8 Renal Impairment 9 DRUG ABUSE AND DEPENDENCE 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Muta genesis, Impairment of Fertility 14 CLINICAL STUDIES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING NFORMATION 17.1 Information for Patients *Sections or subsections omitte d from the full prescribing information are not listed
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Page 2 FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE Plan B® One-Step is a progestin-only emergency contraceptive indicated for prevention of pregnancy fo llowing unprotected intercourse or a known or suspected contraceptive failure. To obtain optimal e fficacy, the tablet should be taken as s oon as possible within 72 hours of intercour se. Plan B One-Step is available only by prescription for women y ounger than age 17 years, and available over the counter for women 17 years and older. Plan B One-Step is not indicated for routine use as a contraceptive. 2 DOSAGE AND ADMINISTRATION Take Plan B One-Step orally as soon as possible within 72 hours after unprotected intercourse or a known or suspect ed contraceptive failure. Efficacy is better if the tablet is taken as soon as possible af ter unprotected intercourse. Plan B One-Step can be used at any time during the mens trual cycle. If vomiting occurs within two hours of taking the tablet, consideration should be given to repeating the dose. 3 DOSAGE FORMS AND STRENGTHS The Plan B One-Step tablet is supplied as an almost white, round tablet containing 1. 5 mg of levonorgestrel and is marked G00 o n one side. 4 CONTRAINDICATIONS Plan B One-Step is contraindicated for use in the case of known or suspected pregnancy. 5 WARNINGS AND PRECAUTIONS 5.1 Ectopic Pregnancy Ectopic pregnancies account for appr oximately 2% of all reported pregnancies. Up to 10% of pregnancies reported in clinical st udies of routine use of progestin- only contraceptives are ectopic. A history of ectopic pregnancy is not a contraindication to use of this emergency contraceptiv e 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 One-Step. A follow-up physical or pelvic examination is recommended if there is any doubt concerni ng the general health or pregnanc y status of any woman after ta king Plan B One-Step. 5.2 Existing Pregnancy Plan B One-Step is not effective in termina ting an existing pregnancy. 5.3 Effects on Menses Some women may experience spotting a few days after taking Plan B One-Step. Menstrual bleeding patterns are often irregular am ong women using progestin- only oral contraceptives and wome n using levonorgestrel for postcoita l and emergency contraception. If there is a delay in the onset of expected menses beyond 1 week, consider the possibility of pregnancy. 5.4 STI/HIV Plan B One-Step does not protect against HIV infection (AID S) or other sexually transm itted infections (STIs). 5.5 Physical Examination and Follow-up A physical examination is not required prior to prescribing Plan B One-Step. A 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 One-Step. 5.6 Fertility Following Discontinuation A rapid return of fertility is likely followi ng treatment with Plan B One-Step for em ergency contraception; therefore, routine contraception should be continued or initiated as soon as possible following use of Plan B One-Step to ensure ongoing prevention of pregnancy. 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditio ns, adverse reaction rates observe d in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and ma y not reflect the rates observed in clinical practice. Plan B One-Step was studied in a randomi zed, double-blinded multicenter clinical trial. In this study, all women who had recei ved at least one dose of study medication were included in the safety analysis: 1,379 women in the Plan B One-Step group, and 1,377 women in the Plan B group (2 doses of 0.75 mg levonorgestrel taken 12 hours apart). The mean age of women given Pl an B One-Step was 27 years. The racial demographic of tho se enrolled was 54% Chinese, 12% Other Asian or Black, and 34% were Caucasian in each treatmen t group. 1.6% of women in the Plan B One-Step group and 1.4% in Plan B group were lost to follow-up. The most common adverse events (>10%) in th e clinical trial for women receiving Plan B One-Step included heavier menstrual bleeding (30.9%), nausea (13.7%), lower abdominal pain (13.3%), fati gue (13.3%), and headache (10.3%). Table 1 lists those adverse events that were re ported in > 4% of Plan B One- Step users.
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Page 3 Table 1. Adverse Events in > 4% of Women, by % Frequency Most Common Adverse Events (MedDRA) Plan B One-Step N = 1359 (%) Heavier menstrual bleeding 30.9 Nausea 13.7 Lower abdominal pain 13.3 Fatigue 13.3 Headache 10.3 Dizziness 9.6 Breast tenderness 8.2 Delay of menses (> 7 days) 4.5 6.2 Postmarketing Experience The following adverse reactions have been identified during post- approval use of Plan B (2 doses of 0.75 mg levonorgestrel take n 12 hours apart). Because these reactions are reported voluntarily from a popul ation of uncertain size, it is not alwa ys possible to reliably estimate their fr equency or establish a causal relationship to drug exposure. Gastrointestinal Disorders Abdominal Pain, Nausea, Vomiting General Disorders and Administration Site Conditions Fatigue Nervous System Disorders Dizziness, Headache Reproductive System and Breast Disorders Dysmenorrhea, Irregular Menstruation, Oligomenorrhea, Pelvic Pain 7 DRUG INTERACTIONS Drugs or herbal products that induce enzymes, including CYP3A4, that metabolize progestins may decrease the plasma concentratio ns 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 • griseofulvin • oxcarbazepine • phenytoin • rifampin • St. John™s wort • topiramate Significant changes (increase or decrease) in the plasma levels of the progestin have been noted in some cases of co-administra tion with HIV protease inhibitors or with non-nucleoside reverse transcriptase inhibitors. Consult the labeling of all concurrently used drugs to obtain further information about interac tions with progestin-only pills or the potential for enzyme alterations. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Many studies have found no harmful effects on fetal development associated with long-te rm use of contraceptive doses of oral pr ogestins. The few studies of infant growth and development that have been conducted with progestin-only pills have not demonstrated significant adverse effe cts. 8.3 Nursing Mothers In general, no adverse effects of progestin -only pills have been found on breastfeedi ng performance or on the health, growth, o r development of the infant. However, isolated post-marketing cases of decreased milk produc tion 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.
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Page 4 8.4 Pediatric Use Safety and efficacy of progestin-only pills for long-term contraception have been estab lished in women of reproductive age. Sa fety and efficacy are expected to be the same for postpubertal adolescents less than 17 years and for users 17 years and older. Use of Plan B One-Step 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 a higher pregnancy rate in Chinese women with both Plan B and the Yuzpe regimen (another form of emergency contraception). There was a non-statistically significant increased rate of pregnancy among Chinese women in the Plan B One-Step trial. The reason for this apparent increase in the pregnancy rate with emergency contr aceptives in Chinese wo men is unknown. 8.7 Hepatic Impairment No formal studies were conducted to ev aluate the effect of hepatic disease on the disposition of Plan B One-Step. 8.8 Renal Impairment No formal studies were conducted to evaluate the effect of renal disease on the disposition of Plan B One-Step. 9 DRUG ABUSE AND DEPENDENCE Levonorgestrel is not a controlled substance. There is no info rmation about dependence associated with the use of Plan B One-Step. 10 OVERDOSAGE There are no data on overdosage of Plan B One-Step, although the common adverse event of na usea and associated vomiting may be anticipated. 11 DESCRIPTION The Plan B One-Step tablet contains 1.5 mg of a single active steroid i ngredient, levonorgestrel [18,19-Dinor pregn-4-en-20-yn-3-one-13-eth yl-17-hydroxy-, (17 )-(-)-], a totally synthetic progestogen. The inactive ingredients are colloidal s ilicon dioxide, corn starch, lactose monohydr ate, magnesium stearate, potato starch, and talc. Levonorgestrel has a molecular weight of 312.45, and the following structural and molecular formulas: C21H28O2 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Emergency contraceptive pills are not effectiv e if a woman is already pregnant. Plan B One-Step 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 implantat ion (by altering the endometrium). It is not effective once the process of implantation has begun. 12.3 Pharmacokinetics Absorption Following a single dose administration of Plan B One-Step in 30 women under fasting conditions, maximum plasma concentrations o f levonorgestrel of 19.1 ng/mL were reached at 1.7 hours. See Table 2.
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Page 5 Table 2. Pharmacokinetic Parameter Values Follo wing Single Dose Administration of Plan B One-Step (levonorgestrel) tablet 1.5 mg to 30 Heal thy Female Volunteers under Fasting Conditions Mean (± SD) Cmax (ng/mL) AUCt (ng·hr/mL)* AUCinf (ng·hr/mL)* Tmax (hr)** t1/2 (hr) Levonorgestrel 19.1 ( 9.7) 294.8 ( 208.8) 307.5 ( 218.5) 1.7 (1.0-4.0) 27.5 ( 5.6) Cmax = maximum concentration AUCt = area under the drug concentration curve from time 0 to time of last determinable concentration AUCinf = area under the drug concentration curve from time 0 to infinity Tmax = time to maximum concentration t1/2 = elimination half life * N=29 ** median (range) Effect of Food: The effect of food on the rate and the extent of levonorgestrel absorption following single oral administration of Plan B One-Step has not been evaluated. Distribution The apparent volume of distributi on of levonorgestrel is reported to be approximate ly 1.8 L/kg. It is about 97.5 to 99% protein -bound, principally to sex hormone binding globulin (SHBG) and, to a lesser extent, serum albumin. Metabolism Following absorption, levonorgestrel is conjugated at the 17 -OH position to form sulfate conjugates and, to a lesser extent, glucuronide conjugates in plasma. Significant amounts of conjug ated and unconjugated 3 , 5-tetrahydrolevonorgestrel are also present in plasma, along with much smaller amounts of 3 , 5tetrahydrolevonorgestrel and 16 hydroxylevonorgestrel. Le vonorgestrel and its phase I 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 l evonorgestrel concentrations among users. Excretion About 45% of levonorgestrel and its metabolites are excreted in th e urine and about 32% are excreted in feces, mostly as glucur onide conjugates. Specific Populations Pediatric This product is not intended for use in the premenarcheal popula tion, and pharmacokinetic data are not available for this popul ation. 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. However, clinical trials demonstrated a higher pregnancy rate in Chinese women with both Plan B and the Yuzpe regimen (another form of emergency contraception). There was a non-statistically significant increased rate of pregnancy among Chinese women in the Plan B One-Step trial. The reason for this apparent increase in the pregnancy rate with emergency contr aceptives in Chinese wo men is unknown [see USE IN SPECIFIC POPULATIONS (8.6)]. Hepatic Impairment No formal studies were conducted to ev aluate the effect of hepatic disease on the disposition of Plan B One-Step. Renal Impairment No formal studies were conducted to evaluate the effect of renal disease on the disposition of Plan B One-Step. Drug-Drug Interactions No formal drug-drug interaction studies were conducted with Plan B One-Step [see DRUG INTERACTIONS (7)]. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesi s, Impairment of Fertility Carcinogenicity: There is no evidence of incr eased risk of cancer with short-term use of progestins. There was no increase in tumorgenicity following administration of levonorgestrel to rats for 2 years at approxima tely 5 µg/day, to dogs for 7 years at up to 0.125 mg/kg/day, o r to rhesus monkeys for 10 years at up to 250 µg/kg/day. In another 7 year dog study, ad ministration of levonorgestrel at 0.5 mg/kg/day did increase t he number of mammary adenomas in treated dogs compared to controls. There were no malignancies.
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Page 6 Genotoxicity: Levonorgestrel was not found to be mutagenic or genotoxic in the Ames A ssay, in vitro mammalian culture assays u tilizing mouse lymphoma cells and Chinese hamster ovary cells, a nd in an in vivo micronucleus assay in mice. Fertility: There are no irreversible effects on fertility followi ng cessation of exposures to le vonorgestrel or progestins in general. 14 CLINICAL STUDIES A double-blind, randomized, multicenter, multinational study evaluate d and compared the efficacy and safety of three different regimens for emergency contraception. Subjects were enrolled at 15 sites in 10 countri es; the racial/ethnic characteristics of the study population o verall were 54% Chinese, 34% Caucasian, and 12% Black or Asian (other than Chinese). 2,381 hea lthy women with a mean age of 27 years, who needed emergency c ontraception within 72 hours of unprotected intercourse were invol ved and randomly allocated into one of th e two levonorgestrel groups. A single dose of 1.5 mg of levonorgestrel (Plan B One-Step) was administered to women allocated into group 1. Two doses of 0.75 mg levonorgestrel 12 hours apart (Plan B) were administered to women in group 2. In the Plan B One-Step group, 16 pregnancies occurred in 1,198 women and in the Plan B group, 20 pregnancies occurred in 1,183 women. The number of pregnancies expected in each group was calculated based on the timing of intercourse with regard to each woman™s menstrual c ycle. Among women receiving Plan B One-Step, 84% of expected pregnancie s were prevented and among those women taki ng Plan B, 79% of expected pregnancies we re prevented. The expected pregnancy rate of 8% (with no contraceptive use) was reduced to approximately 1% with Plan B One-Step. Emergency contraceptives are not as effective as routine cont raception since their failure rate, while low based on a single us e, would accumulate over time with repeated use [see INDICATIONS AND USAGE (1) ]. In the clinical study, bleeding disturbances were the most common adverse event reported after taking the levonorgestrel-contai ning regimens. More than half of the women had menses within two days of th e expected time; however, 31% of women expe rienced change in their bleeding pattern d uring the study period; 4.5% of women had menses more than 7 days after the expected time. 16 HOW SUPPLIED/STORAGE AND HANDLING The Plan B One-Step (levonorgestrel) tablet 1.5 mg is available in a PVC/ aluminum foil blister package. The tablet is almost white, round, and marked G00 on one side. NDC 51285-088-88 (1 tablet unit of use package) Store Plan B One-Step at 20º to 25ºC (68º to 77ºF ) [see USP Controlled Room Temperature]. 17PATIENT COUNSELING INFORMATION 17.1 Information for Patients •Take Plan B One-Step as soon as possible and not more than 72 hours after unprotected intercourse or a known or suspected contraceptive fai lure. •If you vomit within two hours of taking the tablet, immediately contact your healthcare provider to discuss whether to take ano ther tablet. •Seek medical attention if you experience seve re lower abdominal pain 3 to 5 weeks afte r taking Plan B One-Step, in order to be evaluated for an ectopic pregnancy. •After taking Plan B One-Step, consider the possibility of pregnancy if your period is delayed more than one week beyond the dat e you expected your period. •Do not use Plan B One-Step as routine contraception. •Plan B One-Step is not effective in te rminating an existing pregnancy. •Plan B One-Step does not protect against HIV-infection (AID S) and other sexually transmitted diseases/infections. •For women younger than age 17 years, Plan B One-Step is available only by prescription. Mfg. by Gedeon Richter, Ltd., Budapest, Hungary for Duramed Pharmaceuticals, Inc. Subsidiary of Barr Pharmaceuticals, Inc. Pomona, New York 10970 Phone: 1-800-330-1271 Website: www.PlanBOneStep.com Revised: July 2009 11001459
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What is Plan B¨ One-Step? Plan B¨ One-Step is emergency contraception that helps prevent pregnancy after birth control failure or unprotected sex. It is a backup method of preventing pregnancy and is not to be used routinely. Plan B¨ One-Step can reduce your chance of pregnancy after unprotected sex (if your regular birth control was used incorrectly or fails, or if you have had sex without birth control). For example, if you were using a condom and it broke or slipped, if you did not use your regular birth control as you should have, or if you did not use any birth control, Plan B ¨ One-Step may work for you. 2
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(levonorgestrel) tablet15 mg 3 , . What Plan B¨ One-Step is not. Plan B¨ One-Step will not work if you are already pregnant and will not affect an existing pregnancy. Plan B ¨ One-Step should not be used as regular birth control. It is important to have another reliable source of birth control that is right for you. Plan B ¨ One-Step will not protect you from HIV infection (the virus that causes AIDS) and other sexually transmitted diseases.
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When is the appropriate time to use Plan B ¨ One-Step? You can use Plan B ¨ One-Step after you have had unprotected sex in the last 72 hours (3 days), and you do not want to become pregnant. Plan B¨ One-Step can be used as a backup or emergency method to regular birth control if, for example, ¥ Your regular birth control method was used incorrectly or failed (your partnerÕs condom broke or slipped) ¥ You made a mistake with your regular method ¥ You did not use any birth control method 4
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(levonorgestrel) tablet15 mg , . 5 When is it not appropriate to use Plan B ¨ One-Step? ¥ Plan B¨ One-Step should not be used as a regular birth control method. It does not work as well as most other forms of birth control when they are used consistently and correctly. Plan B ¨ One-Step is a backup or emergency method of contraception. ¥ Plan B¨ One-Step should not be used if you are already pregnant because it will not work. ¥ Plan B¨ One-Step should not be used if you are allergic to levonorgestrel or any other ingredients in Plan B¨ One-Step.
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