50 O B .GYN. NEWS • February 1, 2005

T HE M ASTER C LASS

A Practical Perspective on a to reduce this unacceptably high rate of cine at the University of California, San preterm . Francisco. Complicated Problem Washington Clark Hill, M.D., the guest ex- He is director of the perinatal center and pert for the Master Class this month, has long the division of maternal-fetal medicine at he health of any country is judged by the survival of studied preterm labor in the context of both the Sarasota (Fla.) Memorial Hospital. Dr. Tits . The spends 15% of its gross singleton and multiple gestations. He has pub- Hill brings a clinical and practical perspec- national product on health care, yet it ranks 21st in the lished comprehensive overviews of research tive to this complicated problem. His in- world in its mortality rate of 8 deaths per 1,000 live on the complications of tocolysis and the pre- sights will allow us to disentangle fact from , according to the World Health Organization. The vention and treatment of preterm labor. fiction and what works from what doesn’t. two main contributors to this death rate are prematuri- A graduate of Temple University School of ty and birth defects. Medicine in Philadelphia, Dr. Hill did his res- DR. REECE, who specializes in maternal- Aggressive research programs are aimed at trying to idency training at William Beaumont Army BY E. ALBERT fetal medicine, is the vice chancellor and understand the pathophysiology of , and Medical Center in El Paso, Tex., before com- REECE, M.D., PH.D, dean of the college of medicine at the clinical interventions have been introduced in an attempt pleting a fellowship in maternal-fetal medi- M.B.A. University of Arkansas in Little Rock. Managing Preterm Labor in Multiple Gestations

reterm labor is one of the most im- high. Then, options for the should effective treatment for preterm labor. In sition that agents work for a short portant and vexing challenges com- be discussed with her and with the neona- fact, the initial administration of bolus in- period—about 48 hours, although Roger B. Pplicating . Premature ba- tal intensive care unit at your hospital or the travenous fluids may pose some risk to pa- Newman, M.D., and colleagues have bies account for an estimated 6%-10% of institution to which she will be transferred. tients with multiple gestations. These pa- shown that some multiple gestations can be births, yet they account for 70%-85% of Depending on the circumstances, the tients already have an increased prolonged for more than 7 days (Am. J. Ob- neonatal morbidity and mortality. treatment of preterm labor may be un- volume and could develop pulmonary ede- stet. Gynecol. 1989;161:547-55; “Multifetal In multiple gestations, which are in- dertaken for several reasons: ma from fluid overload if tocolytic thera- Pregnancy: A Handbook for Care of the creasingly common as a result of delayed Ǡ To delay delivery until the patient can py is initiated after unnecessary fluids are Pregnant Patient” [Philadelphia: Lippincott childbearing and the use of be transferred to a tertiary administered. Williams & Wilkins, 2000]). assisted reproductive tech- medical center with a high- Each tocolytic agent carries its own ben- nologies, preterm labor is an level neonatal intensive care efits, risks, contraindications, and adverse even greater risk. The litera- unit. A study by Paul J. Meis, M.D., and col- effects profile. Numerous sources are ture points to an incidence of Ǡ To delay delivery 24-48 leagues (N. Engl. J. Med. 2003;348:2379- available for this information; for quick preterm labor of 20%-75% in hours for the administration 85) suggests recurrent preterm birth in reference; I recently published a summa- multiple gestations. Al- of therapy. singleton can be prevented by ry in chart form (Clin. Obstet. Gynecol. though these figures may be Ǡ To reduce the strength 17 a-hydroxyprogesterone caproate. The 2004;47:216-26). Keep in mind that women somewhat high, I think it is and frequency of uterine jury is still out on whether progesterone with multiple gestations have an elevated safe to say that at least 1 in 10 contractions, enabling the fe- can be useful in managing active or threat- risk of cardiovascular complications, such multiple gestations seen at tus to further develop in the ened preterm labor in a multiple gestation as pulmonary resulting from ane- my institution are compli- uterus. pregnancy. mia, lower colloid oncotic pressure, and cated by preterm labor. Not BY WASHINGTON C. Ǡ To minimize hospital Studies are underway that may provide higher blood volume. all of these patients will be HILL, M.D. stays for the mother and the us with more guidance in the use of this I would take a middle-of-the-road ap- admitted or will deliver ear- neonate. agent. However, no evidence exists that it proach in choosing an agent or agents for ly, but the very common nature of this Ǡ To reduce the risk of neonatal morbid- is safe and efficacious in multiple gestation tocolysis. For example, oral , problem and the potentially lethal conse- ity and mortality by preventing preterm pregnancies, so I quences of premature multiple deliveries delivery, the most dangerous suggest its use be re- make this an issue that every physician and of multiple gestation pregnancies. served for patients institution should approach carefully. When I consult with a woman in in clinical trials. First, it is important to consider the de- preterm labor, I go through a list of avail- livery goal of a multiple gestation preg- able options. Unfortunately, a careful re- Antibiotics nancy. Overall, most are delivered at view of the literature reveals few really It is tantalizing to 37-38 weeks. For triplets, the gestational good, effective treatments. believe antibiotics age is closer to 34 weeks, and quadruplets Although new ideas emerge every few would be helpful in are born at around 30 weeks. These are years, not many interventional strategies preventing or treat- reasonable numbers applicable to com- have withstood attempts to corroborate re- ing preterm labor. ILL munity practice. sults from single institutions. It may be Many researchers H If a patient arrives in preterm labor, you tempting to “just do something,” but we theorize that in- have to decide what to do, considering her owe it to our patients to stick to scientifi- trauterine situation and the capabilities of your local cally valid and efficacious treatments. or fetal infection ASHINGTON . W . hospital and medical staff. It is clear that may be responsible R D premature babies fare best when they are for preterm labor, cared for in the institution where they are Bed rest or activity restriction will not pre- particularly in preg- OURTESY born. If someone needs to be transferred, vent preterm labor. Rest neither lengthens nancies that are not C it should be the mother, not the baby. gestation nor reduces neonatal morbidity in complicated by A pregnancy at 25 weeks’ gestation shows discordancy Obviously, if a patient carrying twins multiple gestation pregnancies. In some multiple . for fetal size. The patient presented in preterm labor and will presents in labor at 35 or 36 weeks, most studies these patients did worse. However, the data be followed closely. obstetricians would be inclined to do very If a patient carrying multiples has a do not show that little to cut short the labor, because—in short and threatened preterm labor, antibiotic treatment is any more effica- oral calcium channel blockers, and oral In- the absence of other complications—these there is some evidence to support getting cious than placebo in prolonging pregnan- docin have been well-studied and widely babies are likely to do well. However, if her off her feet rather than having her con- cy or preventing preterm delivery. used, with varying levels of success. she presents at 29 weeks, it would make tinue working at a very active job. John P. Elliott, M.D., and Tari Radin, sense to be more aggressive. Once a multiple pregnancy is compli- Ph.D., studied a small number of high-or- Can the patient be safely and aggressive- cated by preterm labor, hospitalization The use of tocolytics to decrease or halt der multiple gestations and found similar ly managed for preterm labor in her local may be necessary for observation and im- preterm labor is controversial in multiple levels of serum in triplets and community? The answer hinges on the plementation of a treatment course. gestations as well as in singleton pregnan- quadruplets and in singleton pregnancies plan for delivery if the treatment fails. Each cies because the drugs pose risks to the after the administration of magnesium hospital and service has to pick a gestational Hydration mother and, in some cases, to the . age at which neonatal survival is acceptably There is no evidence that hydration is an However, the available data support the po- Continued on following page February 1, 2005 • www.eobgynnews.com 51

Continued from previous page terval delivery of the second twin is desired. fers support, diversion, and empathy in the subtle indications of infection and other form of wheelchair outings, Internet ac- potential causes of preterm labor. sulfate for tocolysis (J. Reprod. Med. Treating the Whole Patient cess, flexible visitation for family members In multiple gestations, of course, 1995;40:450-2). However, they concluded Not infrequently, preterm labor in a mul- (including children), manicures, pedicures, preterm labor is often caused simply be- that higher levels of tiple gestation pregnancy requires the pro- movies, and get-togethers. cause there are too many fetuses in the are needed in multiple gestations to inhibit longed hospitalization of the mother, who The success of our program and the womb. Uterine overdistension will not be labor. They suggested administration at in- may be a busy professional woman or the gratitude expressed by the on our an easy problem to overcome, except by re- fusion rates of 4-5 g/h in triplet and of other small children. Spending 5- service have convinced me that this is a ducing multiple gestations. Many of our quadruplet pregnancies. 10 weeks in a hospital is a long, frustrating kind and therapeutic approach worth con- colleagues in reproductive endocrinology Research on combination tocolytic ther- time, replete with boredom and . sidering and implementing elsewhere. have gotten the message that implanting apy has produced conflicting results. Most At my institution, a clinical nurse spe- too many embryos is unwise and unethical. of the studies on this topic are dated, lim- cialist who was concerned with the psy- The Future I believe that in the coming years, we ited in scope, and not specifically focused chosocial effect of hospitalization on the The road to safe and effective therapy for will gain a better understanding of organic on multiple gestations. Some concerns, women in our unit proposed what has be- preterm labor has been a long and frus- causes of preterm labor, permitting us to however, have been raised. For example, come a highly successful multidimensional trating one. I am hopeful that researchers customize therapy according to individual magnesium sulfate administered in con- program: Mom Matters. The program of- are now on the right track, focusing on circumstances of each pregnancy. ■ junction with can result in sig- nificant neuromuscular blockage and a ® contraception at different ages. These estimates include the combined risk of death associ- antifungals,anticonvulsants,and other drugs that increase metabolism of contraceptive steroids. ORTHO EVRA ated with contraceptive methods plus the risk attributable to pregnancy in the event of method This could result in or breakthrough . Examples include barbi- subsequent marked hypotensive effect. (NORELGESTROMIN / ETHINYL failure. Each method of contraception has its specific benefits and risks. The study concluded turates, griseofulvin, rifampin, phenylbutazone, phenytoin, carbamazepine, felbamate, oxcar- TRANSDERMAL SYSTEM) that with the exception of combination oral contraceptive users 35 and older who smoke, and bazepine, topiramate and possibly with ampicillin. The proposed mechanism of interaction of My recommendation is to administer 40 and older who do not smoke, mortality associated with all methods of is low antibiotics is different from that of liver enzyme-inducing drugs. Literature suggests possible Patients should be counseled that this product does not protect against HIV infec- and below that associated with . interactions with the concomitant use of hormonal contraceptives and ampicillin or tetracy- tion (AIDS) and other sexually transmitted . combination tocolytic therapy only with The observation of a possible increase in risk of mortality with age for combination oral con- cline. In a pharmacokinetic drug interaction study, oral administration of tetracycline HCl, ® only traceptive users is based on data gathered in the 1970’s but not reported until 1983. Current 500 mg q.i.d. for 3 days prior to and 7 days during wear of ORTHO EVRA® did not significantly great caution, using agents such as intra- ORTHO EVRA® is a combination transdermal contraceptive patch with a contact surface area clinical recommendation involves the use of lower estrogen dose formulations and a careful affect the pharmacokinetics of norelgestromin or EE. Several of the anti-HIV protease inhibitors of 20 cm2. It contains 6.00 mg norelgestromin and 0.75 mg ethinyl estradiol (EE), and releases consideration of risk factors.In 1989,the Fertility and Drugs Advisory Committee have been studied with co-administration of oral combination hormonal contraceptives; 150 micrograms of norelgestromin and 20 micrograms of EE to the bloodstream per 24 hours. was asked to review the use of combination hormonal contraceptives in women 40 years of significant changes (increase and decrease) in the mean AUC of the estrogen and progestin venous magnesium sulfate with oral age and over. The Committee concluded that although cardiovascular risks may be have been noted in some cases.The efficacy and safety of oral contraceptive products may be IMPORTANT NOTE – This information is a BRIEF SUMMARY of the complete prescribing increased with combination hormonal contraceptive use after age 40 in healthy non-smoking affected; it is unknown whether this applies to ORTHO EVRA®. Healthcare professionals should terbutaline or indomethacin. The mother information provided with the product and therefore should not be used as the basis for women (even with the newer low-dose formulations), there are also greater potential health refer to the label of the individual anti-HIV protease inhibitors for further drug-drug interaction prescribing the product.This summary was prepared by deleting from the complete pre- risks associated with pregnancy in older women and with the alternative surgical and medical information. Herbal products containing St. John’s Wort (hypericum perforatum) may induce and fetus also should be monitored close- scribing information certain text,tables and references.The physician should be thoroughly procedures that may be necessary if such women do not have access to effective and acceptable hepatic enzymes (cytochrome P450) and p-glycoprotein transporter and may reduce the familiar with the complete prescribing information before prescribing the product. means of contraception. The Committee recommended that the benefits of low-dose combi- effectiveness of contraceptive steroids.This may also result in breakthrough bleeding.Increase INDICATIONS AND USAGE: ORTHO EVRA® is indicated for the prevention of pregnancy. nation hormonal contraceptive use by healthy non-smoking women over 40 may outweigh the in Plasma Hormone Levels Associated with Co-Administered Drugs: Co-administration of ly by professionals well-versed in side ef- atorvastatin and certain oral contraceptives containing ethinyl estradiol increase AUC values Like oral contraceptives, ORTHO EVRA® is highly effective if used as recommended in this label. possible risks. Although the data are mainly obtained with oral contraceptives, this is likely to apply to ORTHO EVRA® as well. Women of all ages who use combination hormonal contra- for ethinyl estradiol by approximately 20%. Ascorbic acid and acetaminophen may increase fects linked to this form of therapy. ORTHO EVRA® has not been studied for and is not indicated for use in emergency ceptives, should use the lowest possible dose formulation that is effective and meets the indi- plasma ethinyl estradiol levels, possibly by inhibition of conjugation. CYP 3A4 inhibitors such contraception. vidual patient needs. 3.Carcinoma Of The Reproductive Organs And Breasts:Numerous as itraconazole or ketoconazole may increase plasma hormone levels.Changes in Plasma Levels Should tocolytic therapy be maintained CONTRAINDICATIONS: ORTHO EVRA® should not be used in women who currently have the epidemiological studies give conflicting reports on the relationship between breast cancer and of Co-Administered Drugs: Combination hormonal contraceptives containing some synthetic following conditions: 1. Thrombophlebitis, thromboembolic disorders 2. A past history of deep COC use.The risk of having breast cancer diagnosed may be slightly increased among current estrogens (e.g., ethinyl estradiol) may inhibit the metabolism of other compounds. Increased after successful cessation of labor? A care- vein thrombophlebitis or thromboembolic disorders 3. Cerebrovascular or coronary artery and recent users of combination oral contraceptives. However, this excess risk appears to plasma concentrations of cyclosporine,prednisolone,and theophylline have been reported with disease (current or past history) 4. Valvular heart disease with complications 5. Severe hyper- decrease over time after COC discontinuation and by 10 years after cessation the increased concomitant administration of oral contraceptives. In addition, oral contraceptives may induce tension 6. with vascular involvement 7. Headaches with focal neurological symptoms risk disappears. Some studies report an increased risk with duration of use while other stud- the conjugation of other compounds. Decreased plasma concentrations of acetaminophen and ful reading of the available evidence sug- 8. Major surgery with prolonged immobilization 9. Known or suspected carcinoma of the breast ies do not and no consistent relationships have been found with dose or type of steroid. Some increased clearance of temazepam, salicylic acid, morphine and clofibric acid have been noted or personal history of breast cancer 10. Carcinoma of the or other known or studies have found a small increase in risk for women who first use COCs before age 20. Most when these drugs were administered with oral contraceptives. Although norelgestromin and gests the answer is no. In well-designed suspected estrogen-dependent neoplasia 11.Undiagnosed abnormal genital bleeding 12.Cholestatic studies show a similar pattern of risk with COC use regardless of a woman’s reproductive its metabolites inhibit a variety of P450 enzymes in human liver microsomes, the clinical of pregnancy or jaundice with prior hormonal contraceptive use 13. Acute or chronic history or her family breast cancer history. In addition, breast cancers diagnosed in current or consequence of such an interaction on the levels of other concomitant medications is likely to studies, maintenance tocolytic therapy has hepatocellular disease with abnormal liver function 14. Hepatic adenomas or carcinomas ever oral contraceptive users may be less clinically advanced than in never-users.Women who be insignificant.Under the recommended dosing regimen,the in vivo concentrations of norelge- 15. Known or suspected pregnancy 16. Hypersensitivity to any component of this product currently have or have had breast cancer should not use hormonal contraceptives because stromin and its metabolites, even at the peak serum levels, are relatively low compared to the breast cancer is usually a hormonally sensitive tumor. Some studies suggest that combination inhibitory constant (Ki) (based on results of in vitro studies). Health care professionals are reduced neither preterm deliveries nor WARNINGS oral contraceptive use has been associated with an increase in the risk of cervical intraep- advised to also refer to prescribing information of co-administered drugs for recommendations Cigarette smoking increases the risk of serious cardiovascular side effects ithelial neoplasia in some populations of women. However, there continues to be controversy regarding management of concomitant therapy.9.Interactions With Laboratory Tests:Certain perinatal morbidity or mortality. from hormonal contraceptive use.This risk increases with age and with heavy about the extent to which such findings may be due to differences in sexual behavior and other endocrine and liver function tests and blood components may be affected by hormonal smoking (15 or more cigarettes per day) and is quite marked in women factors. In spite of many studies of the relationship between oral contraceptive use and breast contraceptives: a. Increased prothrombin and factors VII, VIII, IX, and X; decreased antithrom- over 35 years of age.Women who use hormonal contraceptives, including and cervical cancers, a cause-and-effect relationship has not been established. It is not known bin 3; increased norepinephrine-induced platelet aggregability. b. Increased binding ORTHO EVRA®, should be strongly advised not to smoke. whether ORTHO EVRA® is distinct from oral contraceptives with regard to the above state- globulin (TBG) leading to increased circulating total thyroid hormone, as measured by protein- ments. 4.Hepatic Neoplasia: Benign hepatic adenomas are associated with hormonal con- bound iodine (PBI), T4 by column or by radioimmunoassay. Free T3 resin uptake is decreased, ORTHO EVRA® and other contraceptives that contain both an estrogen and a progestin are reflecting the elevated TBG, free T4 concentration is unaltered. c. Other binding proteins may called combination hormonal contraceptives. There is no epidemiologic data available to traceptive use, although the incidence of benign tumors is rare in the United States. Indirect calculations have estimated the attributable risk to be in the range of 3.3 cases/100,000 for be elevated in serum. d. Sex hormone binding globulins are increased and result in elevated determine whether safety and efficacy with the transdermal route of administration would be levels of total circulating endogenous sex steroids and corticoids; however, free or biologically Corticosteroids are among the few non- ® users, a risk that increases after four or more years of use, especially with hormonal contra- different than the oral route. Practitioners prescribing ORTHO EVRA should be familiar with active levels either decrease or remain unchanged. e. Triglycerides may be increased and the following information relating to risks. ceptives containing 50 micrograms or more of estrogen. Rupture of benign, hepatic adenomas controversial agents for use during may cause death through intra-abdominal hemorrhage. Studies from Britain and the US have levels of various other lipids and lipoproteins may be affected. f. Glucose tolerance may be The use of combination hormonal contraceptives is associated with increased risks of several shown an increased risk of developing hepatocellular carcinoma in long term (≥ 8 years) oral decreased. g. Serum levels may be depressed by hormonal contraceptive therapy. This serious conditions including myocardial infarction, thromboembolism, stroke, hepatic contraceptive users. However, these cancers are extremely rare in the U.S. and the attributa- may be of clinical significance if a woman becomes pregnant shortly after discontinuing preterm labor. These agents—which clear- neoplasia, and gallbladder disease, although the risk of serious morbidity or mortality is very ble risk (the excess incidence) of liver cancers in oral contraceptive users approaches less than ORTHO EVRA®.10.Carcinogenesis: No carcinogenicity studies were conducted with norelge- small in healthy women without underlying risk factors. The risk of morbidity and mortality one per million users. It is unknown whether ORTHO EVRA® is distinct from oral contraceptives stromin. However, bridging PK studies were conducted using doses of NGM/EE which were ly reduce the incidence and severity of increases significantly in the presence of other underlying risk factors such as , in this regard. 5.Ocular Lesions: There have been clinical case reports of retinal thrombosis used previously in the 2-year rat carcinogenicity study and 10-year monkey toxicity study to hyperlipidemias, and diabetes. associated with the use of hormonal contraceptives. ORTHO EVRA® should be discontinued if support the approval of ORTHO-CYCLEN and ORTHO TRI-CYCLEN under NDAs 19-653 and The information contained in the package insert is principally based on studies carried out in there is unexplained partial or complete loss of vision; onset of proptosis or diplopia; 19-697, respectively.The PK studies demonstrated that rats and monkeys were exposed to 16 neonatal respiratory distress syndrome, ® women who used combination oral contraceptives with higher formulations of estrogens and papilledema; or retinal vascular lesions. Appropriate diagnostic and therapeutic measures and 8 times the human exposure, respectively, with the proposed ORTHO EVRA transdermal progestins than those in common use today. The effect of long-term use of combination should be undertaken immediately. 6.Hormonal Contraceptive Use Before Or During Early contraceptive system.Norelgestromin was tested in in-vitro mutagenicity assays (bacterial plate intraventricular hemorrhage, necrotizing hormonal contraceptives with lower doses of both estrogen and progestin administered by any Pregnancy: Extensive epidemiological studies have revealed no increased risk of birth defects incorporation mutation assay, CHO/HGPRT mutation assay, chromosomal aberration assay route remains to be determined. in women who have used oral contraceptives prior to pregnancy. Studies also do not indicate using cultured human peripheral lymphocytes) and in one in-vivo test (rat micronucleus assay) enterocolitis, and neonatal mortality— a teratogenic effect, particularly in so far as cardiac anomalies and limb reduction defects are and found to have no genotoxic potential. See WARNINGS Section. 11.Pregnancy: Pregnancy Throughout this labeling, epidemiological studies reported are of two types: retrospective or Category X. See CONTRAINDICATIONS and WARNINGS Sections. Norelgestromin was tested for case control studies and prospective or cohort studies. Case control studies provide a meas- concerned,when oral contraceptives are taken inadvertently during early pregnancy.Combination ® its reproductive toxicity in a rabbit developmental toxicity study by the SC route of administra- ure of the of a disease, namely, a ratio of the incidence of a disease among oral hormonal contraceptives such as ORTHO EVRA should not be used to induce withdrawal bleed- should be administered to any patient in ® tion. Doses of 0, 1, 2, 4 and 6 mg/kg body weight, which gave systemic exposure of approxi- contraceptive users to that among nonusers. The relative risk does not provide information ing as a test for pregnancy. ORTHO EVRA should not be used during pregnancy to treat threat- ened or habitual .It is recommended that for any patient who has missed two consecutive mately 25 to 125 times the human exposure with ORTHO EVRA®, were administered daily on preterm labor at 24-34 weeks, using the on the actual clinical occurrence of a disease. Cohort studies provide a measure of attributa- gestation days 7–19. Malformations reported were paw hyperflexion at 4 and 6 mg/kg and ble risk, which is the difference in the incidence of disease between hormonal contraceptive periods, pregnancy should be ruled out. If the patient has not adhered to the prescribed sched- ® paw hyperextension and cleft palate at 6 mg/kg. 12.Nursing Mothers: The effects of users and nonusers. The attributable risk does provide information about the actual occur- ule for the use of ORTHO EVRA the possibility of pregnancy should be considered at the time same regimen as in singleton gestations. of the first missed period. Hormonal contraceptive use should be discontinued if pregnancy is ORTHO EVRA® in nursing mothers have not been evaluated and are unknown. Small amounts rence of a disease in the population (adapted from refs. 2 and 3 with the author’s permission). of combination hormonal contraceptive steroids have been identified in the of nursing For further information, the reader is referred to a text on epidemiological methods. confirmed. 7.Gallbladder Disease: Earlier studies have reported an increased lifetime rela- The accepted corticosteroid treatment tive risk of gallbladder surgery in users of hormonal contraceptives and estrogens. More re- mothers and a few adverse effects on the child have been reported, including jaundice and 1.Thromboembolic Disorders And Other Vascular Problems: a.Thromboembolism:An cent studies,however,have shown that the relative risk of developing gallbladder disease among breast enlargement. In addition, combination hormonal contraceptives given in the postpartum increased risk of thromboembolic and thrombotic disease associated with the use of hormonal hormonal contraceptive users may be minimal.The recent findings of minimal risk may be re- period may interfere with lactation by decreasing the quantity and quality of . Long- consists of two intramuscular doses of contraceptives is well established. Case control studies have found the relative risk of users lated to the use of hormonal contraceptive formulations containing lower hormonal doses of term follow-up of infants whose mothers used combination hormonal contraceptives while breast compared to nonusers to be 3 for the first episode of superficial venous thrombosis, 4 to 11 estrogens and progestins. Combination hormonal contraceptives such as ORTHO EVRA® may feeding has shown no deleterious effects. However, the nursing mother should be or four intramuscular dos- for deep vein thrombosis or pulmonary , and 1.5 to 6 for women with predisposing worsen existing gallbladder disease and may accelerate the development of this disease in advised not to use ORTHO EVRA® but to use other forms of contraception until she has com- conditions for venous thromboembolic disease. Cohort studies have shown the relative risk to previously asymptomatic women. Women with a history of combination hormonal pletely weaned her child. 13.Pediatric Use: Safety and efficacy of ORTHO EVRA® have been es of . be somewhat lower, about 3 for new cases and about 4.5 for new cases requiring hospitaliza- contraceptive-related cholestasis are more likely to have the condition recur with subsequent established in women of reproductive age. Safety and efficacy are expected to be the same for tion. The risk of thromboembolic disease associated with hormonal contraceptives is not combination hormonal contraceptive use. 8.Carbohydrate And Lipid Metabolic Effects: post-pubertal adolescents under the age of 16 and for users 16 years and older. Use of this related to length of use and disappears after hormonal contraceptive use is stopped.A two- to Hormonal contraceptives have been shown to cause a decrease in glucose tolerance in some product before menarche is not indicated. 14.Geriatric Use: This product has not been stud- In higher-order gestations, Dr. Elliott four-fold increase in relative risk of post-operative thromboembolic complications has been users. However, in the non-diabetic woman, combination hormonal contraceptives appear to ied in women over 65 years of age and is not indicated in this population. 15.Sexually reported with the use of hormonal contraceptives. The relative risk of venous thrombosis in have no effect on fasting blood glucose. Prediabetic and diabetic women in particular should Transmitted Diseases: Patients should be counseled that this product does not protect against and Dr. Radin have observed that beta- women who have predisposing conditions is twice that of women without such medical con- be carefully monitored while taking combination hormonal contraceptives such as ORTHO EVRA®. HIV infection (AIDS) and other sexually transmitted diseases. 16.Patch Adhesion: Experience ditions. If feasible, hormonal contraceptives should be discontinued at least four weeks prior In clinical trials with oral contraceptives containing ethinyl estradiol and norgestimate there with more than 70,000 ORTHO EVRA® patches worn for contraception for 6-13 cycles showed methasone can increase uterine contrac- to and for two weeks after elective surgery of a type associated with an increase in risk of were no clinically significant changes in fasting blood glucose levels. There were no clinically that 4.7% of patches were replaced because they either fell off (1.8%) or were partly detached thromboembolism and during and following prolonged immobilization. Since the immediate significant changes in glucose levels over 24 cycles of use. Moreover, glucose tolerance tests (2.9%). Similarly, in a small study of patch wear under conditions of physical exertion and vari- is also associated with an increased risk of thromboembolism, hormonal showed no clinically significant changes from baseline to cycles 3, 12 and 24. In a 6-cycle able temperature and humidity, less than 2% of patches were replaced for complete or partial tions and advance labor in patients with contraceptives should be started no earlier than four weeks after delivery in women who elect clinical trial with ORTHO EVRA® there were no clinically significant changes in fasting blood detachment. If the ORTHO EVRA® patch becomes partially or completely detached and not to breast-feed. In the large clinical trials (N= 3,330 with 1,704 women-years of exposure), glucose from baseline to end of treatment. A small proportion of women will have persistent remains detached, insufficient drug delivery occurs.A patch should not be re-applied if it is no frequent contractions. They therefore rec- one case of non-fatal pulmonary embolism occurred during ORTHO EVRA® use, and one case hypertriglyceridemia while taking hormonal contraceptives. As discussed earlier (see WARN- longer sticky, if it has become stuck to itself or another surface, if it has other material stuck of post-operative non-fatal pulmonary embolism was reported following ORTHO EVRA® use. It INGS 1a and 1d), changes in serum triglycerides and lipoprotein levels have been reported in to it, or if it has become loose or fallen off before. If a patch cannot be re-applied, a new patch ommend that corticosteroids be reserved is unknown if the risk of venous thromboembolism with ORTHO EVRA® use is different than hormonal contraceptive users. 9.Elevated Blood Pressure: Women with significant hyper- should be applied immediately. Supplemental adhesives or wraps should not be used to hold with use of combination oral contraceptives. As with any combination hormonal contracep- tension should not be started on hormonal contraception. Women with a history of hyperten- the ORTHO EVRA® patch in place. If a patch is partially or completely detached for more than tives, the clinician should be alert to the earliest manifestations of thrombotic disorders (throm- sion or hypertension-related diseases, or renal disease should be encouraged to use another one day (24 hours or more) OR if the woman is not sure how long the patch has been detached, in these pregnancies for patients having bophlebitis, pulmonary embolism, cerebrovascular disorders, and retinal thrombosis). Should method of contraception.If women elect to use ORTHO EVRA®,they should be monitored closely she may not be protected from pregnancy. She should stop the current contraceptive cycle and any of these occur or be suspected, ORTHO EVRA® should be discontinued immediately. and if a clinically significant elevation of blood pressure occurs, ORTHO EVRA® should be start a new cycle immediately by applying a new patch. Back-up contraception, such as con- fewer than three contractions per hour b.Myocardial Infarction: An increased risk of myocardial infarction has been attributed to discontinued. For most women, elevated blood pressure will return to normal after stopping doms, spermicide, or diaphragm, must be used for the first week of the new cycle. hormonal contraceptive use. This risk is primarily in smokers or women with other underlying hormonal contraceptives, and there is no difference in the occurrence of hypertension between INFORMATION FOR THE PATIENT: See Patient Package Insert. risk factors for coronary artery disease such as hypertension, hypercholesterolemia, morbid former and never users. An increase in blood pressure has been reported in women taking (Obstet. Gynecol. 1995;85:250-54). Uterine obesity, and diabetes.The relative risk of heart attack for current hormonal contraceptive users ADVERSE REACTIONS: The most common adverse events reported by 9 to 22% of women hormonal contraceptives and this increase is more likely in older hormonal contraceptive users using ORTHO EVRA® in clinical trials (N= 3,330) were the following, in order of decreasing has been estimated to be two to six compared to non-users.The risk is very low under the age and with extended duration of use. Data from the Royal College of General Practitioners and activity in higher-order gestations should of 30. Smoking in combination with oral contraceptive use has been shown to contribute sub- incidence: breast symptoms, headache, application site reaction, nausea, upper respiratory subsequent randomized trials have shown that the incidence of hypertension increases with infection, menstrual cramps, and abdominal . stantially to the incidence of myocardial infarctions in women in their mid-thirties or older with increasing progestational activity. 10.Headache: The onset or exacerbation of migraine smoking accounting for the majority of excess cases. Mortality rates associated with circula- The most frequent adverse events leading to discontinuation in 1 to 2.4% of women using be closely monitored following the ad- headache or the development of headache with a new pattern that is recurrent, persistent or ® tory disease have been shown to increase substantially in smokers,especially in those 35 years ® ORTHO EVRA in the trials included the following: nausea and/or vomiting, application site severe requires discontinuation of ORTHO EVRA and evaluation of the cause. 11.Bleeding reaction, breast symptoms, headache, and emotional lability. ministration of corticosteroids. of age and older among women who use oral contraceptives. Hormonal contraceptives may Irregularities: Breakthrough bleeding and spotting are sometimes encountered in women using compound the effects of well-known risk factors, such as hypertension, diabetes, hyperlipi- ORTHO EVRA®. Non-hormonal causes should be considered and adequate diagnostic meas- Listed below are adverse events that have been associated with the use of combination demias, age and obesity. In particular, some progestins are known to decrease HDL choles- ures taken to rule out malignancy, other pathology, or pregnancy in the event of breakthrough hormonal contraceptives. These are also likely to apply to combination transdermal hormonal It once was suggested that multiple terol and cause glucose intolerance, while estrogens may create a state of hyperinsulinism. bleeding, as in the case of any abnormal . If pathology has been excluded, time contraceptives such as ORTHO EVRA®. Hormonal contraceptives have been shown to increase blood pressure among some users (see or a change to another contraceptive product may resolve the bleeding. In the event of amen- An increased risk of the following serious adverse reactions has been associated with the use courses of prenatal corticosteroids might Section 9 in WARNINGS).Similar effects on risk factors have been associated with an increased orrhea, pregnancy should be ruled out before initiating use of ORTHO EVRA®. Some women of combination hormonal contraceptives (see WARNINGS Section): 1. Thrombophlebitis and risk of heart disease. Hormonal contraceptives, including ORTHO EVRA®, must be used with may encounter amenorrhea or oligomenorrhea after discontinuation of hormonal contracep- venous thrombosis with or without embolism 2. Arterial thromboembolism 3. Pulmonary be of benefit. This recommendation is no caution in women with risk factors. Norgestimate and norelgestromin tive use, especially when such a condition was pre-existent. Bleeding Patterns: In the clinical embolism 4.Myocardial infarction 5.Cerebral hemorrhage 6.Cerebral thrombosis 7.Hypertension have minimal androgenic activity (see CLINICAL PHARMACOLOGY in full Prescribing Information). trials most women started their withdrawal bleeding on the fourth day of the drug-free 8. Gallbladder disease 9. Hepatic adenomas or benign liver tumors longer made, because there is no good ev- There is some evidence that the risk of myocardial infarction associated with hormonal interval, and the median duration of withdrawal bleeding was 5 to 6 days. On average 26% of There is evidence of an association between the following conditions and the use of combina- contraceptives is lower when the progestin has minimal androgenic activity than when the women per cycle had 7 or more total days of bleeding and/or spotting (this includes both with- tion hormonal contraceptives: 1. Mesenteric thrombosis 2. Retinal thrombosis activity is greater. c.Cerebrovascular diseases: Hormonal contraceptives have been shown drawal flow and breakthrough bleeding and/or spotting). 12.: Ectopic as The following adverse reactions have been reported in users of combination hormonal con- idence for enhanced efficacy and because to increase both the relative and attributable risks of cerebrovascular events (thrombotic and well as intrauterine pregnancy may occur in contraceptive failures. hemorrhagic strokes), although, in general, the risk is greatest among older (>35 years), traceptives and are believed to be drug-related:1.Nausea 2.Vomiting 3.Gastrointestinal symp- repeated doses are associated with clear hypertensive women who also smoke.Hypertension was found to be a for both users PRECAUTIONS: Women should be counseled that ORTHO EVRA® does not protect against toms (such as abdominal cramps and bloating) 4. Breakthrough bleeding 5. Spotting 6. Change and nonusers, for both types of strokes, and smoking interacted to increase the risk of stroke. HIV infection (AIDS) and other sexually transmitted .1.Body Weight≥198 lbs. in menstrual flow 7.Amenorrhea 8.Temporary after discontinuation of treatment 9.Edema In a large study, the relative risk of thrombotic strokes has been shown to range from 3 for (90 kg): Results of clinical trials suggest that ORTHO EVRA® may be less effective in women 10. which may persist 11. Breast changes: tenderness, enlargement, secretion risks, including decreased fetal growth and normotensive users to 14 for users with severe hypertension. The relative risk of hemorrhagic with body weight ≥198 lbs. (90 kg) than in women with lower body weights. 2.Physical 12. Change in weight (increase or decrease) 13. Change in cervical erosion and secretion stroke is reported to be 1.2 for non-smokers who used hormonal contraceptives, 2.6 for smok- Examination And Follow-Up: It is good medical practice for women using ORTHO EVRA®,as 14. Diminution in lactation when given immediately postpartum 15. Cholestatic jaundice reduced . ers who did not use hormonal contraceptives, 7.6 for smokers who used hormonal contra- for all women, to have annual medical evaluation and physical examinations. The physical 16. Migraine 17. (allergic) 18. Mental depression 19. Reduced tolerance to carbohydrates ceptives,1.8 for normotensive users and 25.7 for users with severe hypertension.The attributable examination, however, may be deferred until after initiation of hormonal contraceptives if 20. Vaginal 21. Change in corneal curvature (steepening) 22. Intolerance to risk is also greater in older women. d.Dose-related risk of vascular disease from hormonal requested by the woman and judged appropriate by the clinician. The physical examination contact lenses contraceptives: A positive association has been observed between the amount of estrogen should include special reference to blood pressure, breasts, abdomen and pelvic organs, The following adverse reactions have been reported in users of combination hormonal and progestin in hormonal contraceptives and the risk of vascular disease. A decline in serum including cervical cytology, and relevant laboratory tests. In case of undiagnosed, persistent or contraceptives and a cause and effect association has been neither confirmed nor refuted: Adjunctive Treatments high-density lipoproteins (HDL) has been reported with many progestational agents. A decline recurrent abnormal vaginal bleeding, appropriate measures should be conducted to rule out 1. Pre-menstrual syndrome 2. Cataracts 3. Changes in appetite 4. Cystitis-like syndrome in serum high-density lipoproteins has been associated with an increased incidence of ischemic malignancy or other pathology. Women with a strong family history of breast cancer or who 5. Headache 6. Nervousness 7. Dizziness 8. Hirsutism 9. Loss of scalp hair 10. Isolated studies have suggested a role in heart disease. Because estrogens increase HDL , the net effect of a hormonal con- have breast nodules should be monitored with particular care. 3.Lipid Disorders: Women multiforme 11. 12. Hemorrhagic eruption 13. 14. Porphyria traceptive depends on a balance achieved between doses of estrogen and progestin and the who are being treated for hyperlipidemias should be followed closely if they elect to use 15. Impaired renal function 16. Hemolytic uremic syndrome 17. 18. Changes in libido preterm labor for such interventions as activity of the progestin used in the contraceptives. The activity and amount of both hormones ORTHO EVRA®. Some progestins may elevate LDL levels and may render the control of hyper- 19. Colitis 20. Budd-Chiari Syndrome should be considered in the choice of a hormonal contraceptive. e.Persistence of risk of vas- lipidemias more difficult. 4.Liver Function: If jaundice develops in any woman using OVERDOSAGE: Serious ill effects have not been reported following accidental ingestion of large cular disease: There are two studies that have shown persistence of risk of vascular disease ORTHO EVRA®, the medication should be discontinued. The hormones in ORTHO EVRA® may doses of hormonal contraceptives.Overdosage may cause nausea and vomiting,and withdrawal vaginal lever , blood transfusions, for ever-users of combination hormonal contraceptives. In a study in the United States, the risk be poorly metabolized in patients with impaired liver function. 5.Fluid Retention: Steroid hor- bleeding may occur in females. Given the nature and design of the ORTHO EVRA® patch, it is of developing myocardial infarction after discontinuing combination hormonal contraceptives mones like those in ORTHO EVRA® may cause some degree of fluid retention. ORTHO EVRA® unlikely that overdosage will occur. Serious ill effects have not been reported following acute and cerclage. None of these have been put persists for at least 9 years for women 40-49 years who had used combination hormonal con- should be prescribed with caution, and only with careful monitoring, in patients with conditions ingestion of large doses of oral contraceptives by young children.In case of suspected overdose, traceptives for five or more years, but this increased risk was not demonstrated in other age which might be aggravated by fluid retention. 6.Emotional Disorders: Women who become all ORTHO EVRA® patches should be removed and symptomatic treatment given. to rigorous scientific scrutiny. Cerclage ob- groups. In another study in Great Britain, the risk of developing cerebrovascular disease significantly depressed while using combination hormonal contraceptives such as persisted for at least 6 years after discontinuation of combination hormonal contraceptives, ORTHO EVRA® should stop the medication and use another method of contraception in an at- although excess risk was very small. However, both studies were performed with combination tempt to determine whether the symptom is drug related. Women with a history of depression viously has no role in patients who do not hormonal contraceptive formulations containing 50 micrograms or higher of estrogens. It is should be carefully observed and ORTHO EVRA® discontinued if significant depression occurs. unknown whether ORTHO EVRA® is distinct from other combination hormonal contraceptives 7.Contact Lenses: Contact lens wearers who develop visual changes or changes in lens tol- have an incompetent cervix, or in such with regard to the occurrence of venous and arterial thrombosis. 2.Estimates Of Mortality erance should be assessed by an ophthalmologist.8.Drug Interactions: Changes in Contraceptive ORTHO-McNEIL PHARMACEUTICAL, INC. From Combination Hormonal Contraceptive Use: One study gathered data from a variety Effectiveness Associated with Co-Administration of Other Drugs: Contraceptive effectiveness Raritan, New Jersey 08869 specific cases as the previable delivery of of sources that have estimated the mortality rate associated with different methods of may be reduced when hormonal contraceptives are co-administered with some antibiotics, © OMP 2001 Revised: May 2003 631-10-660-2B one dichorionic twin when a delayed-in-