Prescription Drugs

CLINICAL PHARMACOLOGY Levonorgestrel is a totally synthetic and biologically active progestin which exhibits no significant estrogenic activity and is highly progestational. The absolute configuration conforms to that of D-natural steroids. Levonorgestrel is not subjected to a “first-pass” effect and is virtually 100% bioavailable. Plasma concentrations average approximately 0.30 ng/mL over 5 years but are highly variable as a function of individual metabolism and body weight. Diffusion of levonorgestrel through the wall of each capsule provides a continuous low dose of the progestin. Resulting blood levels are substantially below those generally observed among users of combination oral contraceptives containing the progestins norgestrel or levonorgestrel. Because of the range of variability in blood levels and variation in individual response, blood levels alone are not predictive of the risk of pregnancy in an individual woman. At least two mechanisms are active in preventing pregnancy: ovulation inhibition and thickening of the cervical mucus. Other mechanisms may add to these contraceptive effects. Levonorgestrel concentrations among women show considerable variation depending on individual clearance rates, body weight, and possibly other factors. Levonorgestrel concentrations reach a maximum, or near maximum, within 24 hours after placement with mean values of 1600 ± 1100 pg/mL. They decline rapidly over the first month partially due to a circulating protein, SHBG, that binds levonorgestrel and which is depressed by the presence of levonorgestrel. At 3 months, mean levels decline to values of around 400 pg/mL while concentrations normalized to a 60 kg body weight were 327 ± 119 (SD) pg/mL at 12 months with further decline by 1.4 pg/mL/month to reach 258 ± 95 (SD) pg/mL at 60 months. Concentrations decreased with increasing body weight by a mean of 3.3 pg/mL/kg. After capsule removal, mean concentrations drop to below 100 pg/mL by 96 hours and to below assay sensitivity (50 pg/mL) by 5 to 14 days. Fertility rates return to levels comparable to those seen in the general population of women using no method of contraception. Circulating concentrations can be used to forecast the risk of pregnancy only in a general statistical sense. Mean concentrations associated with pregnancy have been 210 ± 60 (SD) pg/mL. However, in clinical studies, 20 percent of women had one or more values below 200 pg/mL but an average annual gross pregnancy rate of less than 1.0 per 100 women through 5 years. Although lipoprotein levels were altered in several clinical studies with the NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM, the long-term clinical effects of these changes have not been determined. A decrease in total cholesterol levels has been reported in all lipoprotein studies and reached statistical significance in several. Both increases and decreases in high-density lipoprotein (HDL) levels have been reported in clinical trials. No statistically significant increases have been reported in the ratio of total cholesterol to HDL-cholesterol. Low-density lipoprotein (LDL) levels decreased during NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM use. Triglyceride levels also decreased from pretreatment values.

CLINICAL PHARMACOLOGY Levonorgestrel is a totally synthetic and biologically active progestin that exhibits no significant estrogenic activity and is highly progestational. The absolute configuration conforms to that of D-natural steroids. At least two mechanisms are active in preventing pregnancy: ovulation inhibition and thickening of the cervical mucus. Other mechanisms may add to these contraceptive effects. Pharmacokinetics Absorption Levonorgestrel is delivered directly into interstitial fluids from the subdermal implants. However, the bioavailability of levonorgestrel after insertion of Jadelle® (levonorgestrel implants (unavailable in us)) implants compared with intravenous administration is not known. After placement of Jadelle® implants, maximum levonorgestrel concentrations are reached in about 2 to 3 days, with the mean ± standard deviation being 772 ± 414 pg/mL at 2 days. After the initial phase, mean levonorgestrel concentrations slowly decline to approximately 435 ± 172 pg/mL at 1 month, 357 ±155 pg/mL at 6 months, and 280 ± 123 pg/mL at 3 years. Concentrations at 4 and at 5 years are similar to those at 3 years. TABLE 1: Serum Concentrations During Jadelle® Use Time After Placement (months) Mean ± SD (pg/mL) n 1 435 ± 172 181 3 393 ± 191 165 6 357 ± 155 160 12 340 ± 159 148 24 312 ± 153 126 36 280 ± 123 89 48 271 ± 126 67 60 279 ± 123 65 Serum levonorgestrel concentrations were found to be inversely related to body weight. Serum levonorgestrel concentrations in women weighing more than 70 kg were approximately half as high as in women weighing less than 50 kg. Because of the range in serum concentrations and variation in individual response, serum concentrations alone are not predictive of the risk of pregnancy in an individual woman. Serum levonorgestrel concentrations in Jadelle® (levonorgestrel implants (unavailable in us)) users are substantially below those generally observed in users of oral contraceptives containing the progestins norgestrel or levonorgestrel. Distribution Levonorgestrel in serum is primarily protein bound. Approximately half is bound to sex hormone binding globulin (SHBG) and half to albumin. SHBG concentrations are depressed by levonorgestrel within a few days of administration, with resultant decreases in circulating levonorgestrel concentrations. Metabolism Levonorgestrel metabolic pathways have been only partially delineated. 16β-hydroxylation is an identified pathway of metabolism. Concentrations of metabolites in circulation soon exceed those of levonorgestrel, mostly as conjugated sulfates. Metabolic clearance rates may differ among individuals by several fold, which is believed to account in part for the wide variation observed in levonorgestrel serum concentrations among implant users. Excretion The elimination half-life of levonorgestrel is approximately 13 to 18 hours. Levonorgestrel and its metabolites are primarily excreted in the urine (40% to 68%) and about 16% to 48% are excreted in feces. After removal of the implants, levonorgestrel concentrations decrease below 100 pg/mL by 96 hours and below sensitivity of the assay by 5 days to 2 weeks. Special Populations Race Studies were conducted among women of different races in Asia, North and South America, Europe and Africa. However, data on race were not collected in the clinical trials with Jadelle® (levonorgestrel implants (unavailable in us)) implants. Hepatic Insufficiency No formal studies have evaluated the effect of hepatic disease on the disposition of levonorgestrel. However, since levonorgestrel is metabolized in the liver, use in patients with markedly impaired liver function or liver disease is not recommended. Renal Insufficiency No formal studies have evaluated the effect of renal disease on the disposition of levonorgestrel. Drug-Drug Interactions See "DRUG INTERACTIONS" under PRECAUTIONS.

NORPLANT® SYSTEM (levonorgestrel) Implants This product's label may have been revised after this insert was printed. For further product information and current package insert, please visit www.wyeth.com or call our medical communications department toll-free at 1-800-934-5556. Patients should be counseled that this product does not protect against transmission of HIV (AIDS) and other sexually transmitted diseases (STDs) such as chlamydia, genital herpes, genital warts, gonorrhea, hepatitis B, and syphilis. DESCRIPTION The NORPLANT SYSTEM kit contains levonorgestrel implants, a set of six flexible closed capsules made of silicone rubber tubing (Silastic® , dimethylsiloxane/methylvinylsiloxane copolymer), each containing 36 mg of the progestin levonorgestrel contained in an insertion kit to facilitate implantation. The capsules are sealed with Silastic (polydimethylsiloxane) adhesive and sterilized. Each capsule is 2.4 mm in diameter and 34 mm in length. The capsules are inserted in a superficial plane beneath the skin of the upper arm. Information contained herewith regarding safety and efficacy was derived from studies which used two slightly different Silastic tubing formulations. The formulation being used in the NORPLANT SYSTEM has slightly higher release rates of levonorgestrel and at least comparable efficacy. Evidence indicates that the dose of levonorgestrel provided by the NORPLANT (levonorgestrel implants unavailable in us) SYSTEM is initially about 85 mcg/day followed by a decline to about 50 mcg/day by 9 months and to about 35 mcg/day by 18 months with a further decline thereafter to about 30 mcg/day. The NORPLANT (levonorgestrel implants unavailable in us) SYSTEM is a progestin-only product and does not contain estrogen. Levonorgestrel, (18,19-Dinorpregn-4-en-20-yn-3-one, 13-ethyl-17-hydroxy-, (17α)-(–)-), the active ingredient in the NORPLANT (levonorgestrel implants unavailable in us) SYSTEM, has a molecular weight of 312.45 and the following structural formula: Levonorgestrel C21H28O2

JADELLE® (levonorgestrel) Implants Patients should be counseled that this product does not protect against HIV infection (AIDS) or other sexually transmitted diseases. DESCRIPTION Jadelle® (levonorgestrel implants unavailable in us) is a set of two flexible cylindrical implants, consisting of a dimethylsiloxane/ methylvinylsiloxane copolymer core enclosed in thin-walled silicone tubing. Each implant contains 75 mg of the progestin levonorgestrel. The implants are sealed with polydimethylsiloxane adhesive and sterilized. Each implant is approximately 2.5 mm in diameter and 43 mm in length. The implants are inserted in a superficial plane beneath the skin of the upper arm. The calculated mean daily in vivo release rate of levonorgestrel provided by the implants is about 100 µg/day at month 1 followed by a decline to about 40 µg/day at 12 months and to about 30 µg/day at 24 months with a stabilization thereafter at about 30 µg/day. Jadelle® (levonorgestrel implants unavailable in us) implants are a progestin-only product and do not contain estrogen. The active ingredient in the implants is levonorgestrel, (-)-13-ethyl-17-hydroxy-18,19-dinor-17α-pregn-4-en-20-yn-3-one. It has a molecular weight of 312.45 and the following structural formula:

INDICATIONS The NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM is indicated for the prevention of pregnancy and is a long-term (up to 5 years) reversible contraceptive system. The capsules should be removed by the end of the 5th year. New capsules may be inserted at that time if continuing contraceptive protection is desired. In multicenter trials with the NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM, involving 2470 women, the relationship between body weight and efficacy was investigated. Tabulated below is the pregnancy experience as a function of body weight. Because NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM is a long-term method of contraception, this is reported over five years of use. TABLE 1: Annual and Five-Year Cumulative Pregnancy Rates Per 100 Users by Weight Class Weight class year 1 year 2 year 3 year 4 year 5 Cumulative < 50kg ( < 110 lbs) 0.2 0 0 0 0 0.2 50-59 kg (110-130 lbs) 0.2 0.5 0.4 2.0 0.4 3.4 60-69 kg (131-153 lbs) 0.4 0.5 1.6 1.7 0.8 5.0 ≥ 70 kg ( ≥ 154 lbs) 0 1.1 5.1 2.5 0 8.5 All 0.2 0.5 1.2 1.6 0.4 3.9 Typically, pregnancy rates with contraceptive methods are reported for only the first year of use as shown below. The efficacy of these contraceptive methods, except the IUD and sterilization, depends in part on the reliability of use. The efficacy of the NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM does not depend on patient compliance. However, no contraceptive method is 100% effective. TABLE 2: Percentage Of Women Experiencing An Unintended Pregnancy During The First Year Of Typical Use And The First Year Of Perfect Use Of Contraception And The Percentage Continuing Use At The End Of The First Year. United States. % of Women Experiencing an Unintended Pregnancy within the First Year of Use % of Women Continuing Use at One Year 3 Method (1) Typical Use1 (2) Perfect Use2 (3) (4) Chance 4 85 85 Spermicides 5 26 6 40 Periodic abstinence 25 63 Calendar 9 Ovulation Method 3 Sympto-Thermal 6 2 Post-Ovulation 1 Cap 7 Parous Women 40 26 42 NulliparousWomen 20 9 56 Sponge Parous Women 40 20 42 NulliparousWomen 20 9 56 Diaphragm7 20 6 56 Withdrawal 19 4 Condom 8 Female (Reality) 21 5 56 Male 14 3 61 Pill 5 71 Progestin only 0.5 Combined 0.1 IUD Progesterone T 2.0 1.5 81 Copper T380A 0.8 0.6 78 LNg 20 0.1 0.1 81 Depo-Provera® 0.3 0.3 70 Levonorgestrel Implants (Norplant® ) 0.05 0.05 88 Female Sterilization 0.5 0.5 100 Male Sterilization 0.15 0.10 100 Lactation Amenorrhea Method: LAM is a highly effective, temporary method of contraception.9 Source: Trussell J. Contraceptive efficacy. In: Hatcher RA, Trussell J, Stewart F, Cates W, Stewart GK, Kowel D, Guest F. Contraceptive Technology: Seventeenth Revised Edition. New York NY: Irvington Publishers; 1998. 1.Among typical couples who initiate use of a method (not necessarily for the first time), the percentage who experience an accidental pregnancy during the first year if they do not stop use for any other reason. 2.Among couples who initiate use of a method (not necessarily for the first time) and who use it perfectly (both consistently and correctly), the percentage who experience an accidental pregnancy during the first year if they do not stop use for any other reason. 3.Among couples attempting to avoid pregnancy, the percentage who continue to use a method for one year. 4.The percents becoming pregnant in columns (2) and (3) are based on data from populations where contraception is not used and from women who cease using contraception in order to become pregnant. Among such populations, about 89% become pregnant within one year. This estimate was lowered slightly (to 85%) to represent the percent who would become pregnant within one year among women now relying on reversible methods of contraception if they abandoned contraception altogether. 5.Foams, creams, gels, vaginal suppositories, and vaginal film. 6.Cervical mucus (ovulation) method supplemented by calendar in the pre-ovulatory and basal body temperature in the post-ovulatory phases. 7.With spermicidal cream or jelly. 8.Without spermicides. 9.However, to maintain effective protection against pregnancy, another method of contraception must be used as soon as menstruation resumes, the frequency or duration of breastfeeds is reduced, bottle feeds are introduced, or the baby reaches 6 months of age. NORPLANT SYSTEM (levonorgestrel implants) gross annual discontinuation and continuation rates are summarized in Table 3. TABLE 3: Annual and Five-Year Cumulative Rates per 100 Users year 1 year 2 year 3 year 4 year 5 Cumulative Pregnancy 0.2 0.5 1.2 1.6 0.4 3.9 Bleeding Irregularities 9.1 7.9 4.9 3.3 2.9 25.1 Medical (excl. bleeding irreg.) 6.0 5.6 4.1 4.0 5.1 22.4 Personal 4.6 7.7 11.7 10.7 11.7 38.7 Continuation 81.0 77.4 79.2 76.7 77.6 29.5 DOSAGE AND ADMINISTRATION The NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM consists of six Silastic® capsules, each containing 36 mg of the progestin, levonorgestrel. The total administered (implanted) dose is 216 mg. Implantation of all six capsules should be performed during the first 7 days of the onset of menses by a health-care professional instructed in the NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM insertion technique. Insertion is subdermal in the midportion of the upper arm about 8 to 10 cm above the elbow crease. Distribution should be in a fanlike pattern, about 15 degrees apart, for a total of 75 degrees. Proper insertion will facilitate later removal. (See section on Insertion/Removal.) HOW SUPPLIED The NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM Kit includes the following items: 1 NORPLANT SYSTEM (levonorgestrel implants), a set of six implants (capsules) 1 NORPLANT SYSTEM trocar 1 Package of skin closures 1 Scalpel 3 Packages of gauze sponges 1 Forceps 1 Stretch bandage 1 Syringe 1 Surgical drape (fenestrated) 2 Syringe needles 2 Surgical drapes Store at room temperature away from excess heat and moisture. NDC 0008-2564-01 References available upon request. Instructions For Insertion And Removal The NORPLANT SYSTEM consists of six levonorgestrel-releasing capsules that are inserted subdermally in the medial aspect of the upper arm. The NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM provides up to 5 years of effective contraceptive protection. The basis for successful use and subsequent removal of NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM capsules is a correct and carefully performed subdermal insertion of the six capsules. It is recommended that health-care professionals performing insertions or removals of NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM capsules avail themselves of instruction and supervision in the proper technique prior to attempting these procedures. During insertion, special attention should be given to the following: asepsis. correct subdermal placement of the capsules. careful technique to minimize tissue trauma. This will help to avoid infections and excessive scarring at the insertion area and will help keep the capsules from being inserted deeply in the tissue. If the capsules are placed deeply, they will be more difficult to remove than correctly placed subdermal capsules. Insertion Procedure Insertion should be performed within seven days from the onset of menses. However, NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM capsules may be inserted at any time during the cycle provided pregnancy has been excluded and the possibility that ovulation and conception have already occurred has been considered. It is recommended that a complete history and physical examination, including a gynecologic examination, be performed before the insertion of NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM capsules. Determine if the subject has any allergies to the antiseptic or anesthetic to be used or contraindications to progestin-only contraception. If none are found, the capsules are inserted using the procedure outlined below. One NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM set consists of six capsules in a sterile pouch. The insertion is performed under aseptic conditions using a trocar to place the capsules under the skin. Figure 1: The following equipment is recommended for the insertion: an examining table for the patient to lie on. sterile surgical drapes, sterile gloves (free of talc), antiseptic solution. local anesthetic, needles, and syringe. #11 scalpel, #10 trocar, forceps. skin closure, sterile gauze, and compresses. The plastic cover and tray are NOT STERILE. Figure 2: Have the patient lie on her back on the examination table with her left arm (if the patient is left-handed, the right arm) flexed at the elbow and externally rotated so that her hand is lying by her head. The capsules will be inserted subdermally through a small 2-mm incision and positioned in a fanlike manner with the fan opening towards the shoulder. Figure 3: Prep the patient's upper arm with antiseptic solution; cover the arm above and below the insertion area with a sterile cloth. The optimal insertion area is in the inside of the upper arm about 8 to 10 cm above the elbow crease. Figure 4: Open the sterile NORPLANT SYSTEM (levonorgestrel implants) package carefully by pulling apart the sheets of the pouch, allowing the capsules to fall onto a sterile drape. Count the six capsules. Figure 5: After determining the absence of known allergies to the anesthetic agent or related drugs, fill a 5-mL syringe with the local anesthetic. Since blood loss is minimal with this procedure, use of epinephrine-containing anesthetics is not considered necessary. Anesthetize the insertion area by first inserting the needle under the skin and injecting a small amount of anesthetic. Then anesthetize six areas about 4 to 4.5 cm long, to mimic the fanlike position of the implanted capsules. Figure 6: Use the scalpel to make a small incision (about 2 mm) just through the dermis of the skin. Alternatively, the trocar may be inserted directly through the skin without making an incision with the scalpel. The bevel of the trocar should always face up during the insertion. Figure 7: The trocar has two marks on it. The first mark is closer to the hub and indicates how far the trocar should be introduced under the skin before the loading of each capsule. The second mark is close to the tip and indicates how much of the trocar should remain under the skin following the insertion of each implant. Figure 8: Insert the tip of the trocar through the incision beneath the skin at a shallow angle. Once the trocar is inserted, it should be oriented with the bevel up toward the skin to keep the capsules in a superficial plane. It is important to keep the trocar subdermal by tenting the skin with the trocar, as failure to do so may result in deep placement of the capsules and could make removal more difficult. Advance the trocar gently under the skin to the first mark near the hub of the trocar. The tip of the trocar is now at a distance of about 4 to 4.5 cm from the incision. Do not force the trocar, and if resistance is felt, try another direction. Figure 9: When the trocar has been inserted the appropriate distance, remove the obturator and load the first capsule into the trocar using the thumb and forefinger. Figure 10: Gently advance the capsule with the obturator towards the tip of the trocar until you feel resistance. Never force the obturator. Figure 11: Hold the obturator steady, and bring the trocar back until it touches the handle of the obturator. Figure 12: The capsule should have been released under the skin when the mark close to the tip of the trocar is visible in the incision. Release of the capsule can be checked by palpation. It is important to keep the obturator steady and not to push the capsule into the tissue. Figure 13: Do not remove the trocar from the incision until all capsules have been inserted. The trocar is withdrawn only to the mark close to its tip. Each succeeding capsule is always inserted next to the previous one, to form a fanlike shape. Fix the position of the previous capsule with the forefinger and middle finger of the free hand, and advance the trocar along the tips of the fingers. This will ensure a suitable distance of about 15 degrees between capsules and keep the trocar from puncturing any of the previously inserted capsules. Leave a distance of about 5 mm between the incision and the tips of the capsules. This will help avoid spontaneous expulsions. The correct position of the capsules can be ensured by feeling them with the fingers after the insertion has been completed. Figure 14: After placement of the sixth capsule, a sterile gauze may be used to apply pressure briefly to the insertion site to ensure hemostasis. Palpate the distal ends of the capsules to make sure that all six have been properly placed. Figure 15: Press the edges of the incision together, and close the incision with a skin closure. Suturing the incision should not be necessary. Figure 16: Cover the insertion area with a dry compress, and wrap gauze around the arm to ensure hemostasis. Observe the patient for a few minutes for signs of syncope or bleeding from the incision before she is discharged. Advise the patient to keep the insertion area dry and avoid heavy lifting for 2 to 3 days. The gauze may be removed after 1 day, and the butterfly bandage as soon as the incision has healed, i.e., normally in 3 days. Removal Procedure Described below is a removal procedure which was developed and used during the clinical trials for the NORPLANT SYSTEM (levonorgestrel implants). As with many surgical procedures, variations of the technique have appeared and some have been published. No one particular procedure routinely appears to have any advantage over another. It is recommended that removals be prescheduled so that preparations for carrying out the procedure can be facilitated. Removal of the capsules should be performed very gently and will usually take more time and may be more difficult and/or more painful than insertion. Capsules are sometimes nicked, cut, or broken during removal, or may be difficult to locate. The incidence of overall removal difficulties, including those that did not result in patient complaints (e.g., damage to the capsules), was 13.2%. Less than half of these removal difficulties have caused inconvenience to the patient. If the removal of some of the capsules proves difficult, have the patient return for another visit. The remaining capsule(s) will be easier to remove after the area is healed. It may be appropriate to seek consultation or provide referral for patients in whom initial attempts at capsule removal prove difficult. If contraception is still desired, a barrier method should be advised until all capsules are removed. The position of the patient and the asepsis are the same as for insertion. Figure 17: The following equipment is needed for the removal: an examining table for the patient to lie on. sterile surgical drapes, sterile gloves (free of talc), antiseptic solution. local anesthetic, needles, and syringe. #11 scalpel, forceps (straight and curved mosquito). skin closure, sterile gauze, and compresses. Figure 18: Palpate the capsules to make sure that all six capsules have been located, marking their position with a sterile marker. If all six capsules cannot be located by palpation, they may be localized by ultrasound (7 MHz), X-ray, or compression mammography. Figure 19: Once all six capsules are located, apply a small amount of local anesthetic under the capsule ends nearest the original incision site. This will serve to raise the ends of the capsules. Anesthetic injected over the capsules will obscure them and make removal more difficult. Additional small amounts of the anesthetic can be used for the removal of each of the capsules, if required. Figure 20: Make a 4-mm incision with the scalpel close to the ends of the capsules. Do not make a large incision. Figure 21: Push each capsule gently towards the incision with the fingers. When the tip is visible or near to the incision, grasp it with a mosquito forceps. Figure 22: Use the scalpel, forceps, or gauze to very gently open the tissue sheath that has formed around the capsule. Figures 23 and 24: Remove the capsule from the incision with the second forceps. Figures 25 and 26: After the procedure is completed, the incision is closed and bandaged as with insertion. The upper arm should be kept dry for a few days. Following removal, fertility rates return to levels comparable to those seen in the general population of women using no method of contraception, and a pregnancy may occur at any time. If the patient wishes to continue using the method, a new set of NORPLANT SYSTEM (levonorgestrel implants) capsules can be inserted through the same incision in the same or opposite direction. Hints Insertion Counseling of the patient on the benefits and side effects of the method prior to insertion will greatly increase patient satisfaction. Correct subdermal placement of the capsules will facilitate removal. Before insertion, apply the anesthetic just beneath the skin so as to raise the dermis above the underlying tissue. Never force the trocar. To ensure subdermal placement, the trocar with bevel up should be supported by the index finger and should visibly raise the skin at all times during insertion. To avoid damaging the previous implanted capsule, stabilize the capsule with your forefinger and middle finger and advance the trocar alongside the finger tips at an angle of 15 degrees. After insertion, make a drawing for the patient's file showing the location of the six capsules and describe any variations in placement. This will greatly aid removal. Removal Alternate removal techniques have been developed. The removal of the implants will usually take more time and may be more difficult and/or more painful than the insertion. Capsules are sometimes nicked, cut, or broken during removal, or may be difficult to locate. Before initiating removal, all capsules should be located by palpation. If all six capsules cannot be located by palpation, they may be localized by ultrasound (7 MHz), X-ray, or compression mammography. Before removal, apply the anesthetic under the capsule ends nearest the original incision site. If the removal of some of the capsules proves difficult, interrupt the procedure and have the patient return for another visit. The remaining capsule(s) will be easier to remove after the area is healed. It may be appropriate to seek consultation or provide referral for patients in whom initial attempts at capsule removal prove difficult. Distributed by : Wyeth Pharmaceuticals Inc. Philadelphia, PA 19101. Rev 03/05. FDA revision date: 5/21/2001

INDICATIONS Jadelle® (levonorgestrel implants (unavailable in us)) implants are indicated for the prevention of pregnancy and are a long-term (up to 5 years) reversible method of contraception. Both implants must be removed by the end of the fifth year. New implants may be inserted at that time if continuing contraceptive protection is desired. Following removal, fertility rates return to levels comparable to those in a population of similar women using no method of contraception. Eight (8) pregnancies occurred within 5 years of Jadelle® (levonorgestrel implants (unavailable in us)) placement in multicenter clinical trials involving 1393 women. One of the eight pregnancies was ectopic. The following table shows pregnancy rate as Pearl Indices for each year. Pearl Indices (Pregnancies per 100 woman-years) by Year for Jadelle (levonorgestrel implants (unavailable in us)) Year 1 Year 2 Year 3 Year 4 Year 5 Annual Pearl Index 0.08 0.09 0.11 0.00 0.84 95% CI (0.00,0.43) (0.00, 0.50) (0.00, 0.61) (0.00, 0.50) (0.27, 1.95) Cumulative Pearl Index 0.08 0.08 0.09 0.07 0.17 95% CI (0.00, 0.43) (0.01, 0.30) (0.02, 0.26) (0.01, 0.22) (0.07, 0.34) Jadelle (levonorgestrel implants (unavailable in us)) is likely to be less effective in obese women. Mean serum levonorgestrel levels decrease as weight increases, and the risk of pregnancy increases as serum levonorgestrel levels decrease (see Pharmacokinetics section). Typically, pregnancy rates with contraceptive methods are reported only for the first year of use, as shown in Table 2. The efficacy of these contraceptive methods, except for NORPLANT®, the intrauterine device (IUD), and sterilization, depends in part on the reliability of use. The efficacy of Jadelle® (levonorgestrel implants (unavailable in us)) implants does not depend on patient compliance. However, no contraceptive method is 100% effective. TABLE 2: Percentage of Women Experiencing an Unintended Pregnancy During the First Year of Use of a Contraceptive Method Method Typical Use Perfect Use Chance 85 85 Spermicides 26 6 Periodic Abstinence 25 Calendar 9 Ovulation 3 Symptothermal 2 Post-ovulation 1 Cap Parous women 40 26 Nulliparous women 20 9 Sponge Parous women 40 20 Nulliparous women 20 9 Diaphragm 20 6 Withdrawal 19 4 Condom Female (Reality) 21 5 Male 14 3 Pill 5 Progestin only 0.5 Combined 0.1 IUD Progesterone 2.0 1.5 Copper T 380A 0.8 0.6 LNg 20 0.1 0.1 Depo-Provera 0.3 0.3 NORPLANT® and NORPLANT® 2 0.05 0.05 Female sterilization 0.5 0.5 Male sterilization 0.15 0.1 From Hatcher RA et al., Contraceptive Technology, 17th Revised Edition. New York, NY: Irvington Publishers, 1998. Table 9-2 The gross cumulative rates of discontinuation and continuation in clinical trials of Jadelle® (levonorgestrel implants (unavailable in us)) are summarized in Table 3. TABLE 3: Discontinuation and Continuation Rates (Cumulative Rates per 100 Users, n=1393) Year Reasons for discontinuing 1 3 5 Pregnancy 0.1±0.1 0.3±0.2 1.1±0.4 Menstrual 4.5±0.6 14.1±1.0 19.3±1.2 Medical 4.7±0.6 14.7±1.0 23.1±1.3 Used other method 0.2±0.1 0.9±0.3 3.7±0.7 Plan pregnancy 1.1±0.3 9.7±0.9 18.6±0.3 Personal (other) 1.6±0.3 7.2±0.8 12.5±0.1 Continuation 88.3±0.9 60.6±1.3 41.5±1.3 DOSAGE AND ADMINISTRATION Jadelle® (levonorgestrel implants (unavailable in us)) implants are a set of two flexible cylindrical implants, each containing 75 mg of the progestin levonorgestrel. The total administered (implanted) dose is 150 mg. Insertion of the two implants should be performed during the first 7 days following the onset of menses by a health-care professional familiar with the levonorgestrel implant insertion technique. It is strongly recommended that all health-care providers receive instruction in the proper insertion and removal procedures. Insertion is subdermal in the midportion of the inner surface of the upper arm about 8 to 10 cm above the medial epicondyle. The two implants should be placed in a "V" shape about 30 degrees apart. Proper insertion will facilitate removal. (See "Instructions for Insertion and Removal.") HOW SUPPLIED Jadelle® implants are supplied in a sterile package containing a set of two levonorgestrel-containing implants. Store at room temperature, 15-30° C (59-86°F) References available upon request. Instructions For Insertion And Removal Jadelle® implants are a set of two cylindrical levonorgestrel-releasing implants that are inserted subdermally in the medial aspect of the upper arm. Jadelle® (levonorgestrel implants (unavailable in us)) implants provide up to 5 years of effective contraceptive protection. The basis for successful use and subsequent removal of Jadelle® (levonorgestrel implants (unavailable in us)) implants is a correct and carefully performed subdermal insertion of the two implants. It is recommended that health-care professionals performing insertions or removals of Jadelle® (levonorgestrel implants (unavailable in us)) implants be instructed and supervised in proper techniques prior to attempting these procedures independently. During insertion, special attention should be given to the following: -aseptic technique -correct subdermal placement of the implants -careful technique to minimize tissue trauma. This will help to avoid infections and excessive scarring at the insertion area and will help keep the implants from being inserted too deeply in the tissue. If the implants are placed too deeply, they will be more difficult to remove than correctly placed subdermal implants. Insertion Procedure Insertion should be performed within 7 days from the onset of menses. However, Jadelle® (levonorgestrel implants (unavailable in us)) implants may be inserted at any time during the cycle provided that the possibility of ovulation and conception has been considered, pregnancy has been excluded, and a nonhormonal contraceptive method is used for at least 7 days. If ovulation and conception have already occurred, pregnancy may be established in the month of insertion. It is recommended that a complete history and physical examination, including a gynecologic examination, be performed before the insertion of Jadelle® (levonorgestrel implants (unavailable in us)) implants. Determine if the subject has any allergies to the antiseptic or anesthetic to be used or any contraindications to the use of levonorgestrel or any of the components of the implants. If none are found, the implants are inserted using the procedure outlined below. One Jadelle® unit consists of two levonorgestrel implants in a sterile pouch. The insertion is performed under aseptic conditions using a trocar to place the implants under the skin. Figure 1: The following equipment is recommended for the insertion: — an examining table for the patient to lie on. — sterile surgical drapes, sterile gloves (free of talc), antiseptic solution. — local anesthetic, needles, and syringe. — #11 scalpel, #10 trocar, forceps. — skin closure, sterile gauze, and compresses. Figure 2: Have the patient lie on her back on the examination table with her nondominant arm flexed at the elbow and externally rotated so that her hand is lying by her head. The implants will be inserted subdermally and positioned in a "V" shape. The optimal insertion area is in the inner surface of the upper arm about 8 to 10 cm above the medial epicondyle. Figure 3: Clean the patient's upper arm with antiseptic solution and then frame the insertion area with a fenestrated drape. Figure 4: Open the Jadelle® (levonorgestrel implants (unavailable in us)) package carefully by pulling apart the sheets of the pouch, allowing the two implants to fall onto a sterile drape. Figure 5: After determining the absence of known allergies to the anesthetic agent or related drugs, fill a 5-mL syringe with the local anesthetic. Since blood loss is minimal with this procedure, use of epinephrine-containing anesthetics is not considered necessary. Anesthetize the insertion area by first inserting the needle under the skin and injecting a small amount of anesthetic. Then anesthetize two areas about 4.5 cm long, to mimic the V shape of the implantation site. Figure 6: Use the scalpel to make a small incision (about 2 mm) just through the dermis of the skin. Alternatively, the trocar may be inserted directly through the skin without making an incision with the scalpel. The bevel of the trocar should always face up during the insertion. Figure 7: The trocar has three marks on it. The mark closest to the hub indicates how far the trocar should be introduced under the skin to place the Jadelle® (levonorgestrel implants (unavailable in us)) implants. The middle mark (indicated by the small arrow) is not used with Jadelle® (levonorgestrel implants (unavailable in us)) insertions and should be ignored. The mark closest to the tip indicates how much of the trocar should remain under the skin following placement of the first implant. Figure 8: Insert the tip of the trocar beneath the skin at a shallow angle. Throughout the insertion procedure, the trocar should be oriented with the bevel up. It is important to keep the trocar subdermal by tenting the skin with the trocar, as failure to do so may result in deep placement of the implants and could make removal more difficult. Advance the trocar gently under the skin to the mark nearest the hub of the trocar; be careful to use the appropriate mark. Do not force the trocar, and if resistance is encountered, try another direction. Figure 9: When the trocar has been inserted the appropriate distance, remove the obturator and load the first implant into the trocar using the thumb and forefinger. Figure 10: Gently advance the implant with the obturator towards the tip of the trocar until you feel resistance. Never force the obturator. Figure 11: Then holding the obturator stationary, withdraw the trocar to the mark closest to the trocar tip. It is important to keep the obturator stationary and not to push the implant into the tissue. Do not completely remove the trocar until both implants have been placed. The trocar is withdrawn only to the mark closest to its tip. Figure 12: The implant should have been released under the skin when the mark closest to the tip of the trocar is visible at the insertion point. Release of the implant can be checked by palpation. Figure 13a: To place the second implant, align the trocar so that the second implant will be positioned at about a 30-degree angle relative to the first. Fix the position of the previous implant with the forefinger and middle finger of the free hand, and advance the trocar along the tips of the fingers. This will ensure a suitable distance of about 30 degrees between implants and keep the trocar from puncturing the previously inserted implant. Figure 13b: Leave a distance of about 5 mm between the incision and the tips of the implants. This will help avoid spontaneous expulsions. Figure 14: After placement of the second implant, a sterile gauze may be used to apply pressure briefly to the insertion site and ensure hemostasis. Palpate the distal ends of the implants to make sure that both have been properly placed. Figure 15: Press the edges of the incision together, and close the incision with a skin closure. Suturing the incision should not be necessary. Figure 16: Cover the placement area with a dry compress, and wrap gauze snugly around the arm to ensure hemostasis. Observe the patient for a few minutes for signs of syncope or bleeding from the insertion site before she is discharged. Advise the patient to keep the insertion area dry and avoid heavy lifting for 2 to 3 days. The gauze may be removed after 1 day, and the skin closure as soon as the insertion area has healed, ie, typically in 3 days. Removal Procedure Described below is a removal procedure which was used during the clinical trials for NORPLANT® implants and for Jadelle® (levonorgestrel implants (unavailable in us)) implants. As with many surgical procedures, variations of the technique have appeared and some have been published. No one particular procedure routinely appears to have advantage over another. It is recommended that removals be scheduled so that preparations for carrying out the procedure can be facilitated. Removal of the implants should be performed very gently and will take more time than insertion. Implants are sometimes nicked, cut, or broken during removal. The overall incidence of removal difficulties in the clinical trials, including damage to the implants, was 7.5%. If removal of the implant(s) proves difficult, close the incision and bandage the wound, and have the patient return for another visit. The remaining implant(s) will be easier to remove after the area is healed. It may be appropriate to seek consultation or provide referral for patients in whom initial attempts at implant removal prove difficult. A nonhormonal method of contraception should be used until both implants are completely removed. The position of the patient and the need for aseptic technique are the same as for insertion. Figure 17: The following equipment is needed for the removal: — an examining table for the patient to lie on. — sterile surgical drapes, sterile gloves (free of talc), antiseptic solution. — local anesthetic, needles, and syringe. — #11 scalpel, forceps (straight and curved mosquito). — skin closure, sterile gauze, and compresses. Figure 18: Palpate the area to locate both implants. If the implants cannot be palpated, they may be located by ultrasound (7 MHz) or X-ray (soft tissue). Once both implants are located, clean the patient's upper arm with antiseptic solution and then frame the area with a fenestrated drape. You may mark the position of the Jadelle® (levonorgestrel implants (unavailable in us)) implants with a sterile marker. Figure 19: Once both implants are located, apply a small amount of local anesthetic at the skin and under the ends of the implants nearest the original incision site. This will serve to raise the ends of the implants. Anesthetic injected over the implants will obscure them and make removal more difficult. Additional small amounts of the anesthetic can be used for removal of the second implant, if required. Figure 20: Make a 4-mm incision with the scalpel close to the proximal ends of the implants (below the bottom of the "V"). Do not make a large incision. Figure 21: Push each implant gently towards the incision with the fingers. When the tip is visible or near to the incision, grasp it with a mosquito forceps. Figure 22: Use the scalpel, the other forceps, or gauze to very gently open the tissue sheath that has formed around the implant. Figures 23 and 24: Grasp the proximal end of the implant with the second forceps and gently remove it. Repeat the procedure for the second implant. Figures 25 and 26: After the procedure is completed, the incision is closed and bandaged as with insertion. The upper arm should be kept dry for a few days. Following removal, the contraceptive effects reverse quickly and a woman can become pregnant at a rate similar to women who have not used the method. If the patient wishes to continue using the method, a new set of Jadelle® (levonorgestrel implants (unavailable in us)) implants can be inserted through the same incision in the same or opposite direction. Hints Insertion - Counselling of the patient on the benefits and side effects of the method and the insertion and removal procedures before insertion will greatly increase patient satisfaction. - Correct subdermal placement of the implants will facilitate removal. - Before insertion, apply the anesthetic just beneath the skin so as to raise the dermis above the underlying tissue. - Never force the trocar. - To ensure subdermal placement, the trocar should be held with the bevel up and should be supported by the index finger to raise the skin visibly at all times during insertion. - To avoid damaging the first implant, stabilize it with your forefinger and middle finger and then advance the trocar alongside the fingertips at an angle of about 30 degrees. -After insertion, make a drawing for the patient's file showing the location of the 2 implants and describe any variations in placement. This will greatly aid removal. - Jadelle® (levonorgestrel implants (unavailable in us)) packaging contains stick-on labels identifying the lot number for both the provider's and the patient's records. Both the provider and the patient should retain these stick-on labels in case a need arises to determine which lot is being used by the woman. The stick-on label for the patient may be affixed to her copy of the patient information materials. Please also be sure to inform the patient on the patient package insert that she is to retain the stick-on label identifying the lot number in case of future problems with the lot. Removal - The removal of the implants will take more time than the insertion. - Before initiating removal, the two implants should be located by palpation. If both implants cannot be palpated, they may be located by ultrasound (7 MHz) or X-ray (soft tissue). - Before removal, apply the anesthetic under the ends of the implants nearest the original insertion site. - If removal of the implants proves difficult, interrupt the procedure, close the incision and bandage the wound, and have the patient return for another visit. The remaining implant(s) will be easier to remove after the area is healed. It may be appropriate to seek consultation or provide referral for patients in whom initial attempts at implant removal prove difficult. References provided on request. Manufacturer information: n/a. FDA rev date: n/a

PATIENT INFORMATION NORPLANT® SYSTEM (levonorgestrel implants) This product is intended to prevent pregnancy. It does not protect against transmission of HIV (AIDS) and other sexually transmitted diseases (STDs) such as chlamydia, genital herpes, genital warts, gonorrhea, hepatitis B, and syphilis. WHAT YOU SHOULD KNOW ABOUT NORPLANT (levonorgestrel implants (unavailable in us)) BEFORE YOU DECIDE TO USE IT You need to read and understand this leaflet before you decide to use the NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM. The leaflet contains information vital to your health. It tells you about the benefits and risks of NORPLANT (levonorgestrel implants (unavailable in us)) . Discuss it with your health-care professional. Ask them to explain anything you do not understand. There is a more technical leaflet about NORPLANT (levonorgestrel implants (unavailable in us)) that was written for health-care professionals. If you would like to read that leaflet too, ask your health-care professional for a copy. You may need their help to understand some of the information. There is also a videotape that provides more information about the NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM. If you would like to watch it, ask your health-care professional. Before you decide to use NORPLANT (levonorgestrel implants (unavailable in us)) or any other birth control method, compare it to other birth control methods. If you want to learn more about other methods, ask your health-care professional. One of these other methods may be better for you than NORPLANT (levonorgestrel implants (unavailable in us)) . NORPLANT (levonorgestrel implants (unavailable in us)) is different from other methods of birth control. The capsules are made of Silastic® , a silicone rubber tubing. It must be inserted in your arm during a minor surgical procedure. The procedure can be performed by a health-care professional in the office. It is important that health-care professionals who insert NORPLANT (levonorgestrel implants (unavailable in us)) be instructed in both insertion and removal procedures. You should know that some health-care professionals have more experience than others in inserting and removing NORPLANT (levonorgestrel implants (unavailable in us)) . Be sure to discuss with your health-care professional whether he/she has received instruction in how to insert NORPLANT (levonorgestrel implants (unavailable in us)) and remove it and his/her level of confidence in insertion and removal procedures. You can decide to have NORPLANT (levonorgestrel implants (unavailable in us)) removed at any time. Removals can also be performed by a health-care professional in the office. You should know that removing NORPLANT (levonorgestrel implants (unavailable in us)) may be more difficult than inserting it. It may take longer and involve more pain. It may leave scars. This risk does not exist with most other birth control methods. Some women should not use NORPLANT (levonorgestrel implants (unavailable in us)) . To find out whether you are one of those women, talk to your health-care professional and read below the sections entitled “WHO SHOULD NOT USE THE NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM” and “OTHER CONSIDERATIONS BEFORE CHOOSING THE NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM.” Some women who use NORPLANT (levonorgestrel implants (unavailable in us)) will experience side effects. You should know the danger signs. To learn about them, talk to your health-care professional and read below the sections entitled “RISKS OF USING THE NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM,” “WARNING SIGNALS,” “PRECAUTIONS,” and “SIDE EFFECTS OF THE NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM.” INTRODUCTION Each woman who considers using the NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM should understand the benefits and risks of this form of family planning as compared with other contraceptive methods. This leaflet will give you much of the information you will need to make this decision, but it is not a replacement for a careful discussion with your health-care professional. You should discuss the information provided in this leaflet with him or her, both when choosing whether to use the NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM and during revisits. You should also follow your health-care professional's advice with regard to regular checkups while using the NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM. The NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM consists of six thin, flexible capsules, made of silicone rubber tubing (Silastic® ), that are inserted just under the skin on the inside of your upper arm in a minor, outpatient surgical procedure. The capsules contain a synthetic hormone, levonorgestrel (a progestin), that is also used as one of the active ingredients in many oral contraceptives. Immediately after insertion of the NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM, a low continuous dose of the hormone is released into your body. Pregnancy is prevented through a combination of mechanisms. The most important ways are by inhibiting ovulation, so eggs will not be produced regularly, and thickening the cervical mucus, making it more difficult for the sperm to reach the egg. There may also be other mechanisms that contribute to these contraceptive effects. When the NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM capsules are removed, the drug is cleared from the body within 5 to 14 days and a woman can become pregnant at a rate similar to women who have not used the method. EFFECTIVENESS OF NORPLANT SYSTEM (levonorgestrel implants) The NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM is one of the most effective reversible contraceptive methods. No contraceptive is 100-percent effective. The average annual pregnancy rate over a 5-year period for the NORPLANT SYSTEM (levonorgestrel implants) is less than 1%. It is less than one pregnancy for every 100 women during the first year of use. In comparison, pregnancy rates that have been experienced with other methods of family planning during the first year of use are as follows: Average Failure Rates (%) During the First Year of Use of a Contraceptive Method Methods Average NORPLANT SYSTEM 0.05 Male sterilization 0.15 Female sterilization 0.5 Depo-Provera® (injectable progestogen) 0.3 Oral contraceptives 5 IUD Progesterone 2.0 Copper T 380A 0.8 Condom (male) without spermicide 14 (female) without spermicide 21 Cervical cap Never given birth 20 Given birth 40 Diaphragm with spermicidal cream or jelly 20 Spermicides alone (foam, creams, jellies, and vaginal suppositories) 26 Periodic abstinence (all methods) 25 Withdrawal 19 No contraception (planned pregnancy) 85 Except for the NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM, sterilization, and the IUD, the efficacy of these methods depends in part on how reliably they are used. The NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM may be less effective in preventing pregnancy in heavier women. Discuss this with your health-care professional. The NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM provides five years of protection against pregnancy but can be removed at any time. At the end of the fifth year, the capsules will be less effective and must be removed; a new set may be inserted at the time of removal for continued protection. WHO SHOULD NOT USE THE NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM Some women should not use the NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM. You should not have the capsules inserted if you are pregnant or think you may be pregnant. You should not use the NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM if you have: Acute liver disease; noncancerous or cancerous liver tumors; Unexplained vaginal bleeding (until a diagnosis is reached by your health-care professional); Known or suspected breast cancer; Blood clots in the legs (thrombophlebitis), lungs (pulmonary embolism), or eyes. Women who have had previous blood clots should consult with their health-care professional whether to use the NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM; History of idiopathic intracranial hypertension (pseudotumor cerebri, benign intracranial hypertension); Hypersensitivity to levonorgestrel or any of the other components of the NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM. OTHER CONSIDERATIONS BEFORE CHOOSING THE NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM Tell your health-care professional if you or any family member has ever had: Breast nodules, fibrocystic disease of the breast, an abnormal breast X-ray or mammogram; Diabetes; Elevated cholesterol or triglycerides; High blood pressure; Headaches; Gallbladder, heart, or kidney disease; History of scanty or irregular menstrual periods; History of blood clots, heart attack or stroke; Depression; Migraine; Ectopic pregnancy. Women with these conditions may need to be checked more often by their health-care professional if they choose the NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM. Be sure to inform your health-care professional if you smoke or are on any medications. RISKS OF USING THE NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM A. Risks Based on Experience with the NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM 1. Insertion and Removal Complications A surgical incision is required to insert NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM capsules. Complications related to insertion such as pain, swelling, and bruising may occur. There have also been reports of infection, blistering, ulcerations, sloughing, excessive scarring, phlebitis (inflammation of a vein), and discoloration of the skin at the insertion site. There have been reports of arm pain, numbness, and tingling following the insertion and removal procedures. There also have been reports of nerve injury, most commonly associated with deep placement and removal. Expulsion of capsules (i.e., when a capsule unintentionally comes out of the insertion site/skin) has been reported more frequently when they were placed too close to the skin or too close to the incision or when infection was present. After NORPLANT SYSTEM (levonorgestrel implants) capsules are inserted, they sometimes move from the original position, which may make them more difficult to remove. Infrequently, movement of a few to several inches has been reported. Some NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM users have reported movement accompanied by pain and discomfort. Contact your health-care professional in the event that capsule movement accompanied by pain and/or discomfort occurs. Removal is also a surgical procedure and may take longer, be more difficult, and/or cause more pain than insertion and may be associated with difficulty locating capsules. These complications may lead to the need for additional incisions and/or office visits. See also “PRECAUTIONS” and “SIDE EFFECTS OF THE NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM.” 2. Irregular Menstrual Bleeding (also see “SIDE EFFECTS OF THE NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM”) Most women experience some change in their usual monthly pattern. These menstrual irregularities vary from woman to woman and include: Prolonged bleeding (more days than you would usually experience), commonly during the first months of use; Untimely bleeding or spotting between periods; No bleeding at all for several months; or A combination of these patterns. It cannot be predicted what kind of change you may experience. If increased frequency of bleeding occurs, the quantity of blood lost is rarely enough to cause anemia, but there have been a few cases that required treatment. In rare instances, patients experienced heavy bleeding that resulted in anemia. The irregularities frequently diminish gradually with continuing use. 3. Delayed Disappearance of Ovarian Follicles/Ovarian Cysts If follicles (eggs and their surrounding cells) in the ovary develop while using the NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM, disintegration or disappearance of the follicles is sometimes delayed, and the follicles may continue to grow beyond the size they would normally reach. These enlarged follicles, which are sometimes called ovarian cysts, may produce discomfort in some women, although most users would not be aware of them unless they were found incidentally on a physical exam. In the majority of women, enlarged follicles will disappear on their own and should not require surgery. Rarely, they may twist or rupture so that surgery is required. You should discuss this with your health-care professional. 4. Ectopic Pregnancies Ectopic pregnancies (development of the fertilized egg outside of the uterus, sometimes called a tubal pregnancy) have occurred among NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM users. Symptoms of an ectopic pregnancy include spotting and cramping pain, which usually begin shortly after the first missed period. Contact your health-care professional should you miss a period or experience abdominal pain. 5. Diseases of the Heart and Blood Vessels As with oral contraceptives, there have been reports of blood clots and blockage of blood vessels in NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM users. Blood clots and blockage of blood vessels can be serious. In particular, a clot in the veins of the legs can cause inflammation and risk of further clots, and a clot that travels to the lungs can cause a sudden blockage of the vessel carrying blood to the lungs, resulting in respiratory collapse and even death. Rarely, clots occur in the blood vessels of the eye and may cause double vision, impaired vision, or even blindness. There have also been reports of heart attacks and strokes while the NORPLANT SYSTEM (levonorgestrel implants) has been in place. Any of these conditions can cause serious disability or death. Patients who develop blood clots in the legs, arms, lungs, or eyes should have the NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM removed. In addition, patients restricted to bed rest or who have limited movement for a prolonged period due to surgery or other illness may be at increased risk of developing blood clots. The NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM may need to be removed in such patients. 6. Idiopathic Intracranial Hypertension (pseudotumor cerebri, benign intracranial hypertension) An increase in intracranial pressure has been reported in NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM users. Symptoms may include headache (associated with a change in frequency, pattern, severity, or persistence; of particular importance are those headaches that do not stop) and visual disturbances. Contact your physician or health-care professional if you experience these symptoms, particularly if you are obese or have had recent weight gain. Your health-care professional may recommend that the NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM be removed. B. Risks Based on Experience with Combination Oral Contraceptives Combination pills contain a progestin such as levonorgestrel and an estrogen, another type of hormone. Some rare but serious side effects have been associated with use of the combination pill. It is unknown whether the risks associated with combined oral-contraceptive use may also be risks with a progestin-only contraceptive like the NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM. Risks Associated with Combination Oral Contraceptives Include: 1. Risk of Heart Attacks and Strokes The combination pill may increase the tendency to develop strokes (stoppage or rupture of blood vessels in the brain), angina pectoris, or heart attacks (blockage of blood vessels to the heart). Any of these conditions can cause death or serious disability. Smoking greatly increases the probability of suffering heart attacks and stroke. Use of combination oral contraceptives together with cigarette smoking greatly increases the risk of serious adverse effects on the heart and blood vessels. This risk increases with age and with the amount of smoking (15 or more cigarettes per day has been associated with a significantly increased risk) and is quite marked in women over 35 years of age who smoke. It is not known whether a similar interaction occurs with the NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM. Therefore, women who use the NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM should not smoke. 2. High Blood Pressure An increase in blood pressure has been reported in combination oral-contraceptive users. 3. Gallbladder Disease Combined-pill users probably have a greater risk than nonusers of gallbladder disease. Since this risk may be related to pills containing high doses of estrogens, it may not be a concern for NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM users. 4. Liver Tumors In rare cases, the combination oral contraceptive can cause noncancerous but dangerous liver tumors. These benign liver tumors can rupture and cause fatal internal bleeding. In addition, a possible but not definite association has been found with the pill and liver cancers. However, liver cancers are very rare. 5. Cancer of the Reproductive Organs Breast cancer has been diagnosed slightly more often in women who use the pill than in women of the same age who do not use the pill. This very small increase in the number of breast cancer diagnoses gradually disappears during the 10 years after stopping use of the pill. It is not known whether the difference is caused by the pill. It may be that women taking the pill were examined more often, so that breast cancer was more likely to be detected. Some studies have found an increase in the incidence of cancer or precancerous lesions of the cervix in women who use oral contraceptives. However, this finding may be related to factors other than the use of oral contraceptives. WARNING SIGNALS If any of these adverse effects occur following insertion of the NORPLANT® SYSTEM (levonorgestrel implants), call your health-care professional immediately: Sharp chest pain, coughing of blood, or sudden shortness of breath (indicating a possible clot in the lung); Pain in the calf or arm (indicating a possible clot in the leg or arm); Crushing chest pain or heaviness in the chest (indicating a possible heart attack); Sudden severe or persistent headache or vomiting, dizziness or fainting, disturbances of vision or speech, weakness, or numbness in an arm or leg (indicating a possible stroke or other neurologic problem); Persistent headaches, particularly if obese or recent weight gain (indicating possible idiopathic intracranial hypertension); Sudden partial or complete loss of vision (indicating a possible clot in the eye); Breast lumps (indicating possible breast cancer or fibrocystic disease of the breast; ask your health-care professional to show you how to examine your breasts); Severe pain or tenderness in the stomach area or lower abdominal area (indicating an ectopic pregnancy, a ruptured or twisted ovarian follicle, or possibly a ruptured liver tumor); Difficulty in sleeping, weakness, lack of energy, fatigue, or change in mood (possibly indicating severe depression); Jaundice or a yellowing of the skin or eyeballs, accompanied frequently by fever, fatigue, loss of appetite, dark-colored urine, or light-colored bowel movements (indicating possible liver problems); Heavy vaginal bleeding; Delayed menstrual cycles after a long interval of regular cycles; Arm pain; Pus or bleeding at implant site; Expulsion of a capsule. PRECAUTIONS General This product is intended to prevent pregnancy. It does not protect against transmission of HIV (AIDS) and other sexually transmitted diseases (STDs) such as chlamydia, genital herpes, genital warts, gonorrhea, hepatitis B, and syphilis. Physical Examination and Follow-Up – Prior to insertion of NORPLANT SYSTEM (levonorgestrel implants) capsules, your health-care professional will inquire about your medical history and perform a physical exam, including a gynecologic exam. Be sure to have periodic checkups as advised by your health-care professional while the capsules are in place. Insertion and Removal – You should not have capsules inserted if you are pregnant. NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM capsules should be inserted within 7 days after onset of menstrual bleeding or immediately following an abortion to provide effective contraception during the first cycle of use. If NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM capsules are inserted at any other time during the cycle, pregnancy must be excluded, and a nonhormonal contraceptive method (such as condoms, spermicides, or diaphragms) must be used for at least 7 days following insertion. The NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM should be inserted and removed by a health-care professional who is familiar with the appropriate insertion and removal techniques. If infection occurs after insertion, contact your health-care professional for treatment. The NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM may need to be removed in the event that infection continues. If expulsion of a capsule occurs, your health-care professional should replace it with a new capsule that has not been previously used. If infection is present, it should be treated and cured before capsule(s) is (are) replaced. To avoid pregnancy, a back-up method of contraception should be used if less than six capsules are in place. The capsules must be removed at the end of five years when the method starts to become less effective. They can be removed at any time before then, however, if you want to stop using the method for any reason. If the capsules are placed deeply, they can be more difficult to remove. If some of the capsules are more difficult to remove, additional visits and incisions may be required. See also “RISKS OF USING THE NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM,” “SIDE EFFECTS OF THE NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM,” and “INSERTION AND REMOVAL OF THE NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM CAPSULES.” Carbohydrate and Lipid Metabolism – Blood sugar levels may be increased by progestin-only contraceptives such as the NORPLANT SYSTEM (levonorgestrel implants). Diabetic patients should be observed carefully while using the NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM. Some progestins may increase lipid (e.g., cholesterol, triglycerides) levels. Patients being treated for increased lipid levels should be followed closely while using the NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM. Liver Function – The NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM may need to be removed if yellowing of the skin or whites of the eyes occurs. Hormones may be poorly metabolized in patients with liver diseases. Fluid Retention – Hormonal contraception may cause fluid retention with swelling of the fingers or ankles and may raise your blood pressure. If you experience fluid retention, contact your health-care professional. Emotional Disorders – The NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM may need to be removed if you become severely depressed. Contact Lenses – If you wear contact lenses and notice a change in vision or an inability to wear your lenses, contact your health-care professional. While Breast-feeding – Women who are breast-feeding or intend to breast-feed should discuss this with their health-care professional when considering the use of the NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM. Studies have shown no significant effects on the growth or health of infants whose mothers used the NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM beginning five to seven weeks after childbirth. There is no experience to support the use of the NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM in breast-feeding mothers earlier than this after childbirth. Drug Interactions Certain drugs may interact with the hormone delivered by the NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM to make the capsules less effective in preventing pregnancy. Such drugs include drugs used for epilepsy, such as phenytoin (Dilantin® is one brand) and carbamazepine (Tegretol® is one brand). Certain other drugs may also make the NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM less effective. You may need to use additional contraception when you take drugs that can make the NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM less effective. Discuss this with your health-care professional. Drug/Laboratory Tests Interactions If you are scheduled for any laboratory tests tell your health-care professional that you are using the NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM. Certain blood tests are affected by synthetic hormones. SIDE EFFECTS OF THE NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM The most frequently reported side effects are menstrual cycle irregularities. Such changes vary from woman to woman and may include: Prolonged menstrual bleeding (more days than you would usually experience), commonly during the first months of use; Untimely bleeding or spotting between periods; Frequent onset of bleeding; Scanty bleeding; No bleeding at all for several months; or A combination of these patterns. It cannot be predicted before insertion of the NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM what kind of bleeding pattern you will have. Many women can expect an altered bleeding pattern to become more regular after 9 to 12 months. Despite the increased frequency of bleeding in some women, the monthly blood loss is usually less than normal menses. In fact, in some studies, patient blood counts have improved. Contact your health-care professional if you experience heavy bleeding. If you have normal cyclic periods and then miss a period, a pregnancy test should be obtained. If you are pregnant, the NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM must be removed. There have been rare reports of birth defects in offspring of women who were using the NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM unintentionally during early pregnancy. Though the association has been neither confirmed nor refuted, you should check with your health-care professional about the risks to your unborn child of any medication taken during pregnancy. Women using the NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM have complained about the following conditions, which are probably related to the NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM: Headache; Nervousness/Anxiety; Nausea/Vomiting; Dizziness; Enlargement of the ovaries and/or fallopian tubes; Dermatitis (inflammation of the skin)/Rash; Acne; Change of appetite; Weight gain; Mastalgia (breast tenderness); Hirsutism (excessive growth of body or facial hair) or alopecia (hair loss); Discoloration of the skin over the site of implantation (usually reversible). Preexisting conditions of acne or excessive growth of body or facial hair could also be worsened. Occasionally, an infection may occur at the implant site, or there may be a brief incidence of pain or itching. Removals may be more difficult than insertions in some cases. An enlargement of ovarian follicles (sometimes called ovarian cysts) may occur in NORPLANT SYSTEM (levonorgestrel implants) users. These would be detectable during a physical examination. The enlarged follicles usually disappear on their own without surgical intervention, but in rare instances they may twist or rupture, so that surgery is required. Women using the NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM have complained about the following conditions, which are possibly related to the NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM: Abdominal discomfort; Arm pain; Breast discharge; Cervicitis (inflammation of the cervix, detected by physician); Gallbladder disease; High blood pressure; Idiopathic intracranial hypertension (pseudotumor cerebri); Implantation site reactions including blistering; bruising; excessive scarring; hyperpigmentation (darkening of the skin); induration (hardening of tissue); infection; nerve injury; numbness; sloughing; swelling (edema); tingling; ulcerations; Leukorrhea (whitish discharge from the vagina and uterine cavity); Migraine headaches; Muscle and skeletal pain; Phlebitis (inflammation of a vein); Vaginitis (inflammation of the vagina). There are a number of other complaints reported by NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM users or discovered by health-care professionals, but an association with the NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM has been neither confirmed nor refuted: Birth defects; Blood clots (for example in the arms, legs, or lungs); Breast cancer; Dysmenorrhea (pain during menstruation); Fatigue/Weakness; Heart attack; Mood swings, including depression, sometimes severe; Stroke; Thrombotic thrombocytopenic purpura (TTP); Urticaria (hives), pruritus (itching); Vaginal bleeding, heavy; Vision disturbances; Weight gain of more than 10 pounds. INSERTION AND REMOVAL OF THE NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM CAPSULES A. Insertion Insertion and removal of the NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM should be performed by a health-care professional knowledgeable of the procedures. Prior to insertion of NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM capsules, your health-care professional will inquire about your medical history and perform a physical examination. To make sure you are not already pregnant, NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM capsules should be inserted within 7 days after the onset of menstrual bleeding or immediately following an abortion. If NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM capsules are inserted at any other time during the cycle, pregnancy must be excluded, and a nonhormonal contraceptive method (such as condoms, spermicides, or diaphragms) must be used for at least 7 days following insertion. NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM capsules are inserted under the skin on the inner surface of your upper arm during a minor, outpatient surgical procedure under sterile conditions. A local anesthetic is used to numb a small area in the upper arm, after which a small incision, less than 1/8 inch long, is made in the same area. The six capsules are placed one at a time with a special instrument just under the skin in a fan shape. The incision is covered with a small adhesive bandage and protective gauze. Because a local anesthetic is used, there should be little or no discomfort during insertion. When the anesthetic wears off, there may be some tenderness in the area of the implants for a day or two. Some discoloration, bruising, and swelling may also be present for a few days after the procedure. This should not interfere with your usual activities. Other skin reactions that have been reported include blistering, sloughing, and ulceration. Following insertion, you can resume work and other activities. Be careful, however, not to bump the site or get the incision wet for at least 3 days. Also avoid heavy lifting for 2 to 3 days. The protective gauze should remain in place for 24 hours and a small adhesive bandage for 3 days. If the capsules are inserted during menses, you may resume sexual relations as soon as you wish. If the capsules are inserted more than 7 days after the onset of menses, then a nonhormonal contraceptive method must be used for at least 7 days following insertion. Be sure to have periodic checkups as advised by your health-care professional while the capsules are in place. B. Removal The capsules must be removed at the end of five years when the method starts to become less effective. They can be removed at any time before then, however, if you want to stop using the method for any reason. Just as for insertion, your health-care professional will apply a local anesthetic. Under sterile conditions, a small (1/8-inch) incision will be made through which all the capsules should be removed. The removal process usually takes more time and may be more difficult and/or more painful than the insertion procedure. Capsules are sometimes nicked, cut, or broken during removal, or may be difficult to locate. If the capsules are placed deeply, they can be more difficult to remove. If some of the capsules are more difficult to remove, additional visits and incisions may be required. A nonhormonal method of contraception (such as condoms, spermicides, or diaphragms) should be used if less than six capsules are in place. As after insertion, avoid bumping the incision site for a few days. The area should be kept clean, dry, and bandaged until healed (3 to 5 days) to avoid infection. Bruising may occur at the implant site following removal. If you want to continue using the NORPLANT SYSTEM (levonorgestrel implants), you may receive a new set of capsules at the same time the old set is removed. The second set can be placed in the same arm, and frequently through the incision from which the earlier set was removed, or in the other arm. If you do not want to continue with the NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM and do not want to become pregnant, make sure your health-care professional recommends another contraceptive method. Once the capsules are removed, the contraceptive effects cease quickly and a woman can become pregnant at a rate similar to women who have not used the method. Insertion and removal of the NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM should be performed by a health-care professional knowledgeable of the procedures. There have been reports of arm pain, numbness, tingling, and scarring following these procedures. There also have been reports of nerve injury, most commonly associated with deep placement and removal. ADDITIONAL INFORMATION If you would like more information about the NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM, a copy of the Prescribing Information can be obtained from your health-care professional. WHAT I KNOW ABOUT NORPLANT® (levonorgestrel implants) I have read this leaflet and have discussed it with my health-care professional. They have answered all my questions. I understand that there are risks as well as benefits from using NORPLANT (levonorgestrel implants (unavailable in us)) . I understand that there are other forms of contraception that do not have the risks of NORPLANT (levonorgestrel implants (unavailable in us)) , but may have different risks. I also understand that this form is important. It demonstrates that I am making an informed and carefully considered decision to use NORPLANT (levonorgestrel implants (unavailable in us)) . I have checked below those statements that I agree with: ____ I have been told how NORPLANT (levonorgestrel implants (unavailable in us)) works to keep women from getting pregnant. ____ I have been told that the risk of getting pregnant while using NORPLANT (levonorgestrel implants (unavailable in us)) is about 1 percent. (This means that about one woman out of every one hundred who use NORPLANT (levonorgestrel implants (unavailable in us)) may get pregnant each year.) ____ I understand that the NORPLANT (levonorgestrel implants (unavailable in us)) capsules are made of Silastic®, a silicone rubber tubing. ____ I have been told that the NORPLANT (levonorgestrel implants (unavailable in us)) capsules are implanted under the skin of my arm during an in-office surgical procedure. ____ I have been told that the NORPLANT (levonorgestrel implants (unavailable in us)) capsules must be removed at the end of the five years. The removal procedure is also an in-office surgical procedure and may cause more pain and scarring than the insertion procedure. There have been infrequent reports of nerve injury, most commonly associated with deep placement and removal. ____ I have been told that I can have NORPLANT (levonorgestrel implants (unavailable in us)) taken out at any time and for any reason. I have also been told that, if I have trouble finding a health-care professional to remove it, I can call (800) 934-5556 for help. ____ I have been told about the side effects of NORPLANT (levonorgestrel implants (unavailable in us)) , including that most women have changes in their menstrual bleeding. I have been told that the side effects may vary in severity from one woman to another. ____ I have been told about the NORPLANT (levonorgestrel implants (unavailable in us)) warning signs and know that I should seek medical attention if any warning signs appear. ____ I have been told that I need to receive a medical checkup yearly or any time I am having problems. ____ I have been told that NORPLANT (levonorgestrel implants (unavailable in us)) does not protect me from AIDS or any other sexually transmitted disease. I have considered all the information in this leaflet and voluntarily choose to have the NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM inserted by: _______________________________________________ (Name of Health-Care Professional) _______________________________________________ (Patient Signature) (Date) WITNESSED BY: The patient above has signed this leaflet in my presence after I counseled her and answered her questions. _______________________________________________ (Health-Care Professional Signature) (Date) I have provided an accurate translation of this information to the patient whose signature appears above. She has stated that she understands the information and has had an opportunity to have her questions answered. _______________________________________________ (Signature of Translator) (Date)

PATIENT INFORMATION This product is intended to prevent pregnancy. It does not protect against HIV infection (AIDS) or other sexually transmitted diseases. WHAT YOU SHOULD KNOW ABOUT JADELLE® (levonorgestrel implants (unavailable in us)) IMPLANTS BEFORE YOU DECIDE TO USE THEM You need to read and understand this brochure before you decide to use Jadelle® (levonorgestrel implants (unavailable in us)) implants. It tells you about the risks and benefits of Jadelle® (levonorgestrel implants (unavailable in us)) implants. Discuss it with your health care provider. Ask him/her to explain anything you do not understand. There is a more technical brochure about Jadelle® (levonorgestrel implants (unavailable in us)) implants that was written for health care providers. If you would like to read that brochure too, ask your health care provider for a copy. You may need help to understand some of the information. Before you decide to use Jadelle® (levonorgestrel implants (unavailable in us)) implants or any other birth control method, compare it to other birth control methods. If you want to learn more about other methods, ask your health care provider. Another method may be better for you than Jadelle® (levonorgestrel implants (unavailable in us)) implants. Jadelle® (levonorgestrel implants (unavailable in us)) implants differ from most other methods of birth control. Each of the two small, flexible silicone Jadelle (levonorgestrel implants (unavailable in us)) implants contains a hormone. These implants must be inserted in your arm by a minor surgical procedure performed by a health care provider in the office. You should know that some health care providers have more experience than others in inserting Jadelle® (levonorgestrel implants (unavailable in us)) implants. Be sure to ask your health care provider whether he/she has received instruction in how to insert Jadelle® (levonorgestrel implants (unavailable in us)) implants and remove them. You can decide to have Jadelle® (levonorgestrel implants (unavailable in us)) implants removed at any time. You should know that removing Jadelle® (levonorgestrel implants (unavailable in us)) implants may be more difficult than inserting them. It may take longer and involve more pain. It may leave scars. This risk does not exist with most other birth control methods. Some women should not use Jadelle® (levonorgestrel implants (unavailable in us)) implants. To find out whether you are one of these women, talk to health care provider and read this brochure carefully, especially the sections entitled "WHO SHOULD NOT USE JADELLE® (levonorgestrel implants (unavailable in us)) IMPLANTS" and "OTHER CONSIDERATIONS BEFORE CHOOSING JADELLE® (levonorgestrel implants (unavailable in us)) IMPLANTS." Some women who use Jadelle® (levonorgestrel implants (unavailable in us)) implants will have side effects. You should know the danger signs described in this brochure. INTRODUCTION Each woman who considers using Jadelle® (levonorgestrel implants (unavailable in us)) implants should understand the benefits and risks of this form of birth control as compared with other contraceptive methods. This leaflet will give you much of the information you will need to make a decision on whether to use Jadelle® (levonorgestrel implants (unavailable in us)) , but it is not a replacement for a careful discussion with your health-care provider. You should discuss the information provided in this leaflet with him or her, both when choosing whether to use Jadelle® (levonorgestrel implants (unavailable in us)) and during revisits. You should also follow your health-care provider's advice with regard to regular checkups while using Jadelle® (levonorgestrel implants (unavailable in us)) implants. Jadelle® (levonorgestrel implants (unavailable in us)) implants are two thin flexible implants that are inserted just under the skin on the inner surface of your upper arm in a minor, outpatient surgical procedure. The implants contain the synthetic hormone levonorgestrel (a progestin). A similar product, NORPLANT® implants, consists of six capsules that are inserted under the skin and also contain levonorgestrel as the active ingredient. Levonorgestrel is also used in many birth control pills. Immediately after insertion of Jadelle® (levonorgestrel implants (unavailable in us)) implants, a low continuous dose of the hormone is released into your body. Pregnancy is prevented by stopping ovulation (so eggs will not be produced regularly), and thickening the cervical mucus (making it more difficult for the sperm to reach the egg). There may also be other effects that contribute to pregnancy prevention. Following removal, the effects reverse quickly and a woman can become pregnant as easily as if she had never used Jadelle® (levonorgestrel implants (unavailable in us)) implants. EFFECTIVENESS OF JADELLE® (levonorgestrel implants (unavailable in us)) IMPLANTS Jadelle® (levonorgestrel implants (unavailable in us)) implants are one of the most effective reversible birth control methods. No method is 100% effective. The average annual pregnancy rate over a 5-year period for Jadelle® (levonorgestrel implants (unavailable in us)) implants is less than 1%. That is less than one pregnancy for every 100 women during each year of use. Jadelle (levonorgestrel implants (unavailable in us)) may be less effective in obese women. Over the five year period, the cumulative or total pregnancy rate is about 1%. In comparison, pregnancy rates during the first year of using other birth control methods are as follows: Typical Failure Rates (%) During the First Year of Use of a Contraceptive Method Method Typical Use NORPLANT® SYSTEM 0.1 Male sterilization 0.15 Female sterilization 0.5 Depo-Provera® (injectable progestogen) 0.3 Oral contraceptives 5.0 IUD Progesterone 2.0 Copper T 380A 0.8 Condom (male) without spermicide 14 (female) without spermicide 21 Cervical cap Nulliparous women 20 Parous women 40 Sponge Nulliparous 20 Parous 40 Diaphragm with spermicidal cream or jelly 20 Spermicides alone (foam, creams, jellies, and vaginal suppositories) 26 Periodic abstinence (all methods) 25 Withdrawal 19 No contraception (planned pregnancy) 85 Adapted from Hatcher RA et al., Contraceptive Technology, 17th Revised Edition. New York, NY: Irvington Publishers, 1998 Except for Jadelle® (levonorgestrel implants (unavailable in us)) implants, NORPLANT® implants, sterilization, and the IUD, the effectiveness of contraceptive methods depends in part on how reliably they are used. Jadelle® (levonorgestrel implants (unavailable in us)) implants provide 5 years of protection against pregnancy but can be removed at any time. At the end of the fifth year, the implants will be less effective and must be removed; a new set may be inserted at the time of removal for continued protection if desired. WHO SHOULD NOT USE JADELLE® (levonorgestrel implants (unavailable in us)) IMPLANTS Some women should not use Jadelle® (levonorgestrel implants (unavailable in us)) implants. You should not have the implants inserted if you have: Any chance that you may be pregnant. Liver disease, or liver tumors (either benign or cancerous) Unexplained bleeding between your periods. Breast cancer. Blood clots in the legs (thrombophlebitis), lungs (pulmonary embolism), or eyes. Women who have had previous blood clots should consult with their health-care provider on whether to use Jadelle® (levonorgestrel implants (unavailable in us)) implants. History of idiopathic intracranial hypertension. Hypersensitivity or allergy to levonorgestrel or silicone. A need for certain medications for seizures (epilepsy) or tuberculosis (TB) that could make Jadelle® (levonorgestrel implants (unavailable in us)) less effective (see Drug Interactions) OTHER CONSIDERATIONS BEFORE CHOOSING JADELLE® (levonorgestrel implants (unavailable in us)) IMPLANTS Tell your health-care provider if you or any family member has ever had: Breast nodules, fibrocystic disease of the breast, an abnormal breast X-ray or mammogram Diabetes Elevated cholesterol or triglycerides High blood pressure Gallbladder, heart, or kidney disease History of blood clots, heart attack, or stroke Clinical depression Migraine headaches History of scanty or irregular menstrual periods Women with the above conditions may need to be checked more often by their health-care provider if they choose to use Jadelle® (levonorgestrel implants (unavailable in us)) implants. Be sure to inform your health-care provider if you smoke or are on any medications. RISKS OF USING JADELLE® (levonorgestrel implants (unavailable in us)) IMPLANTS Risks Based on Experience with the NORPLANT® SYSTEM and Jadelle® (levonorgestrel implants (unavailable in us)) implants. Insertion and Removal Complications Jadelle® (levonorgestrel implants (unavailable in us)) implants are inserted and removed by a minor surgical procedure in your healthcare provider's office. You may experience pain, swelling, or bruising. Arm pain, itching, numbness and tingling may also occur following insertion or removal. Some women using NORPLANT® implants experienced infection, abscess, blisters, ulcers, peeling, scarring, or darkening of the skin at the insertion site, inflammation of blood vessels, or nerve injury. NORPLANT® implants occasionally come out of the skin or move to a slightly different position. These events could also occur with Jadelle® (levonorgestrel implants (unavailable in us)) implants. Removal may take longer than insertion and may be more difficult and/or cause more pain, especially if the implants are difficult to locate. Occasionally, additional incisions and/or office visits are required. Changes In Menstrual Bleeding Patterns Most women experience some change in their usual monthly bleeding pattern. These menstrual changes vary from woman to woman and include: Prolonged bleeding or spotting (more days than you would usually experience) Bleeding or spotting between periods Heavy bleeding No bleeding at all for several months A combination of these patterns. It cannot be predicted what kind of change you may experience. Contact your health-care provider if you experience heavy bleeding. Persistent heavy bleeding could lead to anemia. If you have regular periods and then miss a period, you should have a pregnancy test. If you are pregnant, Jadelle® (levonorgestrel implants (unavailable in us)) implants must be removed. Ovarian Cysts If follicles (eggs and their surrounding cells) in the ovary develop while using Jadelle® (levonorgestrel implants (unavailable in us)) implants, disappearance of the follicles is sometimes delayed, and the follicles may continue to grow beyond their normal size. These enlarged follicles (cysts) may produce abdominal pain in some women, although most women would not be aware of them unless they were found by chance on a physical exam. In most women, these cysts will disappear on their own and should not require surgery. Rarely, they may twist or rupture, and surgery is required. Ectopic Pregnancies The risk of having an ectopic pregnancy (a pregnancy that develops outside of the uterus) during Jadelle® (levonorgestrel implants (unavailable in us)) use is less than the risk of ectopic pregnancy in women using no birth control method; however, if you become pregnant while using Jadelle® (levonorgestrel implants (unavailable in us)) , that pregnancy is more likely to be ectopic than if you become pregnant using no birth control. Symptoms of an ectopic pregnancy include spotting and cramping pain. Contact your health-care provider if you suspect that you may be pregnant or if you experience abdominal pain. Blood Vessel Complications Inflammation of blood vessels can occur with use of Jadelle® (levonorgestrel implants (unavailable in us)) implants or NORPLANT® implants, usually in the same arm as the implants. This may occur with injury to that arm. There have also been reports of blood clots and cardiovascular problems (stroke, heart attack, blood clots in the lung, and deep-vein blood clots) with NORPLANT® implants use. (See also Risks Based on Experience With Combination Oral Contraceptives below.) Risks Based on Experience With Combination Oral Contraceptives Combination oral contraceptives contain a progestin such as levonorgestrel and an estrogen, another type of hormone. Some rare but serious side effects have been associated with use of combination oral contraceptives. It is unknown whether the risks associated with combination oral contraceptive use may also be risks with a progestin-only birth control method like Jadelle® (levonorgestrel implants (unavailable in us)) implants. Risk of Developing Blood Clots Blood clots and blockage of blood vessels can be serious. In particular, a clot in the veins of the legs can cause inflammation and risk of further clots. A clot that travels to the lungs can cause a sudden blocking of the vessel carrying blood to the lungs, resulting in respiratory collapse and even death. Rarely, clots occur in the blood vessels of the eye and may cause double vision, impaired vision, or even blindness. Any of these conditions can cause serious disability or death. Patients who develop blood clots in the legs, arms, lungs, or eyes should have the Jadelle® (levonorgestrel implants (unavailable in us)) implants removed. In addition, patients restricted to bed rest or who have limited movement for a prolonged period due to surgery or other illness may be at increased risk of developing blood clots. Jadelle® (levonorgestrel implants (unavailable in us)) implants may need to be removed in such patients. Risk of Heart Attacks and Strokes The combination pill may increase the tendency to develop strokes (stoppage or rupture of blood vessels in the brain), angina pectoris, or heart attacks (blockage of blood vessels to the heart). Any of these conditions can cause death or serious disability. Smoking greatly increases the probability of suffering heart attacks and strokes. Use of combination oral contraceptives together with cigarette smoking greatly increases the risk of serious adverse effects on the heart and blood vessels. This risk increases with age and with heavy smoking (15 or more cigarettes per day) and is quite marked in women over 35 years of age who smoke. It is not known whether a similar interaction occurs with Jadelle® (levonorgestrel implants (unavailable in us)) implants. Therefore, women who use Jadelle® (levonorgestrel implants (unavailable in us)) implants should not smoke. High Blood Pressure An increase in blood pressure has been reported in combination oral contraceptive users. Elevated blood pressure occurs more often with long-term oral contraceptive exposure. A similar finding has been reported for women using NORPLANT® implants. Gallbladder Disease Combination pill users probably have a greater risk of gallbladder disease than nonusers. A similar finding has been reported for women using NORPLANT® implants. Liver Tumors In rare cases, the combination pill can cause dangerous liver tumors that can rupture and cause fatal internal bleeding. In addition, a possible but not definite association has been found with the pill and liver cancers. However, liver cancers are very rare. It is not known whether Jadelle (levonorgestrel implants (unavailable in us)) can cause liver tumors. Cancer of the Reproductive Organs and Breasts Various studies give conflicting reports on the relationship between breast cancer and oral contraceptive use. Oral contraceptive use may slightly increase the chance of having breast cancer diagnosed, particularly after use at a young age. After stopping hormonal contraceptive use, the chances of getting breast cancer begin to go back down. You should have regular breast examinations by a health care provider and examine your own breasts monthly. Tell your health care provider if you have a family history of breast cancer or if you have had breast nodules or an abnormal mammogram. Women who currently have or have had breast cancer should not use hormonal contraceptives because breast cancer is usually a hormone-sensitive tumor. Some studies have found an increase in the incidence of cancer of the cervix in women who use oral contraceptives. However, this finding may be related to factors other than the use of oral contraceptives. WARNING SIGNALS If any of these adverse effects occur following insertion of Jadelle® (levonorgestrel implants (unavailable in us)) implants call your health-care provider immediately: Sharp chest pain, coughing of blood, or sudden shortness of breath (indicating a possible clot in the lung) Pain in the calf or arm (indicating a possible clot in the leg or arm) Crushing chest pain or heaviness in the chest (indicating a possible heart attack) Sudden severe or persistent headache or vomiting, dizziness or fainting, disturbances of vision or speech, weakness, or numbness in an arm or leg (indicating a possible stroke or other neurologic problem) Persistent headaches, particularly if you are obese or have had recent weight gain (indicating possible idiopathic intracranial hypertension) Sudden partial or complete loss of vision (indicating a possible clot in the eye) Breast lumps (indicating possible breast cancer or fibrocystic disease of the breast; ask your health-care provider to show you how to examine your breasts) Severe pain or tenderness in the stomach area or lower abdominal area (possibly indicating an ectopic pregnancy, a ruptured or twisted ovarian cyst, or a ruptured liver tumor) Sleep disorders, weakness, lack of energy, fatigue, or change in mood (possibly indicating severe depression) Jaundice or a yellowing of the skin or eyeballs, accompanied frequently by fever, fatigue, loss of appetite, dark-colored urine, or light-colored bowel movements (indicating possible liver problems) Heavy vaginal bleeding Delayed menstrual cycles after a long interval of regular cycles Arm pain Pus or bleeding at implant site Expulsion of an implant. PRECAUTIONS GENERAL Physical Examination and Follow-Up — Prior to insertion of Jadelle® (levonorgestrel implants (unavailable in us)) implants, your health-care provider will inquire about your medical history and perform a physical exam, including a gynecologic exam. Be sure to have periodic checkups as advised by your health-care provider while the implants are in place. Carbohydrate and Lipid Metabolism — Blood sugar levels may be increased by progestin-only contraceptives such as Jadelle® (levonorgestrel implants (unavailable in us)) implants. Diabetic patients should be observed carefully while using Jadelle® (levonorgestrel implants (unavailable in us)) implants. Some progestins may increase lipid (eg, cholesterol, triglyceride) levels. Patients being treated for increased lipid levels should be followed closely while using Jadelle® (levonorgestrel implants (unavailable in us)) implants. Liver Function — Jadelle® (levonorgestrel implants (unavailable in us)) implants may need to be removed if yellowing of the skin or whites of the eyes occurs. Hormones may be poorly metabolized in patients with liver diseases. Fluid Retention —If you experience fluid retention (with swelling of the fingers or ankles, and possibly increased blood pressure) while using Jadelle® (levonorgestrel implants (unavailable in us)) implants, contact your health-care provider. Emotional Disorders — Jadelle® (levonorgestrel implants (unavailable in us)) implants may need to be removed if you become severely depressed. Contact Lenses — If you wear contact lenses and notice a change in vision or an inability to wear your lenses, contact your health-care provider. Idiopathic Intracranial Hypertension (pseudotumor cerebri, benign intracranial hypertension) — An increase in intracranial pressure has been reported in rare cases in NORPLANT® implant users. Symptoms may include headache (associated with a change in the frequency, pattern, severity, or persistence. Of particular importance are visual disturbances and headaches that do not stop. Contact your health-care provider if you experience these symptoms, particularly if you are obese or have had recent weight gain. While it is unclear if this condition is caused by the implants, your health-care provider may recommend that Jadelle® (levonorgestrel implants (unavailable in us)) implants be removed. Use in Early Pregnancy—Birth defects have not been reported with Jadelle® (levonorgestrel implants (unavailable in us)) use. There have been reports of birth defects when NORPLANT® implants were used unintentionally during early pregnancy, but a cause and effect relationship has not been established. You should check with your health-care provider about the risks of any medication taken during pregnancy. Do not have implants placed if you are pregnant or believe you may be pregnant. While Breast-Feeding — Women who are breast-feeding or intend to breast-feed should discuss this with their health-care provider when considering the use of Jadelle® (levonorgestrel implants (unavailable in us)) implants. Studies have shown no significant effects on the growth or health of infants whose mothers used NORPLANT® implants beginning 5 to 7 weeks after childbirth. Infections — Infection at the implant site is uncommon. If infection does occur, contact your health-care provider for treatment. The implants may need to be removed if the infection continues. Expulsion and Displacement (Movement) — Expulsion of an implant (i.e., when an implant comes out of the insertion site/skin) may occur. If an implant is expelled, your health-care provider should replace it with a new sterile implant. If infection is present, it should be resolved before any implant is replaced. To avoid pregnancy when only one implant is in place, a back-up nonhormonal contraceptive method (such as condoms or spermicides) should be used. After Jadelle® (levonorgestrel implants (unavailable in us)) implants are inserted, they may move from the original position. Rarely, movement up to several inches has been reported with NORPLANT® implants. With NORPLANT® implants, movement accompanied by pain and discomfort has been reported. If movement of one or both Jadelle® (levonorgestrel implants (unavailable in us)) implants occurs, particularly if accompanied by pain and/or discomfort, notify your health-care provider. Drug Interactions Certain drugs may interact with the hormone delivered by Jadelle® (levonorgestrel implants (unavailable in us)) implants to make them less effective in preventing pregnancy. Such drugs include drugs used for epilepsy, such as phenytoin (Dilantin® is one brand), carbamazepine (Tegretol® is one brand), oxcarbezepine (Trileptal is one brand), and phenobarbital . Certain other drugs, such as rifampicin, may also make Jadelle® (levonorgestrel implants (unavailable in us)) implants less effective. You may need to use a different birth control method if you require drugs that can make Jadelle® (levonorgestrel implants (unavailable in us)) implants less effective. Discuss this with your health-care provider. Laboratory Tests Interactions If you are scheduled for any laboratory tests, tell your health-care provider that you are using Jadelle® (levonorgestrel implants (unavailable in us)) implants. Certain blood tests are affected by synthetic hormones. SIDE EFFECTS OF JADELLE® (levonorgestrel implants (unavailable in us)) IMPLANTS. The most frequently reported side effects are menstrual cycle changes. SEE RISKS OF USING JADELLE® (levonorgestrel implants (unavailable in us)) IMPLANTS. Women using Jadelle® (levonorgestrel implants (unavailable in us)) implants have also experienced the following conditions. Acne Appetite changes Breast pain Contact dermatitis Dizziness Hair loss Headache Lesions or inflammation of the cervix Leukorrhea (whitish discharge from the vagina) Libido decrease (less interest in sex) Nausea Nervousness Pain, discoloration, or other skin reaction at implant site Pelvic pain Vaginal infection (due to yeast, trichomonas, bacteria), urinary tract symptoms, or genital pruritus (itching) Weight change, usually an increase A woman who already has acne or excess hair on her face or body could experience worsening of these problems The following additional complaints have been reported by NORPLANT® implant users. Migraine Mood swings Muscle and skeletal pain Pruritus (itching) Skin rashes Thrombotic thrombocytopenic purpura (TTP) Urticaria (hives) INSERTION AND REMOVAL OF JADELLE® (levonorgestrel implants (unavailable in us)) IMPLANTS Insertion Insertion and removal of Jadelle® (levonorgestrel implants (unavailable in us)) implants should be performed by a health-care provider knowledgeable of the procedures. Prior to insertion of Jadelle® (levonorgestrel implants (unavailable in us)) implants, your health-care provider will ask about your medical history and perform a physical examination, including a pelvic exam. To make sure you are not already pregnant, Jadelle® (levonorgestrel implants (unavailable in us)) implants should be inserted within 7 days after the onset of menstrual bleeding or immediately following termination of pregnancy. If Jadelle® (levonorgestrel implants (unavailable in us)) implants are inserted at any other time during the cycle, pregnancy must be excluded, and a nonhormonal contraceptive method (such as condoms, spermicides, or diaphragms) must be used for at least 7 days following insertion. If ovulation and conception have already occurred before Jadelle® (levonorgestrel implants (unavailable in us)) is inserted, pregnancy could occur during the month of insertion. Jadelle® (levonorgestrel implants (unavailable in us)) implants are inserted under the skin on the inner surface of your upper arm during a minor, outpatient surgical procedure under sterile conditions. A local anesthetic is used to numb a small V-shaped area in the upper arm, after which a small incision, less than 1/8 inch long, is made in the same area. The two implants are placed one at a time with a special instrument. The incision is covered with a small adhesive bandage and protective gauze. Because a local anesthetic is used, there should be little or no discomfort during insertion. When the anesthetic wears off, there may be some tenderness in the area of the implants for a day or two. Some discoloration, bruising, and swelling may also be present for a few days after the procedure. Following insertion, you can resume work and other activities. Be careful, however, not to bump the site or get the incision wet for at least 3 days. Also avoid heavy lifting for 2 to 3 days. The protective gauze should remain in place for 24 hours and a small adhesive bandage for 3 days. Be sure to have periodic checkups as advised by your health-care provider while Jadelle® (levonorgestrel implants (unavailable in us)) implants are in place. Removal The implants must be removed at the end of 5 years because they become less effective. They can be removed at any time before then, however, if you want to stop using the method for any reason. Removal will take longer than insertion. Just as for insertion, your health-care provider will numb the area with a local anesthetic. Under sterile conditions, a small (1/8 inch) incision will be made through which the implants should be removed. The removal process takes more time than the insertion procedure. If the implants are too deep, they can be more difficult to remove. If both implants cannot be removed, additional visits and incisions may be required. A nonhormonal method of contraception (such as condoms, spermicides, or diaphragms) should be used until both implants are completely removed. Avoid bumping the incision site for a few days. The area should be kept clean, dry, and bandaged until healed (3 to 5 days) to avoid infection. Bruising may occur at the implant site following removal. If you want to continue using Jadelle® (levonorgestrel implants (unavailable in us)) implants, a new set can be inserted at the same time the old set is removed. The second set can be placed in the same arm, and frequently through the incision from which the earlier set was removed, or in the other arm. If you do not want to continue with Jadelle® (levonorgestrel implants (unavailable in us)) implants and do not want to become pregnant, ask your health-care provider to recommend another birth control method. Once the implants are removed, the effects reverse quickly and a woman can become pregnant as easily as if she had not used the method. ADDITIONAL INFORMATION If you would like more information about Jadelle® (levonorgestrel implants (unavailable in us)) implants, a copy of the Prescribing Information can be obtained from your health-care provider. WHAT I KNOW ABOUT JADELLE® (levonorgestrel implants (unavailable in us)) IMPLANTS I have read this brochure and have discussed it with my health care provider. He/she has answered all my questions. I understand that there are risks as well as benefits from using Jadelle® (levonorgestrel implants (unavailable in us)) implants. I understand that there are other forms of contraception that do not have the risks of Jadelle® (levonorgestrel implants (unavailable in us)) implants, but may have different risks. I also understand that this form is important. It demonstrates that I am making an informed and carefully considered decision to use Jadelle® (levonorgestrel implants (unavailable in us)) implants. I have checked below those statements that I agree with: _______I have been told how Jadelle® (levonorgestrel implants (unavailable in us)) implants work to keep women from getting pregnant. _______I have been told that the risk of getting pregnant while using Jadelle® (levonorgestrel implants (unavailable in us)) implants is less than 1%. (This means that less than one woman out of every 100 who uses Jadelle® (levonorgestrel implants (unavailable in us)) implants may get pregnant each year.) _______I have been told that I can have Jadelle® (levonorgestrel implants (unavailable in us)) implants taken out at any time and for any reason. I have also been told that, if I have trouble finding a health care provider to remove them, I can call (800) 934-5556 for help. _______I understand that the Jadelle® (levonorgestrel implants (unavailable in us)) implants are made of a hormone embedded in a flexible solid state silicone polymer. _______I have been told that Jadelle® (levonorgestrel implants (unavailable in us)) implants are implanted under the skin of my arm during an in-office surgical procedure. ________I have been told that the Jadelle® (levonorgestrel implants (unavailable in us)) implants must be removed at the end of 5 years. The removal procedure is also an in-office surgical procedure and may cause more discomfort and scarring than the insertion procedure. ________I have been told about the side effects of Jadelle® (levonorgestrel implants (unavailable in us)) implants, including that most women have changes in their menstrual bleeding. I have been told that the side effects may vary in severity from one woman to another. ________I have been told about warning signs that may indicate serious conditions and know that I should seek medical attention if any warning signs appear. _______I have been told that I need to receive a medical checkup yearly and at any time I am having problems. _______I have been told that Jadelle® (levonorgestrel implants (unavailable in us)) implants do not protect me from HIV infection (AIDS) or any other sexually transmitted disease. ________I have considered all the information in this brochure and voluntarily choose to have Jadelle® (levonorgestrel implants (unavailable in us)) implants inserted by: _________________________ (Name of Health-Care Provider) ____________________________________ (Patient Signature)(Date) WITNESSED BY: The patient above has signed this brochure in my presence after I counseled her and answered her questions. ____________________________________ (Health-Care Provider Signature)(Date) I have provided an accurate translation of this information to the patient whose signature appears above. She has stated that she understands the information and has had an opportunity to have her questions answered. ____________________________________ (Signature of Translator)(Date)

WARNINGS Warnings Based on Experience with the NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM Insertion and Removal Complications A surgical incision is required to insert NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM capsules. Complications related to insertion such as pain, edema, and bruising may occur. There also have been reports of infection (including cellulitis and abscess formation), blistering, ulcerations, sloughing, excessive scarring, phlebitis, and hyperpigmentation at the insertion site. There have been reports of arm pain, numbness, and tingling following the insertion and removal procedures. There also have been reports of nerve injury, most commonly associated with deep placement and removal. Expulsion of capsules has been reported more frequently when placement of the capsules was shallow or too close to the incision or when infection was present. There have been reports of capsule displacement (i.e., movement), most of which involved minor changes in the positioning of the capsules. However, infrequent reports ( < 1%) of significant displacement (a few to several inches) have been received. Some of these reports have been associated with pain and difficult removal. Removal is also a surgical procedure and may take longer, be more difficult, and/or cause more pain than insertion and may be associated with difficulty locating capsules. These complications may lead to the need for additional incisions and/or office visits. See also “PRECAUTIONS” and “ADVERSE REACTIONS.” Bleeding Irregularities Most women can expect some variation in menstrual bleeding patterns. Irregular menstrual bleeding, intermenstrual spotting, prolonged episodes of bleeding and spotting, heavy bleeding, and amenorrhea occur in some women. Irregular bleeding patterns associated with the NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM could mask symptoms of cervical or endometrial cancer. Overall, these irregularities diminish with continuing use. Since some NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM users experience periods of amenorrhea, missed menstrual periods cannot serve as the only means of identifying early pregnancy. Pregnancy tests should be performed whenever a pregnancy is suspected. Six (6) weeks or more of amenorrhea after a pattern of regular menses may signal pregnancy. If pregnancy occurs, the capsules must be removed. Although bleeding irregularities have occurred in clinical trials, proportionately more women had increases rather than decreases in hemoglobin concentrations, a difference that was highly statistically significant. This finding generally indicates that reduced menstrual blood loss is associated with the use of the NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM, although some patients experience heavy bleeding that results in hemoglobin values consistent with anemia. Ovarian Cysts (Delayed Follicular Atresia) If follicular development occurs with the NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM, atresia of the follicle is sometimes delayed, and the follicle may continue to grow beyond the size it would attain in a normal cycle. These enlarged follicles cannot be distinguished clinically from ovarian cysts. In the majority of women, enlarged follicles will spontaneously disappear and should not require surgery. Rarely, they may twist or rupture, sometimes causing abdominal pain, and surgical intervention may be required. Ectopic Pregnancies Ectopic pregnancies have occurred among NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM users, although clinical studies have shown no increase in the rate of ectopic pregnancies per year among NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM users as compared with users of no method or of IUDs. The incidence among NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM users was 1.3 per 1000 woman-years, a rate significantly below the rate that has been estimated for noncontraceptive users in the United States (2.7 to 3.0 per 1000 woman-years); however, any pregnancy that does occur in a woman using Norplant (levonorgestrel implants (unavailable in us)) is more likely to be ectopic than a pregnancy in a woman using no contraceptive at all. The risk of ectopic pregnancy may increase with the duration of NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM use and possibly with increased weight of the user. Health-care professionals should be alert to the possibility of an ectopic pregnancy among women using the NORPLANT SYSTEM (levonorgestrel implants) who become pregnant or complain of lower-abdominal pain. Any patient who presents with lower-abdominal pain must be evaluated to rule out ectopic pregnancy. Foreign-body Carcinogenesis Rarely, cancers have occurred at the site of foreign-body intrusions or old scars. None has been reported in NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM clinical trials. In rodents, which are highly susceptible to such cancers, the incidence decreases with decreasing size of the foreign body. Because of the resistance of human beings to these cancers and because of the small size of the capsules, the risk to users of the NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM is judged to be minimal. Thromboembolic Disorders and Other Vascular Problems An increased risk of thromboembolic and thrombotic disease (pulmonary embolism, superficial venous thrombosis, and deep-vein thrombosis) has been found to be associated with the use of combination oral contraceptives. The relative risk has been estimated to be 4- to 11-fold higher for users than for nonusers. There have also been post-marketing reports of these events coincident with NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM use. The reports of thrombophlebitis and superficial phlebitis have more commonly occurred in the arm of insertion. Some of these cases have been associated with trauma to that arm. Cerebrovascular Disorders: Combination oral contraceptives have been shown to increase both the relative and attributable risks of cerebrovascular events (thrombotic and hemorrhagic strokes), although, in general, the risk is greatest among older ( > 35 years) hypertensive women who also smoke. Hypertension was found to be a risk factor for both users and nonusers for both types of strokes, while smoking interacted to increase the risk for hemorrhagic strokes. There have been post-marketing reports of stroke coincident with NORPLANT SYSTEM (levonorgestrel implants) use. Myocardial Infarction: An increased risk of myocardial infarction has been attributed to combination oral-contraceptive use. This is thought to be primarily thrombotic in origin and is related to the estrogen component of combination oral contraceptives. This increased risk occurs primarily in smokers or in women with other underlying risk factors for coronary-artery disease, such as family history of coronary-artery disease, hypertension, hypercholesterolemia, morbid obesity, and diabetes. The current relative risk of heart attack for combination oral-contraceptive users has been estimated as 2 to 6 times the risk for nonusers. The absolute risk is very low for women under 30 years of age. Studies indicate a significant trend toward higher rates of myocardial infarctions and strokes with increasing doses of progestin in combination oral contraceptives. However, a recent study showed no increased risk of myocardial infarction associated with the past use of levonorgestrel-containing combination oral contraceptives. There have been post-marketing reports of myocardial infarction coincident with NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM use. Patients who develop active thrombophlebitis or thromboembolic disease should have the NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM capsules removed. Removal should also be considered in women who will be subjected to prolonged immobilization due to surgery or other illnesses. Use Before or During Early Pregnancy Extensive epidemiological studies have revealed no increased risk of birth defects in women who have used oral contraceptives prior to pregnancy. Studies also do not suggest a teratogenic effect, particularly insofar as cardiac anomalies and limb-reduction defects are concerned, when taken inadvertently during early pregnancy. There is no evidence suggesting that the risk associated with NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM use is different. There have been rare reports of congenital anomalies in offspring of women who were using the NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM inadvertently during early pregnancy. A cause and effect relationship is not believed to exist. Idiopathic Intracranial Hypertension Idiopathic intracranial hypertension (pseudotumor cerebri, benign intracranial hypertension) is a disorder of unknown etiology which is seen most commonly in obese females of reproductive age. There have been reports of idiopathic intracranial hypertension in NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM users. A cardinal sign of idiopathic intracranial hypertension is papilledema; early symptoms may include headache (associated with a change in frequency, pattern, severity, or persistence; of particular importance are those headaches that are unremitting in nature) and visual disturbances. Patients with these symptoms, particularly obese patients or those with recent weight gain, should be screened for papilledema and, if present, the patient should be referred to a neurologist for further diagnosis and care. NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM should be removed from patients experiencing this disorder. Warnings Based on Experience with Combination (Progestin plus Estrogen) Oral Contraceptives Cigarette Smoking Cigarette smoking increases the risk of serious cardiovascular side effects from the use of combination oral contraceptives. This risk increases with age and with the extent of smoking (in epidemiologic studies, 15 or more cigarettes per day was associated with a significantly increased risk) and is quite marked in women over 35 years old. While this is believed to be an estrogen-related effect, it is not known whether a similar risk exists with progestin-only methods such as the NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM; however, women who use the NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM should be advised not to smoke. Elevated Blood Pressure Increased blood pressure has been reported in users of combination oral contraceptives. The prevalence of elevated blood pressure increases with long exposure. Although there were no statistically significant trends among NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM users in clinical trials, health-care professionals should be aware of the possibility of elevated blood pressure with the NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM. Carcinoma of the Breast and Reproductive Organs Numerous epidemiological studies have examined the association between the use of oral contraceptives and the incidence of breast and cervical cancer. The risk of having breast cancer diagnosed may be slightly increased among current and recent users of combination oral contraceptives. However, this excess risk appears to decrease over time after combination oral contraceptive discontinuation and by 10 years after cessation the increased risk disappears. Some studies report an increased risk with duration of use while other studies do not and no consistent relationships have been found with dose or type of steroid. Some studies have reported a small increase in risk with combination oral contraceptives first used at a younger age. Most studies show a similar pattern of risk with combination oral contraceptive use regardless of a woman's reproductive history or her family breast cancer history. Breast cancers diagnosed in current or previous oral contraceptive users tend to be less clinically advanced than in nonusers. Women who currently have or have had breast cancer should not use hormonal contraceptives because breast cancer is usually a hormonally-sensitive tumor. Some studies suggest that combination oral-contraceptive use has been associated with an increase in the risk of cervical intraepithelial neoplasia or invasive cervical cancer in some populations of women. However, there continues to be controversy about the extent to which such findings may be due to differences in sexual behavior and other factors. In spite of many studies of the relationship between combination oral-contraceptive use and breast and cervical cancers, a cause-and-effect relationship has not been established. Evidence indicates that combination oral contraceptives may decrease the risk of ovarian and endometrial cancer. Irregular bleeding patterns associated with the NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM could mask symptoms of cervical or endometrial cancer. Hepatic Tumors Hepatic adenomas have been found to be associated with the use of combination oral contraceptives with an estimated incidence of about 3 occurrences per 100,000 users per year, a risk that increases after 4 or more years of use. Although benign, hepatic adenomas may rupture and cause death through intra-abdominal hemorrhage. The contribution of the progestin component of oral contraceptives to the development of hepatic adenomas is not known. Ocular Lesions There have been clinical case reports of retinal thrombosis associated with the use of oral contraceptives that may lead to partial or complete loss of vision. Although it is believed that this adverse reaction is related to the estrogen component of oral contraceptives, the NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM capsules should be removed if there is unexplained partial or complete loss of vision; onset of proptosis or diplopia; papilledema; or retinal vascular lesions. Appropriate diagnostic and therapeutic measures should be undertaken immediately. Gallbladder Disease Earlier studies have reported an increased lifetime relative risk of gallbladder surgery in users of oral contraceptives and estrogens. More recent studies, however, have shown that the relative risk of developing gallbladder disease among oral-contraceptive users may be minimal. The recent findings of minimal risk may be related to the use of oral-contraceptive formulations containing lower hormonal doses of estrogens and progestins. The association of this risk with the use of the NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM progestin-only method is not known. PRECAUTIONS General Patients should be counseled that this product does not protect against transmission of HIV (AIDS) and other sexually transmitted diseases (STDs) such as chlamydia, genital herpes, genital warts, gonorrhea, hepatitis B, and syphilis. Physical Examination and Follow-Up A complete medical history and physical examination should be taken prior to the implantation or reimplantation of NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM capsules and at least annually during its use. These physical examinations should include special reference to the implant site, blood pressure, breasts, abdomen and pelvic organs, including cervical cytology and relevant laboratory tests. In case of undiagnosed, persistent or recurrent abnormal vaginal bleeding, appropriate diagnostic measures should be conducted to rule out malignancy. Women with a strong family history of breast cancer or who have breast nodules should be monitored with particular care. Insertion and Removal To be sure that the woman is not pregnant at the time of capsule placement and to assure contraceptive effectiveness during the first cycle of use, it is advisable that insertion be done during the first 7 days of the menstrual cycle or immediately following an abortion. However, NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM capsules may be inserted at any time during the cycle provided pregnancy has been excluded and the possibility that ovulation and conception have already occurred has been considered. Insertion is not recommended before 6 weeks postpartum in breast-feeding women. Insertion and removal instructions must be followed closely. It is strongly advised that all health-care professionals who insert and remove NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM capsules be instructed in the procedures before they attempt them. Proper insertion just under the skin will facilitate removal. If infection develops after insertion, suitable treatment should be instituted. If infection persists, capsules should be removed. In the case of capsule expulsion, the expelled capsule must be replaced using a new sterile capsule, as contraceptive efficacy may be inadequate with fewer than six capsules. If infection is present, it should be treated and cured before capsule replacement. Removal should be done upon patient request, for medical indications, or at the end of 5 years of use, by personnel instructed in the removal technique. If the capsules were placed deeply, they may be harder to remove. The use of general anesthesia during removal should generally be avoided. Before initiating the removal procedure, all NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM capsules should be located via palpation. If all six capsules cannot be located by palpation, they may be localized by ultrasound (7 MHz), X-ray, or compression mammography. If all capsules cannot be removed at the first attempt, removal should be attempted later when the site has healed. Upon removal, NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM capsules should be disposed of in accordance with the Centers for Disease Control and Prevention guidelines for the handling of biohazardous waste. See also “WARNINGS,” “ADVERSE REACTIONS” and “INSTRUCTIONS FOR INSERTION AND REMOVAL—Removal Procedure.” Carbohydrate and Lipid Metabolism An altered glucose tolerance characterized by decreased insulin sensitivity following glucose loading has been found in some users of combination and progestin-only oral contraceptives. The effects of the NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM on carbohydrate metabolism appear to be minimal. In a study in which pretreatment serum-glucose levels were compared with levels after 1 and 2 years of NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM use, no statistically significant differences in mean serum-glucose levels were evident 2 hours after glucose loading. The clinical significance of these findings is unknown, but diabetic patients should be carefully observed while using the NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM. Women who are being treated for hyperlipidemias should be followed closely if they elect to use the NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM. Some progestins may elevate LDL levels and may render the control of hyperlipidemias more difficult. (See “WARNINGS,” A. 6.) Liver Function If jaundice develops in any women while using the NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM, consideration should be given to removing the capsules. Steroid hormones may be poorly metabolized in patients with impaired liver function. Fluid Retention Steroid contraceptives may cause some degree of fluid retention. They should be prescribed with caution, and only with careful monitoring, in patients with conditions which might be aggravated by fluid retention. Emotional Disorders Some cases of depression (including severe depression) have been reported in NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM users, although clinical studies have not demonstrated differences in the risk of depression among NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM users when compared with users of other hormonal contraceptives. Health-care professionals should be alert to the possibility that depression might be related to NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM use, and consideration should be given to removing NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM capsules in women who become significantly depressed. Women with a history of depression should be carefully observed and removal considered if depression recurs to a serious degree. Contact Lenses Contact-lens wearers who develop visual changes or changes in lens tolerance should be assessed by an ophthalmologist. Autoimmune Disease Autoimmune diseases such as scleroderma, systemic lupus erythematosus and rheumatoid arthritis occur in the general population and more frequently among women of childbearing age. There have been rare reports of various autoimmune diseases, including the above, in NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM users; however, the rate of reporting is significantly less than the expected incidence for these diseases. Studies have raised the possibility of developing antibodies against silicone-containing devices; however, the specificity and clinical relevance of these antibodies are unknown. While it is believed that the occurrence of autoimmune disease among NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM users is coincidental, health-care professionals should be alert to the earliest manifestations. Carcinogenesis See “WARNINGS” section. Pregnancy Pregnancy Category X. See “WARNINGS” section. Nursing Mothers Steroids are not considered the contraceptives of first choice for breast-feeding women. Levonorgestrel has been identified in the breast milk. The health of breast-fed infants whose mothers began using the NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM during the 5th to 7th week postpartum was evaluated; no significant effects were observed on the growth or development of infants who were followed to 12 months of age. No data are available on use in breast-feeding mothers earlier than this after parturition. Pediatric Use Safety and efficacy of the NORPLANT SYSTEM (levonorgestrel implants) have been established in women of reproductive age. Safety and efficacy are expected to be similar for postpubertal adolescents under 16 and users 16 and older. Use of this product before menarche is not indicated. Information for the Patient See Patient Labeling. Two copies of the Patient Labeling are included to help describe the characteristics of the NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM to the patient. One copy should be provided to the patient. Patients should also be advised that the Prescribing Information is available to them at their request. It is recommended that prospective users be fully informed about the risks and benefits associated with the use of the NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM, with other forms of contraception, and with no contraception at all. It is also recommended that prospective users be fully informed about the insertion and removal procedures. Health-care professionals may wish to obtain informed consent from all patients in light of the techniques involved with insertion and removal.

WARNINGS Warnings Based On Experience With Levonorgestrel-Containing Implants Insertion and Removal Complications A surgical incision is required to insert Jadelle® (levonorgestrel implants (unavailable in us)) implants. Complications related to insertion such as pain, edema and bruising may occur. Reports of infection (including cellulitis and abscess formation), blistering, ulcerations, sloughing, excessive scarring, phlebitis and hyperpigmentation have been reported at the insertion site for the six NORPLANT® implants and may occur with Jadelle® (levonorgestrel implants (unavailable in us)) implants. Arm pain, numbness and tingling may occur following the insertion and removal procedures. With NORPLANT® implants, there have been reports of nerve injury, most commonly associated with deep placement and removal. Expulsion of 1 or more NORPLANT® implants has been reported, more frequently when implant placement was shallow or too close to the incision or when infection was present. There have been reports of displacement (i.e. movement) of NORPLANT® implants, most of which involved minor changes in the positioning of the implants, but some have involved significant displacement of up to several inches. Some of these reported displacements have been associated with pain and difficult removal. Removal is also a surgical procedure and may take longer, be more difficult and/or cause more pain than insertion and may be associated with difficulty in locating implants. Additional incisions and/or office visits may be required. See also "PRECAUTIONS" and "ADVERSE REACTIONS". Ectopic Pregnancies Physicians should be alert to the possibility of an ectopic pregnancy among women using Jadelle® (levonorgestrel implants (unavailable in us)) implants who become pregnant or complain of lower abdominal pain. Ectopic pregnancies occurred with Jadelle® (levonorgestrel implants (unavailable in us)) implants at a rate less than 0.5 per 1,000 woman-years. This rate is significantly below the rate for US women of reproductive age who do not use contraception, which is 2.7 to 3.0 per 1,000 woman-years. However, any pregnancy that does occur with Jadelle® (levonorgestrel implants (unavailable in us)) use is more likely to be ectopic than a pregnancy occurring in a woman using no contraception. Interaction with Anti-Epileptic and other Drugs Jadelle® (levonorgestrel implants (unavailable in us)) implants are not recommended for women with epilepsy who use phenytoin, phenobarbital, carbamazepine or oxcarbazepine because Jadelle® (levonorgestrel implants (unavailable in us)) implants are likely to be less effective for these women. Although the large clinical trials of NORPLANT® and Jadelle® (levonorgestrel implants (unavailable in us)) implants excluded women with epilepsy, there are published studies showing decreased levonorgestrel concentrations in women using these antiepileptic drugs along with levonorgestrel-containing contraceptives. Women using rifampin have become pregnant during clinical trials of NORPLANT® implants. Rifampin decreases serum levels of progestins. (See also DRUG INTERACTIONS.) Menstrual changes Most women using Jadelle® (levonorgestrel implants (unavailable in us)) implants can expect some variation in menstrual bleeding patterns. Irregular menstrual bleeding, prolonged episodes of bleeding and spotting, heavy bleeding, intermenstrual spotting and amenorrhea occur in some women. Altered bleeding patterns associated with Jadelle® (levonorgestrel implants (unavailable in us)) implants could mask symptoms of cervical or endometrial cancer. See also ADVERSE REACTIONS, Menstrual Complaints. Because some levonorgestrel implant users have periods of amenorrhea, missed menstrual periods cannot serve as the only means of identifying early pregnancy. Pregnancy tests should be performed whenever a pregnancy is suspected. Six (6) weeks or more of amenorrhea after a pattern of regular menses may signal pregnancy. If pregnancy occurs, the implants must be removed. Weight Gain In clinical trials of Jadelle® (levonorgestrel implants (unavailable in us)) use, the average weight change over 5 years of use was a gain of about 9 pounds. Approximately 20% of women gained at least 10 pounds in the first year, and 50% gained at least 10 pounds by the end of the fifth year of use. Ovarian Cysts If follicular development occurs with Jadelle® (levonorgestrel implants (unavailable in us)) implants, atresia of the follicle may be delayed, and the follicle may continue to grow beyond the size it would attain in a normal cycle. In the majority of women, enlarged follicles (cysts) will spontaneously disappear and should not require surgery. Rarely, they may twist or rupture, sometimes causing abdominal pain, and surgical intervention may be required. Foreign-Body Carcinogenesis Rarely, cancers have occurred at the site of foreign-body intrusions or old scars. None have been reported in NORPLANT® users or in clinical trials with Jadelle® (levonorgestrel implants (unavailable in us)) implants. In rodents, which are highly susceptible to such cancers, the incidence decreases with decreasing size of the foreign body. Because of the resistance of human beings to these cancers and because of the small size of the implants, the risk to users of Jadelle® (levonorgestrel implants (unavailable in us)) implants is judged to be minimal. Thrombosis There have been reports of superficial phlebitis in clinical trials of Jadelle® (levonorgestrel implants (unavailable in us)) implant and postmarketing reports of thrombophlebitis and superficial phlebitis coincident with NORPLANT® implant use, more commonly in the arm of insertion. Some of these cases have been associated with trauma to that arm. There have also been reports of other thromboembolic disorders and cardiovascular problems (eg, stroke, myocardial infarction, pulmonary embolism, and deep-vein thrombosis) coincident with NORPLANT® implant use. See also Warnings Based On Experience With Combination (Progestin Plus Estrogen) Oral Contraceptives. Use Before or During Early Pregnancy There were no reports of congenital anomalies for the pregnancies that occurred during use of Jadelle® (levonorgestrel implants (unavailable in us)) implants in clinical trials. However, in postmarketing use of the NORPLANT® implants, there have been reports of congenital anomalies in the offspring of women who were using NORPLANT® implants inadvertently during early pregnancy. A cause and effect relationship has not been established. See also Warnings Based On Experience With Combination (Progestin Plus Estrogen) Oral Contraceptives. Idiopathic Intracranial Hypertension Idiopathic intracranial hypertension (pseudotumor cerebri, benign intracranial hypertension) is a disorder of unknown etiology, which is seen most commonly in obese females of reproductive age. It has been reported in NORPLANT® implant users; however, a causal relationship is unclear. A cardinal sign of idiopathic intracranial hypertension is papilledema; early symptoms may include headache associated with a change in the frequency, pattern, severity, or persistence. Of particular importance are visual disturbances and headaches that are unremitting in nature. Patients with these symptoms, particularly obese patients or those with recent weight gain, should be screened for papilledema and, if present, the patient should be referred to a neurologist for further diagnosis and care. Jadelle® (levonorgestrel implants (unavailable in us)) implants should be removed from patients experiencing this disorder. Warnings Based On Experience With Combination (Progestin Plus Estrogen) Oral Contraceptives Thromboembolic Disorders and Other Vascular Problems Thromboembolic and Thrombotic Disease: An increased risk of thromboembolic and thrombotic disease (pulmonary embolism, superficial venous thrombosis, and deep-vein thrombosis) has been found to be associated with the use of combination oral contraceptives. The relative risk has been estimated to be 4- to 11-fold higher for users than for nonusers. Cerebrovascular Disorders: Combination oral contraceptives have been shown to increase both the relative and attributable risks of cerebrovascular events (thrombotic and hemorrhagic strokes), although in general the risk is greatest among older ( > 35 years), hypertensive women who also smoke. Hypertension was found to be a risk factor for both users and nonusers for both types of strokes, and smoking interacted to increase the risk for hemorrhagic strokes. Myocardial Infarction: An increased risk of myocardial infarction has been attributed to combination oral contraceptive use. This is thought to be primarily thrombotic in origin and is related to the estrogen component of combination oral contraceptives. This increased risk occurs primarily in smokers or in women with other underlying risk factors for coronary artery disease, such as family history of coronary artery disease, hypertension, hypercholesterolemia, morbid obesity, and diabetes. The current relative risk of heart attack for combination oral contraceptive users has been estimated as 2 to 6 times the risk for nonusers. The absolute risk is very low for women under 30 years of age. Studies indicate a significant trend toward higher rates of myocardial infarctions and strokes with increasing doses of progestin in combination oral contraceptives. However, a recent study showed no increased risk of myocardial infarction associated with the past use of levonorgestrel-containing combination oral contraceptives. If thromboembolic disorders or cardiovascular problems occur in levonorgestrel implant users, the implants should be removed. Removal should also be considered in women who will be subjected to prolonged immobilization because of surgery or other illnesses. See also Warnings Based On Experience With Levonorgestrel-Containing Implants. Cigarette Smoking Cigarette smoking increases the risk of serious cardiovascular side effects from the use of combination oral contraceptives. This risk increases with age and with heavy smoking (15 or more cigarettes per day) and is quite marked in women over 35 years old who smoke. While this is believed to be an estrogen-related effect, it is not known whether a similar risk exists with progestin-only methods such as Jadelle® (levonorgestrel implants (unavailable in us)) implants. However, women who use Jadelle® (levonorgestrel implants (unavailable in us)) implants should be advised not to smoke. Elevated Blood Pressure Increased blood pressure has been reported in users of combination oral contraceptives. The prevalence of elevated blood pressure increases with long exposure. Physicians should be aware of the possibility of elevated blood pressure in individual patients using Jadelle® (levonorgestrel implants (unavailable in us)) implants. Use Before or During Early Pregnancy Extensive epidemiologic studies have revealed no increased risk of birth defects in women who have used oral contraceptives before pregnancy. Studies also do not suggest a teratogenic effect, particularly insofar as cardiac anomalies and limb-reduction defects are concerned, when oral contraceptives are taken inadvertently during early pregnancy. There is no evidence suggesting that the risk associated with levonorgestrel-containing implants is different from that of oral contraceptives. See also Warnings Based On Experience With Levonorgestrel-Containing Implants. Carcinoma Numerous epidemiologic studies have been performed to determine the incidence of breast, endometrial, ovarian, and cervical cancer in women using combination oral contraceptives. The risk of having breast cancer diagnosed may be slightly increased among current and recent users of combination oral contraceptives. However this excess risk appears to decrease over time after discontinuation of combination oral contraceptives, and by 10 years after cessation the increased risk disappears. The risk does not appear to increase with duration of use, and no consistent relationships have been found with dose or type of steroid. Most studies show a similar pattern of risk with combination oral contraceptive use regardless of a woman's reproductive history or her family breast cancer history. Some studies have found a small increase in risk for women who first use combination oral contraceptives before age 20. Breast cancers diagnosed in current or previous oral contraceptive users tend to be less clinically advanced than in nonusers. Women who currently have or have had breast cancer should not use hormonal contraceptives because breast cancer is usually a hormone-sensitive tumor. Some studies suggest that combination oral contraceptive use is associated with an increase in the risk of cervical intraepithelial neoplasia in some populations of women. There continues to be controversy about the extent to which such findings may be due to differences in sexual behavior and other factors. Despite the many studies of the relationship between combination oral contraceptive use and cervical cancers, a cause-and-effect relationship has not been established. Hepatic Tumors In some studies, hepatic adenomas have been associated with the use of combination oral contraceptives: the estimated incidence is about 3 occurrences per 100,000 users per year, and the risk increases after 4 or more years of use. Although benign, hepatic adenomas may rupture and cause death through intra-abdominal hemorrhage. The contribution of the progestin component of oral contraceptives to the development of hepatic adenomas is not known. Studies from Britain have shown an increased risk of developing hepatocellular carcinoma in long-term ( > 8 years) oral contraceptive users. However, these cancers are extremely rare in the US, and the attributable risk (the excess incidence) of liver cancers in oral contraceptive users approaches less than one per million users. Ocular Lesions There have been reports of retinal thrombosis associated with the use of oral contraceptives. Although it is believed that this adverse reaction is related to the estrogen component of oral contraceptives, Jadelle® (levonorgestrel implants (unavailable in us)) implants should be removed if there is unexplained partial or complete loss of vision, onset of proptosis or diplopia, papilledema, or retinal vascular lesions. Appropriate diagnostic and therapeutic measures should be undertaken immediately. Gallbladder Disease Some studies have reported an increased lifetime relative risk of gallbladder surgery in users of oral contraceptives and estrogens. More recent studies, however, have shown that the relative increased risk of developing gallbladder disease among oral contraceptive users may be minimal. The recent findings of minimal risk may be related to the use of oral contraceptive formulations containing lower doses of estrogens and progestins. PRECAUTIONS General Patients should be counseled that this product does not protect against HIV infection (AIDS) or other sexually transmitted diseases. Physical Examination and Follow-Up A complete medical history and physical examination should be undertaken before the implantation or reimplantation of Jadelle (levonorgestrel implants (unavailable in us)) implants and at least annually during their use. These physical examinations should include special reference to the implant site, blood pressure, breasts, abdomen and pelvic organs, including cervical cytology, and relevant laboratory tests. In case of undiagnosed, persistent, or recurrent abnormal vaginal bleeding, appropriate diagnostic measures should be conducted to rule out malignancy. Women with a strong family history of breast cancer or who have breast nodules should be monitored with particular care. Insertion To ensure that the woman is not pregnant at the time of implant placement and to assure contraceptive effectiveness during the first cycle of use, it is advisable that insertion be done during the first 7 days of the menstrual cycle or immediately following abortion. However, Jadelle® (levonorgestrel implants (unavailable in us)) implants may be inserted at any other time during the cycle, provided that the possibility of ovulation and conception prior to insertion is considered, pregnancy has been excluded, and a nonhormonal contraceptive method is used for at least 7 days following implant placement. If ovulation and conception have already occurred, pregnancy may be established in the month of insertion. It is strongly advised that all health-care professionals who insert and remove Jadelle® (levonorgestrel implants (unavailable in us)) implants be instructed in the procedures before they attempt them. A proper insertion just under the skin will facilitate removal. Proper insertion and removal should result in minimal scarring. If the implants are placed too deep, they may be more difficult to remove. Bruising may occur at the implant site during insertion or removal. There have also been reports of arm pain, numbness, and tingling following these procedures. In some women, hyperpigmentation occurs over the implantation site but it is usually reversible following removal. During postmarketing use of NORPLANT® implants, other cutaneous reactions that have been reported include blistering, ulcerations, and sloughing. See the detailed "Instructions for Insertion and Removal" section below. Infections Infection at the implant site, including cellulitis, has been uncommon. During clinical trials with the Jadelle® (levonorgestrel implants (unavailable in us)) implants, infection at the insertion site occurred in 0.4% of women Attention to aseptic technique and proper insertion and removal of Jadelle® (levonorgestrel implants (unavailable in us)) implants reduces the possibility of infection. If infection occurs, suitable treatment should be instituted. If infection persists, the implants should be removed. Expulsions and Displacement Expulsion of one or both implants is uncommon. It is more likely to occur when placement of the implants is extremely shallow, too close to the incision, or when infection is present. An expelled implant must be replaced with a new sterile implant. If infection is present, it should be resolved before another implant is inserted. Protection against pregnancy is likely to be inadequate with fewer than two implants. There have been reports of implant displacement (i.e., movement) with NORPLANT® implants, most of which involve minor changes in the position of the implants. However, infrequent reports of significant displacement (up to several inches) have been received. Some instances of displacement have been associated with pain or discomfort. When implant displacement occurs, the removal technique may have to be modified, for example, by an additional incision or visit. Removal Women should be advised that Jadelle® (levonorgestrel implants (unavailable in us)) implants can be removed for any reason whenever the woman wishes and must be removed by the end of five years. The removal should be done by personnel familiar with the removal techniques. Before initiation of the removal procedure, the two Jadelle® (levonorgestrel implants (unavailable in us)) implants should be located by palpation. If both implants cannot be located by palpation, they may be localized by ultrasound (7 MHz), X-ray, or compression mammography. If both implants cannot be removed at the first attempt, removal should be attempted later when the site has healed. Upon removal, Jadelle® (levonorgestrel implants (unavailable in us)) implants should be disposed of in accordance with the Centers for Disease Control and Prevention guidelines for the handling of biohazardous waste. Lipid and Carbohydrate Metabolism Serum lipoprotein levels were altered in three clinical studies involving 544 women using Jadelle (levonorgestrel implants (unavailable in us)) implants. Although these changes were statistically significant, all mean values remained within the normal ranges. The long-term clinical effects of these changes have not been determined. Women who are being treated for hyperlipidemias should be followed closely if they elect to use Jadelle® (levonorgestrel implants (unavailable in us)) implants. Changes in carbohydrate tolerance and insulin sensitivity following oral glucose loads have been reported in some studies among users of NORPLANT® implants and of Jadelle® (levonorgestrel implants (unavailable in us)) implants. These changes include modest elevations of serum insulin concentrations as well as increases in serum glucose levels. These changes were not associated with development of clinical or laboratory evidence of diabetes mellitus. While the clinical significance of these findings is unknown, diabetic patients should be carefully observed while using Jadelle® (levonorgestrel implants (unavailable in us)) implants. Liver Function If jaundice develops in any woman using Jadelle® (levonorgestrel implants (unavailable in us)) implants, consideration should be given to removing the implants. Steroid hormones may be poorly metabolized in patients with impaired liver function. Fluid Retention Steroid contraceptives may cause some degree of fluid retention. They should be prescribed with caution, and only with careful monitoring in patients with conditions that cause or might be aggravated by fluid retention. Emotional Disorders Consideration should be given to removing Jadelle® (levonorgestrel implants (unavailable in us)) implants in women who become significantly depressed, because depression may be drug related. Women with a history of depression should be carefully observed, and removal considered if depression recurs to a serious degree. Contact Lenses Contact lens wearers who develop visual changes or changes in lens tolerance should be assessed by an ophthalmologist. Autoimmune Disease Autoimmune diseases such as scleroderma, systemic lupus erythematosus, and rheumatoid arthritis occur in the general population and more frequently among women of childbearing age. There have been rare reports of various autoimmune diseases, including the above, in NORPLANT® implant users; however, the rate of reporting is significantly lower than the expected incidences for these diseases. Studies have raised the possibility of developing antibodies against silicone-containing devices; however, the specificity and clinical relevance of these antibodies are unknown. While it is believed that the occurrence of autoimmune diseases among NORPLANT® implant users is coincidental, health-care providers should be alert to the earliest manifestations of autoimmune disease in users of Jadelle® (levonorgestrel implants (unavailable in us)) implants. Carcinogenesis See "WARNINGS" section. Pregnancy See "WARNINGS"section. Nursing Mothers Hormonal contraceptives are not considered the contraceptives of first choice for breast-feeding women. Levonorgestrel has been identified in breast milk. When breast-feeding mothers used NORPLANT® implants beginning during the 5th to 7th week postpartum, no significant effects were observed on the growth or development of their infants who were followed up to 12 months of age. Pediatric Use Safety and efficacy of Jadelle® (levonorgestrel implants (unavailable in us)) implants have been established in women of reproductive age. Safety and efficacy are expected to be the same for postpubertal adolescents under the age of 16 and for users 16 years and older. Use of this product before menarche is not indicated. Geriatric Use This product has not been studied in women over 65 years of age and is not indicated in this population. Information for the Patient See "Patient Labeling." Two copies of the Patient Labeling are included. One copy should be provided to the patient. Patients should also be advised that the Prescribing Information is available to them at their request. It is recommended that prospective users be fully informed about the risks and benefits associated with the use of Jadelle® (levonorgestrel implants (unavailable in us)) implants compared to other forms of contraception, and with no contraception at all. It is also recommended that prospective users be fully informed about the insertion and removal procedures. Health-care providers may wish to obtain informed consent from all patients in light of the techniques involved with insertion and removal.