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.

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

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

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)

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.