ParaGard T 380A

ADVERSE REACTIONS The most serious adverse events associated with intrauterine contraception are discussed in WARNINGS and PRECAUTIONS . These include: Intrauterine pregnancy Pelvic infection Septic abortion Perforation Ectopic pregnancy Embedment Table 2 shows discontinuation rates from two clinical studies by adverse event and year. Table 2. Summary of Rates (No. per 100 Subjects) by Year for Adverse Events Causing Discontinuation Adverse Event Year 1 2 3 4 5 6 7 8 9 10 Pregnancy 0.7 0.3 0.6 0.2 0.3 0.2 0.0 0.4 0.0 0.0 Expulsion 5.7 2.5 1.6 1.2 0.3 0.0 0.6 1.7 0.2 0.4 Bleeding/Pain 11.9 9.8 7.0 3.5 3.7 2.7 3.0 2.5 2.2 3.7 Other Medical Event 2.5 2.1 1.6 1.7 0.1 0.3 1.0 0.4 0.7 0.3 No. of Women at Start of Year 4932 3149 2018 1121 872 621 563 483 423 325 *Rates were calculated by weighting the annual rates by the number of subjects starting each year for each of the Population Council (3,536 subjects) and the World Health Organization (1,396 subjects) trials. The following adverse events have also been observed. These are listed alphabetically and not by order of frequency or severity. Anemia Menstrual flow, prolonged Backache Menstrual spotting Dysmenorrhea Pain and cramping Dyspareunia Urticarial allergic skin reaction Expulsion, complete or partial Vaginitis Leukorrhea

CONTRAINDICATIONS ParaGard ® should not be placed when one or more of the following conditions exist: Pregnancy or suspicion of pregnancy Abnormalities of the uterus resulting in distortion of the uterine cavity Acute pelvic inflammatory disease, or current behavior suggesting a high risk for pelvic inflammatory disease Postpartum endometritis or postabortal endometritis in the past 3 months Known or suspected uterine or cervical malignancy Genital bleeding of unknown etiology Mucopurulent cervicitis Wilson’s disease Allergy to any component of ParaGard ® A previously placed IUD that has not been removed

DESCRIPTION ParaGard ® T 380A Intrauterine Copper Contraceptive (ParaGard ® ) is a T-shaped intrauterine device (IUD), measuring 32 mm horizontally and 36 mm vertically, with a 3 mm diameter bulb at the tip of the vertical stem. A monofilament polyethylene thread is tied through the tip, resulting in two white threads, each at least 10.5 cm in length, to aid in detection and removal of the device. The T-frame is made of polyethylene with barium sulfate to aid in detecting the device under x-ray. ParaGard ® also contains copper: approximately 176 mg of wire coiled along the vertical stem and a 68.7 mg collar on each side of the horizontal arm. The total exposed copper surface area is 380 ± 23 mm 2 . One ParaGard ® weighs less than one (1) gram. No component of ParaGard ® or its packaging contains latex. ParaGard ® is packaged together with an insertion tube and solid white rod in a Tyvek ® polyethylene pouch that is then sterilized. A moveable flange on the insertion tube aids in gauging the depth of insertion through the cervical canal and into the uterine cavity. Illustration of ParaGard and its packaging

INDICATIONS AND USAGE ParaGard ® is indicated for intrauterine contraception for up to 10 years. The pregnancy rate in clinical studies has been less than 1 pregnancy per 100 women each year. Table 1: Percentage of women experiencing an unintended pregnancy during the first year of typical use and first year of perfect use of contraception and the percentage continuing use at the end of the first year: United States Footnotes to Table 1 Source: Trussel J, Contraceptive efficacy. In Hatcher RA, Trussel J, Stewart F, Cates W, Stewart GK, Kowal D, Guest F, Contraceptive Technology: Seventeenth Revised Edition. New York NY: Irvington Publishers, 1998. % of Women Experiencing an Accidental Pregnancy within the First Year of Use % of Women Continuing Use at One Year 3 Method (1) Typical Use 1 (2) Perfect Use 2 (3) (4) Chance 4 85 85 Spermicides 5 26 6 40 Periodic Abstinence Calendar Ovulation Method Sympto-thermal 6 Post-ovulation 25 9 3 2 1 63 Cap 7 Parous women Nulliparous women 40 20 26 9 42 56 Sponge Parous women Nulliparous women 40 20 20 9 42 56 Diaphragm 7 20 6 56 Withdrawal 19 4 Condom 8 Female (Reality) Male 21 14 5 3 56 61 Pill Progestin only Combined 5 0.5 0.1 71 IUD Progesterone T Copper T 380A LNg 20 2.0 0.8 0.1 1.5 0.6 0.1 81 78 81 Depo Provera 0.3 0.3 70 Norplant and Norplant-2 0.05 0.05 88 Female sterilization 0.5 0.5 100 Male sterilization 0.15 0.10 100 Emergency Contraceptive Pills: Treatment initiated within 72 hours after unprotected intercourse reduces the risk of pregnancy by at least 75%. 9 Lactational Amenorrhea Method : LAM is a highly effective temporary method of contraception. 10 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. 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 reason. Among couples attempting to avoid pregnancy, the percentage who continue to use a method for one year. 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 percentage who would become pregnant within one year among women now relying on reversible methods of contraception if they abandoned contraception altogether. Foams, creams, gels, vaginal suppositories, and vaginal film. Cervical mucus (ovulation) method supplemented by calendar in the pre-ovulatory and basal body temperature in the post-ovulatory phases. With spermicidal cream or jelly. Without spermicides. The treatment schedule is one dose within 72 hours after unprotected intercourse, and a second dose 12 hours after the first dose. Preven is the only dedicated product specifically marketed for emergency contraception. The Food and Drug Administration has also declared the following brands of oral contraceptive to be safe and effective for emergency contraception: Ovral (1 dose is 2 white pills), Alesse (1 dose is 5 pink pills), Nordette or Levlen (1 dose is 4 light-orange pills), Lo/Ovral (1 dose is 4 white pills), Triphasil or Tri-Levlen (1 dose is 4 yellow pills). 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.

WARNINGS 1. Intrauterine Pregnancy If intrauterine pregnancy occurs with ParaGard ® in place and the string is visible, ParaGard ® should be removed because of the risk of spontaneous abortion, premature delivery, sepsis, septic shock, and, rarely, death. Removal may be followed by pregnancy loss. If the string is not visible, and the woman decides to continue her pregnancy, check if the ParaGard ® is in her uterus (for example, by ultrasound). If ParaGard ® is in her uterus, warn her that there is an increased risk of spontaneous abortion and sepsis, septic shock, and rarely, death. 1 In addition, the risk of premature labor and delivery is increased. 1 Human data about risk of birth defects from copper exposure are limited. However, studies have not detected a pattern of abnormalities, and published reports do not suggest a risk that is higher than the baseline risk for birth defects. 2. Ectopic Pregnancy Women who become pregnant while using ParaGard ® should be evaluated for ectopic pregnancy. A pregnancy that occurs with ParaGard ® in place is more likely to be ectopic than a pregnancy in the general population. However, because ParaGard ® prevents most pregnancies, women who use ParaGard ® have a lower risk of an ectopic pregnancy than sexually active women who do not use any contraception. 2-3 3. Pelvic Infection Although pelvic inflammatory disease (PID) in women using IUDs is uncommon, IUDs may be associated with an increased relative risk of PID compared to other forms of contraception and to no contraception. The highest incidence of PID occurs within 20 days following insertion. Therefore, the visit following the first post-insertion menstrual period is an opportunity to assess the patient for infection, as well as to check that the IUD is in place. (See INSTRUCTIONS FOR USE , Continuing Care .) Since pelvic infection is most frequently associated with sexually transmitted organisms, IUDs are not recommended for women at high risk for sexual infection. Prophylactic antibiotics at the time of insertion do not appear to lower the incidence of PID. 4 PID can have serious consequences, such as tubal damage (leading to ectopic pregnancy or infertility), hysterectomy, sepsis, and, rarely, death. It is therefore important to promptly assess and treat any woman who develops signs or symptoms of PID. Guidelines for treatment of PID are available from the Centers for Disease Control and Prevention (CDC), Atlanta, Georgia at www.cdc.gov or 1-800-311-3435. Antibiotics are the mainstay of therapy. Most healthcare professionals also remove the IUD. The significance of actinomyces-like organisms on Papanicolaou smear in an asymptomatic IUD user is unknown, 5-6 and so this finding alone does not always require IUD removal and treatment. However, because pelvic actinomycosis is a serious infection, a woman who has symptoms of pelvic infection possibly due to actinomyces should be treated and have her IUD removed. 4. Immunocompromise Women with AIDS should not have IUDs inserted unless they are clinically stable on antiretroviral therapy. Limited data suggest that asymptomatic women infected with human immunodeficiency virus may use intrauterine devices. Little is known about the use of IUDs in women who have illnesses causing serious immunocompromise. Therefore these women should be carefully monitored for infection if they choose to use an IUD. The risk of pregnancy should be weighed against the theoretical risk of infection. 5. Embedment Partial penetration or embedment of ParaGard ® in the myometrium can make removal difficult. In some cases, surgical removal may be necessary. 6. Perforation Partial or total perforation of the uterine wall or cervix may occur rarely during placement, although it may not be detected until later. Spontaneous migration has also been reported. If perforation does occur, remove ParaGard ® promptly, since the copper can lead to intraperitoneal adhesions. Intestinal penetration, intestinal obstruction, and/or damage to adjacent organs may result if an IUD is left in the peritoneal cavity. Pre-operative imaging followed by laparoscopy or laparotomy is often required to remove an IUD from the peritoneal cavity. 7. Expulsion Expulsion can occur, usually during the menses and usually in the first few months after insertion. There is an increased risk of expulsion in the nulliparous patient. If unnoticed, an unintended pregnancy could occur. 8. Wilson’s Disease Theoretically, ParaGard ® can exacerbate Wilson’s disease, a rare genetic disease affecting copper excretion.

CLINICAL PHARMACOLOGY The contraceptive effectiveness of ParaGard ® is enhanced by copper continuously released into the uterine cavity. Mechanism(s) by which copper enhances contraceptive efficacy include interference with sperm transport and fertilization of an egg, and possibly prevention of implantation.

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ParaGard T 380A Copper COPPER COPPER POLYETHYLENE GLYCOL, UNSPECIFIED BARIUM SULFATE

NDA018680

ParaGard T 380A

Copper

51285-204

HUMAN PRESCRIPTION DRUG

INTRAUTERINE

Package/Label Display Panel ParaGard® T380A Intrauterine Copper Contraceptive Single Carton ParaGard® T380A Intrauterine Copper Contraceptive Single Carton Text TEVA Women’s Health TEVA WOMEN’S HEALTH, INC. Subsidiary of TEVA PHARMACEUTICALS USA, INC. North Wales, PA 19454 1 UNIT PARAGARD ® T380A intrauterine copper contraceptive NDC 51285- 204 -01 Each unit wound with approximately 176 mg of copper wire. In addition, a single copper sleeve is swaged on each of the two transverse arms. Each sleeve contains approximately 68.7 mg of copper. The total surface area of copper on the device is 380 ± 23mm 2 . IMPORTANT: To be inserted in the uterus only by a licensed clinician or under the supervision of a physician. See detailed instructions for use. NOTE : A Patient Package Insert is provided with each unit. Please ensure that this package insert is provided to the patient. Review patient brochure with each patient before insertion. Store at controlled room temperature: 59° to 86°F (15° to 30°C) TEVA WOMEN’S HEALTH, INC., Subsidiary of TEVA PHARMACEUTICALS USA, INC., North Wales, PA 19454

P/N 1017005 Rev. 9/2014 Rx only PRESCRIBING INFORMATION ParaGard ® T 380A Intrauterine Copper Contraceptive Patients should be counseled that this product does not protect against HIV infection (AIDS) and other sexually transmitted diseases. ParaGard ® T 380A Intrauterine Copper Contraceptive should be placed and removed only by healthcare professionals who are experienced with these procedures.

1. Information for patients Before inserting ParaGard ® discuss the Patient Package Insert with the patient, and give her time to read the information. Discuss any questions she may have concerning ParaGard ® as well as other methods of contraception. Instruct her to promptly report symptoms of infection, pregnancy, or missing strings.

REFERENCES Tatum HJ, Schmidt FH, Jain AK. Management and outcome of pregnancies associated with the Copper T intrauterine contraceptive device. Am J Obstet Gynecol. 1976;126:869-879. Sivin I. Dose- and age-dependent ectopic pregnancy risks with intrauterine contraception. Obstet Gynecol. 1991;78:291-298. Franks AL, Beral V, Cates W Jr, Hogue CJR. Contraception and ectopic pregnancy risk. Am J Obstet Gynecol. 1990;163:1120-1123. Grimes DA, Schulz KF. Prophylactic antibiotics for intrauterine device insertion: a meta-analysis of the randomized controlled trials. Contraception. 1999;60:57-63. Lippes J. Pelvic actinomycosis: a review and preliminary look at prevalence. Am J Obstet Gynecol. 1999;180:265-269. Petitti DB, Yamamoto D, Morgenstern N. Factors associated with actinomyces-like organisms on Papanicolaou smear in users of intrauterine contraceptive devices. Am J Obstet Gynecol. 1983;145:338-341. Grimes D, Schulz K, van Vliet H, Stanwood N. Immediate post-partum insertion of intrauterine devices: a Cochrane review. Hum Reprod. 2002;17:549-554. Cole LP, Edelman DA, Potts DM, Wheeler RG, Laufe LE. Postpartum insertion of modified intrauterine devices. J Reprod Med. 1984;29:677-682. Grimes DA, Schulz KF, Stanwood N. Immediate post-abortal insertion of intrauterine devices. (Cochrane Review). In: The Cochrane Library , Issue 2, 2003. Oxford: Update Software. Hess T, Stepanow B, Knopp MV. Magnetic resonance imaging: safety of intrauterine contraceptive devices during MR imaging. Eur Radiol. 1996;6:66-68. Mark AS, Hricak H. Intrauterine devices. MR imaging. Radiology. 1987;162:311-314. Heick A., Espersen T., Pedersen HL, Raahauge J: Is diathermy safe in women with copper-bearing IUDs? Acta Obstet Gynecol Scand . 1991;70(2):153-5. Rodrigues da Cunha AC, Dorea JG, Cantuaria AA. Intrauterine device and maternal copper metabolism during lactation. Contraception 2001;63:37-9.

HOW SUPPLIED ParaGard ® is available in cartons of 1 (one) sterile unit (NDC 51285-204-01). Each ParaGard ® is packaged together with an insertion tube and solid white rod in a Tyvek ® polyethylene pouch.

PRECAUTIONS Patients should be counseled that this product does not protect against HIV infection (AIDS) and other sexually transmitted diseases. 1. Information for patients Before inserting ParaGard ® discuss the Patient Package Insert with the patient, and give her time to read the information. Discuss any questions she may have concerning ParaGard ® as well as other methods of contraception. Instruct her to promptly report symptoms of infection, pregnancy, or missing strings. 2. Insertion precautions, continuing care, and removal. (See INSTRUCTIONS FOR USE .) 3. Vaginal bleeding In the 2 largest clinical trials with ParaGard ® (see ADVERSE REACTIONS , Table 2), menstrual changes were the most common medical reason for discontinuation of ParaGard ® . Discontinuation rates for pain and bleeding combined are highest in the first year of use and diminish thereafter. The percentage of women who discontinued ParaGard ® because of bleeding problems or pain during these studies ranged from 11.9% in the first year to 2.2 % in year 9. Women complaining of heavy vaginal bleeding should be evaluated and treated, and may need to discontinue ParaGard ® . (See ADVERSE REACTIONS .) 4. Vasovagal reactions, including fainting Some women have vasovagal reactions immediately after insertion. Hence, patients should remain supine until feeling well and should be cautious when getting up. 5. Expulsion following placement after a birth or abortion ParaGard ® has been placed immediately after delivery, although risk of expulsion may be higher than when ParaGard ® is placed at times unrelated to delivery. 7 However, unless done immediately postpartum, insertion should be delayed to the second postpartum month because insertion during the first postpartum month (except for immediately after delivery) has been associated with increased risk of perforation. 8 ParaGard ® can be placed immediately after abortion, although immediate placement has a slightly higher risk of expulsion than placement at other times. 9 Placement after second trimester abortion is associated with a higher risk of expulsion than placement after the first trimester abortion. 9 6. Magnetic resonance imaging (MRI) Limited data suggest that MRI at the level of 1.5 Tesla is acceptable in women using ParaGard ® . One study examined the effect of MRI on the CU-7 ® Intrauterine Copper Contraceptive and Lippes Loop™ intrauterine devices. Neither device moved under the influence of the magnetic field or heated during the spin-echo sequences usually employed for pelvic imaging. 10 An in vitro study did not detect movement or temperature change when ParaGard ® was subjected to MRI. 11 7. Medical diathermy Theoretically, medical (non-surgical) diathermy (short-wave and microwave heat therapy) in a patient with a metal-containing IUD may cause heat injury to the surrounding tissue. However, a small study of eight women did not detect a significant elevation of intrauterine temperature when diathermy was performed in the presence of a copper IUD. 12 8. Pregnancy ParaGard ® is contraindicated during pregnancy. (See CONTRAINDICATIONS and WARNINGS .) 9. Nursing mothers Nursing mothers may use ParaGard ® . No difference has been detected in concentration of copper in human milk before and after insertion of copper IUDs. The literature is conflicting, but limited data suggest that there may be an increased risk of perforation and expulsion if a woman is lactating. 13 10. Pediatric use ParaGard ® is not indicated before menarche. Safety and efficacy have been established in women over 16 years old.