Nexplanon Drug Information

® is indicated for prevention of pregnancy in women of reproductive potential for up to 5 years. NEXPLANON is a progestin indicated for prevention of pregnancy in women of reproductive potential for up to 5 years.

Clinical Trials Experience Adverse reaction rates observed in the clinical trials of

a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice, because clinical trials are conducted under widely varying conditions. In clinical trials of three years duration involving 942 women who were evaluated for safety, change in menstrual bleeding patterns (irregular menses) was the most common adverse reaction causing discontinuation of use of the non-radiopaque etonogestrel implant (IMPLANON) (11.1% of women). Adverse reactions that resulted in a rate of discontinuation of ≥1% are shown in Table 3. Table 3: Adverse Reactions Leading to Discontinuation of Treatment in 1% or More of Subjects in 3-Year Clinical Trials of the Non-Radiopaque Etonogestrel Implant (IMPLANON) Adverse Reactions All Studies N = 942 Bleeding Irregularities Includes "frequent", "heavy", "prolonged", "spotting", and other patterns of bleeding irregularity. 11.1% Emotional Lability Among US subjects (N=330), 6.1% experienced emotional lability that led to discontinuation. 2.3% Weight Increase 2.3% Headache 1.6% Acne 1.3% Depression Among US subjects (N=330), 2.4% experienced depression that led to discontinuation. 1.0% Other adverse reactions that were reported by at least 5% of subjects in the non-radiopaque etonogestrel implant clinical trials are listed in Table 4. Table 4: Common Adverse Reactions Reported by ≥5% of Subjects in 3-Year Clinical Trials with the Non-Radiopaque Etonogestrel Implant (IMPLANON) Adverse Reactions All Studies N = 942 Headache 24.9% Vaginitis 14.5% Weight increase 13.7% Acne 13.5% Breast pain 12.8% Abdominal pain 10.9% Pharyngitis 10.5% Leukorrhea 9.6% Influenza-like symptoms 7.6% Dizziness 7.2% Dysmenorrhea 7.2% Back pain 6.8% Emotional lability 6.5% Nausea 6.4% Pain 5.6% Nervousness 5.6% Depression 5.5% Hypersensitivity 5.4% Insertion site pain 5.2% In a clinical trial of NEXPLANON, in which investigators were asked to examine the implant site after insertion, implant site reactions were reported in 8.6% of women. Erythema was the most frequent implant site complication, reported during or shortly after insertion, occurring in 3.3% of subjects.

Additionally, hematoma (3.0%), bruising (2.0%), pain (1.0%), and swelling (0.7%) were reported. In a separate clinical trial to assess contraceptive efficacy and safety of NEXPLANON beyond 3 years, up to 5 years, where a total of 498 women were evaluated for safety, a similar adverse reaction profile was observed as in Years 1 through 3.The most frequently reported adverse reaction >5% related to NEXPLANON was intermenstrual bleeding (5.4%), Changes in menstrual bleeding patterns were the most frequently reported adverse reaction leading to discontinuation occurring in 4.0% of participants.

Postmarketing Experience Adverse Reactions and Events from Postmarketing Study Nexplanon Observational Risk

Assessment Study (NORA) A postmarketing prospective active surveillance study was conducted among 7,364 patients in the United States to characterize the frequency of insertion-, localization-, and removal-related events. Implant Insertion Insertion difficulty or an insertion-related event occurred in 2.6% of the study participants. The overall incidence of incorrect insertion (unrecognized non-insertion, partial insertion, and deep insertion), reported by healthcare professionals was 12.6 per 1,000 insertions (95% CI, 10.2, 15.5). Table 5 summarizes the types and frequencies of these incorrect insertions.

Table 5: Incorrect Insertion Types and Incidence Reported by Healthcare Professionals Type of Incorrect Insertion Event Number of Events Total Insertion Procedures = 7,364 Incidence per 1,000 Insertions (95% CI) (Initially) Unrecognized Non-insertions 1 0.1 (0.0-0.8) Partial Insertions 27 3.7 (2.4-5.3) Deep Insertions 65 8.8 (6.8-11.2) Injury to nerve or blood vessel 1 0.1 (0.0-0.8) Implant located within muscle 2 0.3 (0.0-1.0) Implant located adjacent to fascial tissue 56 7.6 (5.8-9.9) Implant not palpable 6 0.8 (0.3-1.8) Implant Removal Implant removal information from both healthcare professionals and patients was collected for 5,159 patients (70% of the study population). Of these patients, data were available from healthcare professionals regarding 4,373 removal procedures. Healthcare professionals reported removal-related difficulties or complications in 1.5% of removal procedures. Table 6 provides a summary.

Table 6: Removal-related Events Reported by Healthcare Professionals Removal Related Events Number of Events Total Removal Procedures: N= 4,373 Incidence per 1,000 Removals (95% CI) Any Event Limited to one event per removal procedure 60 13.7 (10.5-17.6) Encased in Fibrotic Tissue 29 6.6 (4.4-9.5) Implant Too Deep 11 2.5 (1.3-4.5) Implant Migrated Only local migrations within the arm reported 6 1.4 (0.5-3.0) Multiple Attempts Required 13 3.0 (1.6-5.1) Other Other included fragmented or bent implants, patient-related issues, wound care required, two incisions required, and difficulty identifying end of device. 14 3.2 (1.8-5.4) At the time of implant removal, eighteen implants (0.4% of all localizations or removals) were not palpable by the healthcare professionals. Of these eighteen, eleven were localized and removed, and one was localized but left in situ. Removal was not attempted for six non-palpable implants due to underlying health conditions, administrative problems, or unspecified reasons.

There were no reports of implants having migrated more than a few centimeters from the insertion site and no reports of implants localized at a site other than the arm. No neurovascular injuries were reported by healthcare professionals. Adverse Reactions Reported by Patients Table 7 provides a summary of adverse reactions reported by patients at the time of implant insertion and after removal.

Table 7: Adverse Reactions Reported by Patients at Implant Insertion and after Removal Patient Reported Adverse Reactions At Insertion After Removal N Total Insertion Procedures: N = 7,364 Incidence per 1000 insertions (95% CI) N Incidence per 1000 insertions (95% CI) Any Event Limited to one event per woman 49 6.7 (4.9-8.8) 42 Based on 3,447 questionnaires 5.7 (4.1-7.7) Pins and Needles/Numbness (arm/hand/fingers) 17 2.3 (1.4-3.7) 24 3.3 (2.1-4.9) Severe Pain 10 1.4 (0.7-2.5) 11 1.5 (0.8-2.7) Altered Strength/Movement 3 0.4 (0.1-1.2) 8 1.1 (0.5-2.1) Injury to Blood Vessels or Blood Clots in Arm No blood clots were observed during the study 2 0.3 (0-1.0) -- -- Other “Other” included localized or insertion site pain, soreness, tenderness, dermatological changes, itching, bruising, and infection, local migrations within the arm, and physical damage to the implant (e.g., fractured or bent implant). 22 3.0 (1.9-4.5) 18 2.4 (1.5-3.9) In summary, this prospective active surveillance study showed that the frequency of insertion-, localization-, and removal-related events is consistent with results previously reported from clinical trials. Adverse Reactions from Postmarketing Spontaneous Reports The following additional adverse reactions have been identified during post-approval use of IMPLANON and NEXPLANON. It is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure because these reactions are reported voluntarily from a population of uncertain size. Gastrointestinal disorders: constipation, diarrhea, flatulence, vomiting.

General disorders and administration site conditions: edema, fatigue, implant site reaction, pyrexia. Immune system disorders: anaphylactic reactions. Infections and infestations: rhinitis, urinary tract infection.

Investigations: clinically relevant rise in blood pressure, weight decreased. Metabolism and nutrition disorders: increased appetite. Musculoskeletal and connective tissue disorders: arthralgia, musculoskeletal pain, myalgia.

Nervous system disorders: convulsions, migraine, somnolence. Pregnancy, puerperium and perinatal conditions: ectopic pregnancy. Psychiatric disorders: anxiety, insomnia, libido decreased.

Renal and urinary disorders: dysuria. Reproductive system and breast disorders: breast discharge, breast enlargement, ovarian cyst, pruritus genital, vulvovaginal discomfort. Skin and subcutaneous tissue disorders: angioedema, aggravation of angioedema and/or aggravation of hereditary angioedema, alopecia, chloasma, hypertrichosis, pruritus, rash, seborrhea, urticaria.

Vascular disorders: hot flush. Reported complications related to insertion or removal of the etonogestrel implants include vasovagal reactions (e.g., hypotension, dizziness, or syncope), bruising, slight local irritation, pain, itching, fibrosis at the implant site, paresthesia or paresthesia-like events, scarring, and abscesses. Implant expulsions and migrations also have been reported.

In some cases, implants have migrated to the chest wall or into the vasculature, including the pulmonary artery. Some cases of implants migrating to the pulmonary artery presented with symptoms of chest pain and/or respiratory disorders (e.g., dyspnea, cough, or hemoptysis); other cases have been reported as asymptomatic. In-patient surgical interventions might be necessary when removing implants associated with complications .

Effects of Other Drugs on Hormonal Contraceptives Substances decreasing the plasma concentrations

of hormonal contraceptives (HCs) and potentially diminishing the efficacy of HCs: Drugs or herbal products that induce certain enzymes, including cytochrome P450 3A4 (CYP3A4), may decrease the plasma concentrations of HCs and potentially diminish the effectiveness of HCs or increase breakthrough bleeding. Some drugs or herbal products that may decrease the effectiveness of HCs include efavirenz, phenytoin, barbiturates, carbamazepine, bosentan, felbamate, griseofulvin, oxcarbazepine, rifampicin, topiramate, rifabutin, rufinamide, aprepitant, and products containing St. John's wort.

Interactions between HCs and other drugs may lead to breakthrough bleeding and/or contraceptive failure. Counsel women to use an alternative non-hormonal method of contraception or a back-up method when enzyme inducers are used with HCs, and to continue back-up non-hormonal contraception for 28 days after discontinuing the enzyme inducer to ensure contraceptive reliability. Substances increasing the plasma concentrations of HCs: Co-administration of certain HCs and strong or moderate CYP3A4 inhibitors such as itraconazole, voriconazole, fluconazole, grapefruit juice, or ketoconazole may increase the serum concentrations of progestins, including etonogestrel.

Human Immunodeficiency Virus (HIV)/Hepatitis C Virus (HCV) protease inhibitors and non-nucleoside reverse transcriptase inhibitors: Significant changes (increase or decrease) in the plasma concentrations of progestin have been noted in cases of co-administration with HIV protease inhibitors (decrease or increase )/HCV protease inhibitors (decrease ) or with non-nucleoside reverse transcriptase inhibitors (decrease or increase ). These changes may be clinically relevant in some cases. Consult the prescribing information of anti-viral and anti-retroviral concomitant medications to identify potential interactions.

Effects of Hormonal Contraceptives on Other Drugs Hormonal contraceptives may affect the

metabolism of other drugs. Consequently, plasma concentrations may either increase (for example, cyclosporine) or decrease (for example, lamotrigine). Consult the labeling of all concurrently-used drugs to obtain further information about interactions with hormonal contraceptives or the potential for enzyme alterations.

Pregnancy Risk Summary NEXPLANON is contraindicated during pregnancy because there is no need for pregnancy prevention in a woman who is already pregnant . Epidemiologic studies and meta-analyses have not shown an increased risk of genital or non-genital birth defects (including cardiac anomalies and limb-reduction defects) following maternal exposure to low dose CHCs prior to conception or during early pregnancy. No adverse development outcomes were observed in pregnant rats and rabbits with the administration of etonogestrel during organogenesis at doses of 315 or 781 times the anticipated human dose (60 µg/day) (see Data ). NEXPLANON should be removed if maintaining a pregnancy. Data Animal Data Teratology studies have been performed in rats and rabbits using oral administration up to 315 and 781 times the human etonogestrel dose (based upon body surface) and revealed no evidence of fetal harm due to etonogestrel exposure.

Pediatric Use The safety and effectiveness of NEXPLANON have been established in women of reproductive potential. Safety and effectiveness of NEXPLANON are expected to be the same in postpubertal adolescents as in adult women. NEXPLANON is not indicated before menarche.

should not be used in women who have Known or suspected pregnancy Current or past history of thrombosis or thromboembolic disorders Liver tumors, benign or malignant, or active liver disease Undiagnosed abnormal uterine bleeding Known or suspected breast cancer, personal history of breast cancer, or other progestin-sensitive cancer, now or in the past Allergic reaction to any of the components of NEXPLANON Known or suspected pregnancy. Current or past history of thrombosis or thromboembolic disorders. Liver tumors, benign or malignant, or active liver disease.

Undiagnosed abnormal uterine bleeding. Known or suspected breast cancer, personal history of breast cancer, or other progestin-sensitive cancer, now or in the past. Allergic reaction to any of the components of NEXPLANON.

Overdosage may result if more than one implant is inserted. In case of suspected overdose, the implant should be removed.