As with all progestin-only contraceptive products, be alert to the possibility of an ectopic pregnancy among women using NEXPLANON who become pregnant or complain of lower abdominal pain. Although ectopic pregnancies are uncommon among women using NEXPLANON, a pregnancy that occurs in a woman using NEXPLANON may be more likely to be ectopic than a pregnancy occurring in a woman using no contraception.
The use of combination hormonal contraceptives (progestin plus estrogen) increases the risk of vascular events, including arterial events (strokes and myocardial infarctions) or deep venous thrombotic events (venous thromboembolism, deep venous thrombosis, retinal vein thrombosis, and pulmonary embolism). NEXPLANON is a progestin-only contraceptive. It is unknown whether this increased risk is applicable to etonogestrel alone. It is recommended, however, that women with risk factors known to increase the risk of venous and arterial thromboembolism be carefully assessed.
There have been postmarketing reports of serious arterial thrombotic and venous thromboembolic events, including cases of pulmonary emboli (some fatal), deep vein thrombosis, myocardial infarction, and strokes, in women using etonogestrel implants. NEXPLANON should be removed in the event of a thrombosis.
Due to the risk of thromboembolism associated with pregnancy and immediately following delivery, NEXPLANON should not be used prior to 21 days postpartum. Women with a history of thromboembolic disorders should be made aware of the possibility of a recurrence.
Evaluate for retinal vein thrombosis immediately if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions.
Consider removal of the NEXPLANON implant in case of long-term immobilization due to surgery or illness.
If follicular development occurs, atresia of the follicle is sometimes delayed, and the follicle may continue to grow beyond the size it would attain in a normal cycle. Generally, these enlarged follicles disappear spontaneously. On rare occasion, surgery may be required.
Women who currently have or have had breast cancer should not use hormonal contraception because breast cancer may be hormonally sensitive [see Contraindications (4)]. Some studies suggest that the use of combination hormonal contraceptives might increase the incidence of breast cancer; however, other studies have not confirmed such findings.
Some studies suggest that the use of combination hormonal contraceptives is associated with an increase in the risk of cervical cancer or intraepithelial neoplasia. However, there is controversy about the extent to which these findings are due to differences in sexual behavior and other factors.
Women with a family history of breast cancer or who develop breast nodules should be carefully monitored.
Disturbances of liver function may necessitate the discontinuation of hormonal contraceptive use until markers of liver function return to normal. Remove NEXPLANON if jaundice develops.
Hepatic adenomas are associated with combination hormonal contraceptives use. An estimate of the attributable risk is 3.3 cases per 100,000 for combination hormonal contraceptives users. It is not known whether a similar risk exists with progestin-only methods like NEXPLANON.
The progestin in NEXPLANON may be poorly metabolized in women with liver impairment. Use of NEXPLANON in women with active liver disease or liver cancer is contraindicated [see Contraindications (4)].
In clinical studies, mean weight gain in U.S. non-radiopaque etonogestrel implant (IMPLANON) users was 2.8 pounds after one year and 3.7 pounds after two years. How much of the weight gain was related to the non-radiopaque etonogestrel implant is unknown. In studies, 2.3% of the users reported weight gain as the reason for having the non-radiopaque etonogestrel implant removed.
Women with a history of hypertension-related diseases or renal disease should be discouraged from using hormonal contraception. For women with well-controlled hypertension, use of NEXPLANON can be considered. Women with hypertension using NEXPLANON should be closely monitored. If sustained hypertension develops during the use of NEXPLANON, or if a significant increase in blood pressure does not respond adequately to antihypertensive therapy, NEXPLANON should be removed.
Studies suggest a small increased relative risk of developing gallbladder disease among combination hormonal contraceptive users. It is not known whether a similar risk exists with progestin-only methods like NEXPLANON.
Use of NEXPLANON may induce mild insulin resistance and small changes in glucose concentrations of unknown clinical significance. Carefully monitor prediabetic and diabetic women using NEXPLANON.
Women who are being treated for hyperlipidemia should be followed closely if they elect to use NEXPLANON. Some progestins may elevate LDL levels and may render the control of hyperlipidemia more difficult.
Women with a history of depressed mood should be carefully observed. Consideration should be given to removing NEXPLANON in patients who become significantly depressed.
In clinical trials with the non-radiopaque etonogestrel implant (IMPLANON), the etonogestrel levels in blood decreased below sensitivity of the assay by one week after removal of the implant. In addition, pregnancies were observed to occur as early as 7 to 14 days after removal. Therefore, a woman should re-start contraception immediately after removal of the implant if continued contraceptive protection is desired.
Hormonal 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. It is unknown if NEXPLANON causes fluid retention.
Contact lens wearers who develop visual changes or changes in lens tolerance should be assessed by an ophthalmologist.
There have been reports of broken or bent implants, which may be related to external forces (e.g., manipulation of the implant or contact sports) while in the patient’s arm. There have also been reports of migration of a broken implant fragment within the arm. Based on in vitro data, when an implant is broken or bent, the release rate of etonogestrel may be slightly increased.
When an implant is removed, it is important to remove it in its entirety [see Dosage and Administration (2.3)].
A woman who is using NEXPLANON should have a yearly visit with her healthcare professional for a blood pressure check and for other indicated health care.
Sex hormone-binding globulin concentrations may be decreased for the first six months after NEXPLANON insertion followed by gradual recovery. Thyroxine concentrations may initially be slightly decreased followed by gradual recovery to baseline.
The following adverse reactions reported with the use of hormonal contraception are discussed elsewhere in the labeling:
- Changes in Menstrual Bleeding Patterns [see Warnings and Precautions (5.2)]
- Ectopic Pregnancies [see Warnings and Precautions (5.3)]
- Thrombotic and Other Vascular Events [see Warnings and Precautions (5.4)]
- Liver Disease [see Warnings and Precautions (5.7)]
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 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.
|Adverse Reactions||All StudiesN = 942|
|Bleeding Irregularities *||11.1%|
|Emotional Lability †||2.3%|
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.
|Adverse Reactions||All StudiesN = 942|
|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.
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.
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.
|Type of Incorrect Insertion Event||Number of Events *||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 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.
|Removal Related Events||Number of Events *||Incidence per 1,000 Removals (95% CI)|
|Any Event †||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 ‡||6||1.4 (0.5-3.0)|
|Multiple Attempts Required||13||3.0 (1.6-5.1)|
|Other §||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.
|Patient Reported Adverse Reactions||At Insertion||After Removal|
|N *||Incidence per 1000 insertions (95% CI)||N *||Incidence per 1000 insertions (95% CI)|
|Any Event †||49||6.7 (4.9-8.8)||42‡||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 §||2||0.3 (0-1.0)||—||—|
|Other ¶||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.
Complications related to insertion or removal of the etonogestrel implants reported include: bruising, slight local irritation, pain or itching, fibrosis at the implant site, paresthesia or paresthesia-like events, scarring and abscess. Expulsion or migration of the implant has been reported, including to the chest wall. In some cases, implants have been found within the vasculature, including the pulmonary artery. Some cases of implants found within the pulmonary artery reported chest pain and/or respiratory disorders (such as dyspnea, cough, or hemoptysis); others have been reported as asymptomatic [see Warnings and Precautions (5.1)]. In-patient surgical interventions might be necessary when removing implants associated with complications.
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