Prescription Drug Information: Nexplanon (Page 4 of 7)

5.8 Weight Gain

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.

5.9 Elevated Blood Pressure

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.

5.10 Gallbladder Disease

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.

5.11 Carbohydrate and Lipid Metabolic Effects

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.

5.12 Depressed Mood

Women with a history of depressed mood should be carefully observed. Consideration should be given to removing NEXPLANON in patients who become significantly depressed.

5.13 Return to Ovulation

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.

5.14 Fluid Retention

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.

5.15 Contact Lenses

Contact lens wearers who develop visual changes or changes in lens tolerance should be assessed by an ophthalmologist.

5.16 Broken or Bent Implant

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)].

5.17 Monitoring

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.

5.18 Drug-Laboratory Test Interactions

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.

6 ADVERSE REACTIONS

The following adverse reactions reported with the use of hormonal contraception are discussed elsewhere in the labeling:

6.1 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 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 Clinical Trials of the Non-Radiopaque Etonogestrel Implant (IMPLANON)
Adverse Reactions All StudiesN = 942
*
Includes “frequent”, “heavy”, “prolonged”, “spotting”, and other patterns of bleeding irregularity.
Among US subjects (N=330), 6.1% experienced emotional lability that led to discontinuation.
Among US subjects (N=330), 2.4% experienced depression that led to discontinuation.
Bleeding Irregularities * 11.1%
Emotional Lability 2.3%
Weight Increase 2.3%
Headache 1.6%
Acne 1.3%
Depression 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 Clinical Trials with the Non-Radiopaque Etonogestrel Implant (IMPLANON)
Adverse Reactions All StudiesN = 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.

6.2 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 * Incidence per 1,000 Insertions (95% CI)
*
Total Insertion Procedures = 7,364
(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 * Incidence per 1,000 Removals (95% CI)
*
Total Removal Procedures: N= 4,373
Limited to one event per removal procedure
Only local migrations within the arm reported
§
Other included fragmented or bent implants, patient-related issues, wound care required, two incisions required, and difficulty identifying end of device.
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.

Table 7: Adverse Reactions Reported by Patients at 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)
*
Total Insertion Procedures: N = 7,364
Limited to one event per woman
Based on 3,447 questionnaires
§
No blood clots were observed during the study
“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).
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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