ETONOGESTREL Drug Interactions: What You Need to Know

INTERACTIONS Consult the labeling of concurrently-used drugs to obtain further information about interactions with hormonal contraceptives or the potential for enzyme alterations. Drugs or herbal products that induce certain enzymes, such as CYP3A4, may decrease the effectiveness of progestin hormonal contraceptives or increase breakthrough bleeding. ( 7.1 )

7.1 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 [e.g., nelfinavir, ritonavir, darunavir/ritonavir, (fos)amprenavir/ritonavir, lopinavir/ritonavir, and tipranavir/ritonavir] or increase [e.g., indinavir and atazanavir/ritonavir])/HCV protease inhibitors (decrease [e.g., boceprevir and telaprevir]) or with non-nucleoside reverse transcriptase inhibitors (decrease [e.g., nevirapine, efavirenz] or increase [e.g., etravirine]). 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.

7.2 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.

NEXPLANON 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 [see Adverse Reactions (6) ] Known or suspected pregnancy. ( 4 ) Current or past history of thrombosis or thromboembolic disorders. ( 4 , 5.5 ) Liver tumors, benign or malignant, or active liver disease. ( 4 , 5.8 ) Undiagnosed abnormal uterine bleeding. ( 4 , 5.3 ) Known or suspected breast cancer, personal history of breast cancer, or other progestin-sensitive cancer, now or in the past. ( 4 , 5.7 ) Allergic reaction to any of the components of NEXPLANON. ( 4 , 6 )

AND PRECAUTIONS The following information is based on experience with the etonogestrel implants (IMPLANON and/or NEXPLANON), other progestin-only contraceptives, or experience with combination (estrogen plus progestin) oral contraceptives. Insertion and removal complications: Pain, paresthesia, bleeding, hematoma, scarring, infection, or migration to vasculature, including pulmonary vessels, may occur. Symptoms associated with implants in pulmonary vessels include chest pain, dyspnea, cough, or hemoptysis. Surgical interventions may be necessary to remove implants. ( 5.1 ) Menstrual bleeding pattern: Counsel women regarding changes in bleeding frequency, intensity, or duration. ( 5.3 ) Ectopic pregnancies: Be alert to the possibility of an ectopic pregnancy in women using NEXPLANON who become pregnant or complain of lower abdominal pain. ( 5.4 ) Thrombotic and other vascular events: The NEXPLANON implant should be removed in the event of a thrombosis. ( 5.5 ) Liver disease: Remove the NEXPLANON implant if jaundice occurs. ( 5.8 ) Elevated blood pressure: The NEXPLANON implant should be removed if blood pressure rises significantly and becomes uncontrolled. ( 5.10 ) Carbohydrate and lipid metabolic effects: Monitor prediabetic and diabetic women using NEXPLANON. ( 5.12 )

5.1 Risk of Complications Due to Improper Insertion and Removal Complications of Insertion and Removal NEXPLANON should be inserted subdermally so that it will be palpable after insertion, and this should be confirmed by palpation immediately after insertion. Failure to insert NEXPLANON properly may go unnoticed unless it is palpated immediately after insertion. Undetected failure to insert the implant may lead to an unintended pregnancy. Complications related to insertion and removal procedures may occur, e.g., pain, paresthesia, bleeding, hematoma, scarring, or infection. If NEXPLANON is inserted deeply (intramuscular or intrafascial), neural or vascular injury may occur. To help reduce the risk of neural or vascular injury, NEXPLANON should be inserted subdermally just under the skin at the inner side of the non-dominant upper arm overlying the triceps muscle, about 8-10 cm (3-4 inches) from the medial epicondyle of the humerus, and 3-5 cm (1.25-2 inches) posterior to (below) the sulcus (groove) between the biceps and triceps muscles. This location is intended to avoid the large nerves and blood vessels lying within and surrounding the sulcus. Deep insertions of NEXPLANON have been associated with paresthesia (due to neural injury), migration of the implant (due to intramuscular or fascial insertion), and intravascular insertion. If infection develops at the insertion site, start suitable treatment. If the infection persists, the implant should be removed. Incomplete insertions or infections may lead to expulsion. Reports of implant migration within the arm may have been related to deep insertion. Postmarketing reports of implants located within the vessels of the arm and the pulmonary artery also may have been related to deep insertions or intravascular insertions. Some cases of implants found within the pulmonary artery were associated with chest pain and/or respiratory disorders (such as dyspnea, cough, or hemoptysis); others were asymptomatic. In cases where the implant has migrated to the pulmonary artery, endovascular or surgical procedures may be needed for removal. Implant removal may be difficult or impossible if the implant is not inserted correctly, is inserted too deeply, not palpable, encased in fibrous tissue, or has migrated. If at any time the implant cannot be palpated, it should be localized, and removal is recommended. When an implant is removed, it is important to remove it in its entirety <span class="opacity-50 text-xs">[see Dosage and Administration (2.3) ]</span> . Exploratory surgery without knowledge of the exact location of the implant is strongly discouraged. Removal of deeply inserted implants should be conducted with caution in order to prevent injury to deeper neural or vascular structures in the arm and be performed by healthcare professionals familiar with the anatomy of the arm. If the implant is located in the chest, healthcare professionals familiar with the anatomy of the chest should be consulted. Failure to remove the implant may result in continued effects of etonogestrel, such as compromised fertility, ectopic pregnancy, or persistence or occurrence of a drug-related adverse event. Broken or Bent Implants Cases of breakage or bending of implants while inserted within a patient’s arm have been reported. Cases of migration of a broken implant fragment within the arm have also occurred. These cases may be related to external forces, e.g., manipulation of the implant or contact sports. The release rate of etonogestrel may be slightly increased in a broken or bent implant, based on in vitro data. As noted previously, when an implant is removed, it is important to remove it in its entirety <span class="opacity-50 text-xs">[see Dosage and Administration (2.3) ]</span> . NEXPLANON is available only through a restricted program under a REMS <span class="opacity-50 text-xs">[see Warnings and Precautions (5.2) ]</span>.

5.2 NEXPLANON REMS NEXPLANON is only available through a restricted program under a REMS called NEXPLANON REMS because of the risk of complications due to improper insertion and removal <span class="opacity-50 text-xs">[see Warnings and Precautions (5.1) ]</span> . Notable requirements of the NEXPLANON REMS include the following: Healthcare providers must be certified with the program by enrolling and completing training on the proper insertion and removal of NEXPLANON prior to first use. Pharmacies must be certified with the program and must only dispense NEXPLANON to certified healthcare providers who dispense NEXPLANON for insertion. Wholesalers and distributors must be registered with the program and must only distribute to certified pharmacies and certified healthcare providers. Further information is available at www.NEXPLANONREMS.com and 1-833-697-7367.

5.3 Changes in Menstrual Bleeding Patterns After starting NEXPLANON, women are likely to have a change from their normal menstrual bleeding pattern. These may include changes in bleeding frequency (absent, less, more frequent or continuous), intensity (reduced or increased) or duration. In clinical trials of the non-radiopaque etonogestrel implant (IMPLANON), bleeding patterns ranged from amenorrhea (1 in 5 women) to frequent and/or prolonged bleeding (1 in 5 women). The bleeding pattern experienced during the first three months of NEXPLANON use is broadly predictive of the future bleeding pattern for many women. Women should be counseled regarding the bleeding pattern changes they may experience so that they know what to expect. Abnormal bleeding should be evaluated as needed to exclude pathologic conditions or pregnancy. In clinical studies of the non-radiopaque etonogestrel implant, reports of changes in bleeding pattern were the most common reason for stopping treatment (11.1%). Irregular bleeding (10.8%) was the single most common reason women stopped treatment, while amenorrhea (0.3%) was cited less frequently. In these studies, women had an average of 17.7 days of bleeding or spotting every 90 days (based on 3,315 intervals of 90 days recorded by 780 patients). The percentages of patients having 0, 1-7, 8-21, or &gt;21 days of spotting or bleeding over a 90-day interval while using the non-radiopaque etonogestrel implant are shown in Table 1 .

Table

1: Bleeding or Spotting: Incidence and Duration Over a 90-Day Interval While Using the Non-Radiopaque Etonogestrel Implant (IMPLANON)

Total

Days of Bleeding or Spotting Percentage of Patients Treatment Days 91-180 (N = 745)

Treatment Days

271-360 (N = 657)

Treatment Days

631-720 (N = 547) 0 Days 19% 24% 17% 1-7 Days 15% 13% 12% 8-21 Days 30% 30% 37% >21 Days 35% 33% 35% Bleeding patterns observed with use of the non-radiopaque etonogestrel implant for up to 2 years, and the proportion of 90-day intervals with these bleeding patterns, are summarized in Table 2 .

Table

2: Bleeding Patterns Using the Non-Radiopaque Etonogestrel Implant (IMPLANON) During the First 2 Years of Use Based on 3315 recording periods of 90 days duration in 780 women, excluding the first 90 days after implant insertion BLEEDING PATTERNS DEFINITIONS % % = Percentage of 90-day intervals with this pattern Infrequent Less than three bleeding and/or spotting episodes in 90 days (excluding amenorrhea)

33.6 Amenorrhea No bleeding and/or spotting in 90 days

22.2 Prolonged Any bleeding and/or spotting episode lasting more than 14 days in 90 days

17.7 Frequent More than 5 bleeding and/or spotting episodes in 90 days

6.7 In case of undiagnosed, persistent, or recurrent abnormal vaginal bleeding, appropriate measures should be conducted to rule out malignancy.

5.4 Ectopic Pregnancies 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.

5.5 Thrombotic and Other Vascular Events 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.

5.6 Ovarian Cysts 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.

5.7 Carcinoma of the Breast and Reproductive Organs Women who currently have or have had breast cancer should not use hormonal contraception because breast cancer may be hormonally sensitive <span class="opacity-50 text-xs">[see Contraindications (4) ]</span> . 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.

5.8 Liver Disease 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 <span class="opacity-50 text-xs">[see Contraindications (4) ]</span> .

5.9 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.

5.10 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.

5.11 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.

5.12 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.

5.13 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.

5.14 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.

5.15 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.

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

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.