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  • CLASSES

    Progestogen Only Contraceptives

    DEA CLASS

    Rx

    DESCRIPTION

    Synthetic progestin; active metabolite of the prodrug desogestrel; available as a subdermal implant device
    Used primarily for routine contraception in women for a 3-year period; highly effective as a contraceptive; allows for rapid return of fertility once removed
    Use requires special physician training for insertion and removal

    HOW SUPPLIED

    Nexplanon Subcutaneous Imp: 68mg

    DOSAGE & INDICATIONS

    For routine contraception.
    Subdermal dosage (Nexplanon contraceptive implant)
    Adult and Adolescent Females

    Insert 1 etonogestrel implant (68 mg) subdermally every 3 years at the inner side of the non-dominant upper arm as per the prescribing information/device instructions. Follow the recommended timing of insertion with regard to the woman's menstrual cycle, prior use of contraceptives, and other clinical needs. If deviating from the recommended time of insertion, rule out pregnancy before insertion and instruct the patient to use back-up non-hormonal contraception for 7 days after implant insertion.[46375] LIMITATIONS OF USE: The etonogestrel implant has not been studied in women who weigh more than 130% of their ideal body weight.
    The recommended timings of insertion are as follows:
    -In women not using hormonal contraceptives in the previous month, counting the first day of menstruation as Day 1, insert the implant between Day 1 and Day 5, even if the woman is still bleeding.
    -For patients switching from a combination oral contraceptive, the Nexplanon implant should preferably be inserted on the day after the last active tablet; at the latest, it should be inserted on the day following the usual tablet-free interval of the previous oral contraceptive.
    -For patients switching from a vaginal ring or transdermal patch contraceptive, the Nexplanon implant should preferably be inserted on the day that the vaginal ring or transdermal patch is removed; at the latest, it should be inserted on the day following the usual ring-free or patch-free interval of the previous contraceptive.
    -In a patient switching from a progestin-only pill, insert the implant on any day of the month; the patient should not skip any days between the last pill and insertion.
    -In a patient switching from a progestin-only implant or IUD, insert the implant on the same day as the removal of the prior implant or IUD.
    -In a patient switching from a progestin-only injection, insert the implant on the day when the next contraceptive injection would be due.
    -Following a complete first trimester miscarriage or abortion, the implant may be inserted immediately; if it is not inserted within 5 days following the event, follow the instructions under "no preceding hormonal contraceptive use in the past month".
    -For use following a second trimester miscarriage/abortion, insert the implant between 21 to 28 days following the event. If more than 4 weeks have elapsed, pregnancy should be ruled out, and the patient should use a non-hormonal method of birth control during the first 7 days after insertion.
    -For use postpartum, insert the implant between 21 to 28 days postpartum if not exclusively breast-feeding. Initiate no sooner than at 3 weeks postpartum. If more than 4 weeks have elapsed, pregnancy should be ruled out, and the patient should use a non-hormonal method of birth control during the first 7 days after insertion. If the patient is exclusively breast-feeding, insert the implant after the fourth postpartum week.

    For the treatment of endometriosis† and associated pain†.
    Subdermal dosage
    Adult and Adolescent females

    Safety and efficacy not definitively established; the implant has been used clinically off-label for this use. 1 implant (68 mg etonogestrel) implanted subdermally every 3 years as directed in the prescribing information; the dose used is the same as that for routine contraception. Data are limited for the use of the implant to reduce pain of endometriosis vs. approved regimens such as depot medroxyprogesterone injections or the levonorgestrel IUD, however, per guidelines and clinical practice recommendations, the implant can be a progestin-based alternative for treatment. Limited data suggest etonogestrel implant was effective at reducing pain in these patients, including when compared to depot medroxyprogesterone acetate (an FDA-approved endometriosis therapy) in small pilot studies.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    One etonogestrel implant (containing 68 mg etonogestrel) subdermally every 3 years.

    Geriatric

    Safety and efficacy have not been established.

    Adolescents

    One etonogestrel implant (containing 68 mg etonogestrel) subdermally every 3 years. While not specifically studied in females less than 18 years of age, safety and efficacy are expected to be the same for postpubertal adolescents as for adult females.

    Children

    Not indicated in prepubescent females. The etonogestrel implant has not been specifically studied in pediatric patients less than 18 years of age.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    The etonogestrel implant is contraindicated for use in active hepatic disease or impairment. If jaundice develops during use, remove the implant.

    Renal Impairment

    Specific guidelines for patients with renal impairment are not available; the etonogestrel implant has not been studied in these patients.

    ADMINISTRATION

    Other Administration Route(s)

    Subdermal Contraceptive Implant Administration
    Proper insertion technique is imperative for efficacy; data indicate that failure to insert the device properly may result in unintended pregnancies.[41651]
     
    Pre-insertion Tasks (Nexplanon)
    Instruct patient on risks and warnings; provide the patient with a copy of the complete patient labeling.
    Perform a complete medical history, physical and gynecologic exam, and relevant laboratory tests.
    Proper insertion is imperative for easy insertion and removal of the implant. Only healthcare providers trained explicitly in administering etonogestrel by this route should implant the device. Manufacturer-sponsored training is required to acquire the drug and to insert the implant. For more information on training, call 1-877-888-4231.
    Provide the patient with a user card and consent form (included in the implant packaging). The card will provide the patient with a record and location of the implant and the date when it should be removed. Also, complete the patient chart label and affix it to the patient's medical record.
    Insertion of the implant during the proper time of the woman's menstrual cycle is essential.
    A new etonogestrel rod may be inserted immediately after the old etonogestrel rod is removed. Insert the new implant in the same arm and through the same incision. Alternatively, a new etonogestrel implant can be inserted in the other arm.[46375]
     
    Insertion Procedure (Nexplanon)
    To help ensure the implant is inserted just under the skin, healthcare providers should be positioned to see the advancement of the needle by viewing the applicator from the side. The side view allows better visualization of the insertion site and the movement of the needle.
    Have the patient lie on her back on the examination table with her non-dominant arm flexed at the elbow and externally rotated so that her hand is underneath the head (or as close as possible).
    Identify the insertion site, which is at the inner side of the non-dominant upper arm overlying the triceps muscle about 8 to 10 cm (3 to 4 inches) above the medial epicondyle of the humerus and 3 to 5 cm (1.25 to 2 inches) posterior to the sulcus (groove) between the biceps and the triceps muscles. If it is not possible to insert in this location in women with thin arms, insert as far posterior from the sulcus as possible.
    Using a surgical marker, mark the insertion site. Make 2 marks: first, mark the spot where the Nexplanon implant will be inserted, and second, mark a spot at 5 centimeters (2 inches) proximal (toward the shoulder) to the first mark. This second mark (guiding mark) will later serve as a direction guide during Nexplanon insertion. After marking the arm, confirm the site is in the correct location on the inner side of the arm.
    Clean the skin from the insertion site to the guiding mark with an antiseptic solution. Next, anesthetize the insertion area using either anesthetic spray or 2 mL of 1% lidocaine injected just under the skin along the planned insertion tunnel.
    Carefully remove the Nexplanon applicator carrying the implant from its blister. The applicator should not be used if sterility is in question.
    Hold the applicator just above the needle at the textured surface area. Remove the transparent protection cap by sliding it horizontally in the direction of the arrow away from the needle; if the cap does not come off easily, do not use the applicator. The white-colored implant is visible by looking into the tip of the needle.
    Do not touch the purple slider until you have fully inserted the needle subdermally, as it will retract the needle and prematurely release the implant from the applicator.
    If the purple slider is released prematurely, restart the procedure with a new applicator.
    With your free hand, stretch the skin around the insertion site towards the elbow with thumb and index finger. The implant should be inserted subdermally just under the skin. Puncture the skin with the tip of the needle slightly angled less than 30 degrees.
    Insert the needle until the bevel is just under the skin (and no further). If you insert the needle past the bevel, withdraw it until only the needle bevel is beneath the skin.
    Lower the applicator to a nearly horizontal position. While lifting the skin with the tip of the needle, slide the needle to its full length. You may feel slight resistance but do not exert excessive force. If the needle is not inserted to its full length, the implant will not be inserted properly.
    If the needle tip emerges from the skin before needle insertion is complete, the needle should be pulled back and readjusted to the subdermal position before completing the insertion procedure.
    You can best see the movement of the needle, and that it is inserted just under the skin, if you are seated and are looking at the applicator from the side and NOT from above. In this position, you can see the insertion site clearly and the movement of the needle just under the skin.
    Keep the applicator in the same position with the needle inserted to its full length. Unlock the purple slider by pushing it slightly down. Move the slider fully back until it stops. Do NOT move the applicator while moving the purple slider.
    The implant is now in its final subdermal position, and the needle is locked inside the body of the applicator. The applicator can now be removed. If the applicator is not kept in the same position during this procedure or if the purple slider is not completely moved fully back until it stops, the implant will not be appropriately inserted and may protrude from the insertion site.
    If the implant is protruding from the insertion site, remove the implant and perform a new procedure at the same insertion site using a new applicator. Do not push the protruding implant back into the incision.
    Apply a small adhesive bandage over the insertion site.
    Always verify the presence of Nexplanon in the patient's arm immediately after insertion by palpating both ends of the implant; you should be able to confirm the presence of the 4-cm rod. If you are not able to feel Nexplanon as a 4-cm long rod, check the applicator. The needle should be fully retracted, and only the purple tip of the obturator should be visible. Other methods to confirm the presence of the implant include: two-dimensional X-ray, computerized tomography (CT scan), ultrasound scanning (USS) with a high-frequency linear array transducer (10 MHz or more), or magnetic resonance imaging (MRI). If these methods fail, call 1-877-888-4231 for information regarding the procedure for measuring etonogestrel blood levels, which can be used for verification of the presence of the implant.
    Deeply-placed implants should be localized and removed as soon as possible to avoid the potential for distant migration.
    Until the presence of the implant has been confirmed, instruct the woman to use a non-hormonal contraceptive method, such as condoms.
    Once proper insertion is confirmed, place a small adhesive bandage over the insertion site and have the patient palpate the implant. Next, apply a pressure bandage with sterile gauze over the small adhesive bandage to minimize bruising. The patient may remove the pressure bandage in 24 hours and the small bandage over the insertion site in 3 to 5 days.
    The applicator is for single use only. Dispose of the applicator following the Center for Disease Control and Prevention guidelines for handling of hazardous waste.[46375]
     
    Removal Procedure (Nexplanon)
    Consult the user card that is kept by the patient or the patient chart label to check the arm in which Nexplanon is located.
    Locate Nexplanon by palpation.
    Removal of the implant should only be performed under aseptic conditions by a healthcare provider who is familiar with the removal technique.
    Only remove a non-palpable implant once the location of Nexplanon has been established. If Nexplanon cannot be palpated, use two dimensional X-ray, X-ray computed tomography (CT), ultrasound scanning (USS) with a high-frequency linear array transducer (10 MHz or more), or magnetic resonance imaging (MRI) to locate.
    If the implant cannot be found in the arm after comprehensive localization attempts, consider applying imaging techniques to the chest as events of migration to the pulmonary vasculature have been reported. If the implant is located in the chest, surgical or endovascular procedures may be needed for removal; healthcare professionals familiar with the anatomy of the chest should be consulted.
    If these imaging methods fail, etonogestrel blood level determination can be used for verification of the presence of the implant. Call 1-877-888-4321 for further instructions. If the implant migrates within in the arm, removal may require a minor surgical procedure with a larger incision or a surgical procedure in an operating room. Removal of deeply inserted implants should be conducted with caution to prevent injury to deeper neural or vascular structures in the arm and be performed by healthcare providers familiar with the anatomy of the arm. Exploratory surgery without knowledge of the exact location of the implant is strongly discouraged.
    Have the patient lie on her back on the examination table with her arm flexed at the elbow and externally rotated so that her hand is underneath the head (or as close as possible).
    Push down the proximal end of the implant to stabilize it; a bulge may appear indicating the distal end of the implant. If the tip does not pop up, removal may be more difficult and should be performed by providers experienced with removing deeper implants.
    Wash the patient's arm and apply an antiseptic. Using palpation, locate Nexplanon and mark the end closest to the elbow with a sterile marker.
    Anesthetize the arm with 0.5 mL to 1 mL of 1% lidocaine at the site where the incision will be made (near the tip of Nexplanon that is closest to the elbow). Be sure to inject the local anesthetic under Nexplanon to keep the implant close to the skin surface. Injection of local anesthetic over the implant may make removal more difficult.
    Push down the end of the implant to stabilize it throughout the procedure. Starting at the distal tip of the implant, closest to the elbow, carefully make a longitudinal incision of 2 mm towards the elbow without cutting the tip of the implant. The tip of the implant should pop out of the incision, if it does not, gently push Nexplanon toward the incision until the tip is visible. Grasp the implant with forceps (preferably curved mosquito forceps) and pull it out gently. If Nexplanon is encapsulated, make an incision into the tissue sheath and then remove Nexplanon with the forceps.
    If the tip of the implant is still not visible after gently pushing it towards the incision, then gently insert a forceps into the incision. Flip the forceps over into your other hand. Using another pair of forceps, carefully dissect the tissue around Nexplanon and then remove Nexplanon. Use caution with the removal of deeply inserted implants to prevent damage to deeper neural or vascular structures in the arm; removal should only be performed by healthcare providers familiar with the anatomy of the arm.
    Cases of in situ broken or bent implants have been reported. Based on in vitro data, a broken or bent implant may increase the release rate of etonogestrel; however, the change is not expected to be clinically significant. Ensure that the Nexplanon rod is completely removed by measuring its length (4 cm long). There have been reports of broken implants while in the patient's arm. In some cases, difficult removal of the broken implant has been reported. If a partial implant (less than 4 cm) is removed, the remaining piece should be removed by following the standard instructions provided by the manufacturer for removal of the etonogestrel implant.
    After removing Nexplanon, close the incision with a steri-strip and apply an adhesive bandage. Apply a pressure bandage with sterile gauze to minimize bruising.[46375]

    STORAGE

    Generic:
    - Avoid temperatures above 86 degrees F
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    Implanon:
    - Protect from light
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    - Store below 86 degrees F
    Nexplanon :
    - Avoid temperatures above 86 degrees F
    - Protect from direct sunlight
    - Protect from light
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Etonogestrel should not be used in patients hypersensitive to any component of the product.

    Ectopic pregnancy, pregnancy

    Etonogestrel is contraindicated for use during pregnancy or suspected pregnancy. Remove the etonogestrel implant if pregnancy is detected. Teratology studies involving rats using oral administration up to 390 times the human etonogestrel dose and rabbits using oral administration up to 790 times the human etonogestrel dose (based upon body surface) have revealed no evidence of fetal harm due to etonogestrel exposure. In addition, studies have revealed no increased risk of birth defects in women who have used combination oral contraceptives before pregnancy or during early pregnancy; no evidence that the risk associated with etonogestrel is different from that of combination oral contraceptives exists. In women who become pregnant or complain of lower abdominal pain while using etonogestrel, the possibility of ectopic pregnancy exists. Although ectopic pregnancies should be uncommon among patients using etonogestrel, a pregnancy that occurs in a patient using etonogestrel may be more likely to be ectopic than a pregnancy occurring in a patient using no contraception. Ectopic pregnancies can cause serious internal bleeding and even death.

    Breast-feeding

    According to the manufacturer, etonogestrel implants can be inserted after the 4th postpartum week in women who are breast-feeding their infants. Use of etonogestrel before the 4th postpartum week has not been studied. Small amounts of etonogestrel are secreted into breast-milk during routine contraceptive use, resulting in about 2.2% of the weight-adjusted maternal daily dose or about 0.2% of the estimated absolute maternal daily dose. In a trial, the safety of breast-fed infants whose mothers began using etonogestrel during the 4th to 8th week postpartum (n=38) was compared with infants of mothers using a non-hormonal IUD (n=33). The infants were breast-fed for a mean duration of 14 months and followed up to 36 months of age; no significant differences between the groups were observed on the physical and psychomotor development of these infants. In addition, no differences in the production or quality of breast milk were detected between the groups. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Cervical cancer, ovarian cyst, vaginal bleeding

    Etonogestrel is absolutely contraindicated in undiagnosed abnormal vaginal bleeding. If a patient using the etonogestrel implant experiences persistent or recurrent abnormal vaginal bleeding, rule out pathologic conditions or pregnancy. Patients who use etonogestrel implant are likely to have changes in their menstrual bleeding patterns; these changes are often unpredictable and may include changes in bleeding frequency, bleeding duration, or amenorrhea. Some studies suggest that oral contraceptive use has been associated with an increase in the risk of cervical intraepithelial neoplasia in some populations of women. However, there continues to be controversy about the extent to which such findings may be due to differences in sexual behavior and other factors. Although several studies on the relationship between combination oral contraceptive use and cervical cancer exist, a cause-and-effect relationship has not been established. According to the World Health Organization Medical Eligibility Criteria (WHO MEC 2010), in women with cervical intraepithelial neoplasia or in women with cervical cancer who are awaiting treatment, the advantages of using etonogestrel implant generally outweigh the theoretical or proven risks. Ovarian cysts may develop in patients in taking etonogestrel implant; if follicular development occurs, atresia of the follicle is sometimes delayed, and the follicle may continue to grow into an ovarian cyst. Generally, these enlarged follicles disappear spontaneously; on rare occasion, they can require surgical intervention.

    Breast cancer

    Etonogestrel is contraindicated in patients with known or suspected breast cancer, a personal history of breast cancer, or other progestin-sensitive cancer, now or in the past. A meta-analysis from 54 epidemiological studies reported that there is a slightly increased relative risk (RR=1.24) of having breast cancer diagnosed in women who are currently using combination oral contraceptives compared to never-users. The increased risk gradually disappears during the course of the 10 years after cessation of combination oral contraceptive use. These studies do not provide evidence for causation. Although the results were broadly similar for progestin-only oral contraceptives, the data are based on much smaller numbers of progestin-only oral contraceptive users and, therefore, are less conclusive than for combination oral contraceptives. In addition, some studies have found a small increase in the risk of breast cancer for women who first used combination oral contraceptives before age 20. Most studies show a similar pattern of risk with combination oral contraceptive use regardless of a woman’s reproductive history or her family breast cancer history. Breast cancers diagnosed in current or ever oral contraceptive users may be less clinically advanced than in never-users. Although several studies on the relationship between combination oral contraceptive use and breast cancer exist, a cause-and-effect relationship has not been established. Women with a family history of breast cancer or who have breast nodules should be monitored closely while using the etonogestrel implant.

    Human immunodeficiency virus (HIV) infection

    Like all hormonal contraceptives, etonogestrel use does not protect against the transmission of human immunodeficiency virus (HIV) infection or other sexually transmitted diseases.

    Diabetes mellitus

    Etonogestrel should be used cautiously in patients with diabetes mellitus. Etonogestrel may induce mild insulin resistance and small changes in glucose concentrations of unknown clinical significance. Among 23 women with type 1 diabetes, the mean HbA1c before insertion of etonogestrel implant was 8.97 (95% CI 8.17—9.77). Similar mean HbA1c and confidence intervals were observed after 24 months of implant insertion. In addition, according to the World Health Organization Medical Eligibility Criteria (WHO MEC 2010), there is no restriction for the use of etonogestrel implant in women with a history of gestational diabetes. In patients with diabetes who have nonvascular disease, microvascular complications, other vascular disease, or diabetes > 20 years, the advantages of using etonogestrel implant generally outweigh the theoretical or proven risks.

    Gallbladder disease, hepatic disease, hepatocellular cancer, jaundice

    Etonogestrel is contraindicated in patients with active hepatic disease or hepatic tumors (benign or hepatocellular cancer). Patients with impaired liver function may poorly metabolize etonogestrel. If jaundice develops in any patient using etonogestrel, remove the implant. Although not specific to etonogestrel, the use of combination oral contraceptives has been linked to the development of benign hepatic adenomas; it should be noted that the incidence of benign tumors is rare in the United States. Indirect calculations have estimated the attributable risk to be in the range of 3.3 cases/100,000 for users; this risk increases after four or more years of use. Benign hepatic adenomas may rupture and cause death through intra-abdominal hemorrhage. British studies have shown an increased risk of developing hepatocellular carcinoma in patients who use oral contraceptives for >8 years. However, these cancers are extremely rare in the U.S. and the attributable risk (the excess incidence) of liver cancers in oral contraceptive users approaches less than one per million users. In addition to benign hepatic adenomas and hepatocellular carcinoma, combination oral contraceptives and estrogens have been linked to an increased lifetime relative risk of gallbladder surgery in earlier studies. Newer findings show that the relative risk of developing gallbladder disease among combination oral contraceptives may be minimal; these findings may be attributed to the lower doses of estrogens and progestins contained in combination oral contraceptives. NOTE: The above data regarding hepatocellular cancer and gallbladder disease are regarding combination oral contraceptives; applicability to the etonogestrel implant is unknown.

    Hyperlipidemia

    Hormonal contraceptives should be used cautiously in women with hyperlipidemia; these patients should be followed closely. Some progestins may elevate LDL levels and may complicate the treatment of hyperlipidemias. According to the World Health Organization Medical Eligibility Criteria for Contraceptive Use (WHO MEC 2010), the advantages of using etonogestrel implant in patients with hyperlipidemia generally outweigh the theoretical or proven risks.

    Cerebrovascular disease, migraine, myocardial infarction, stroke, surgery, thromboembolic disease, thrombophlebitis, tobacco smoking

    Etonogestrel is contraindicated in patients with an active or past history of thrombosis, thrombophlebitis, thromboembolic disorders, or thromboembolic disease. Thromboembolic events have been noted in users of combination hormonal contraceptives. In epidemiological investigations, the use of combination hormonal contraceptives has been associated with an increased risk of venous thromboembolism (VTE, such as deep venous thrombosis, retinal vein thrombosis, myocardial infarction, stroke, and pulmonary embolism); the risk of serious morbidity or mortality is very small in healthy women without underlying risk factors. Because of the higher risk of thromboembolic disease in tobacco smoking women, women should be advised not to smoke, particularly if they are over the age of 35 years. Etonogestrel is a progestin-only contraceptive, and it is unknown whether this increased risk is applicable to etonogestrel alone. There have been rare post-marketing reports of serious arterial and venous thromboembolic events in women using etonorgestrel. It is recommended, however, that women with risk factors known to increase the risk of venous and arterial thromboembolism be carefully assessed. For example, etonorgestrel implant should not be used prior to 21 days postpartum, due to the increased risk of thromboembolism in women in the early postpartum weeks. Consider removal of the etonogestrel implant in the case of long-term immobilization due to surgery or illness. Despite the contraindication against use in patients with known thrombotic disease, progestin-only contraceptives are generally the hormonal contraceptives of choice in patients with a potential risk for thrombosis when reliable contraception must be ensured and the risks of hormonal therapy are acceptable; advantages of these methods usually outweigh proven or theoretical risks. When multiple thrombosis risk factors exist, the risk of thromboembolic disease may increase; determine risk vs. benefit for use of the progestin-only contraceptive. The increase in the risk of thrombosis from newer progestin-only contraceptives (e.g., etonorgestrel implants) is still substantially less than with combined oral contraceptives containing both estrogen and progestin. For women who are at an increased risk of thromboembolism and have multiple-risk factors for thrombosis (e.g., tobacco smoking woman age 35 and older, diabetes, hypercoagulopathy, severe hypertension, etc.), consider an IUD or other estrogen-free contraceptive if appropriate. During use of etonogestrel in patients without a history of thrombosis, the provider should be alert to the earliest manifestations of thrombotic disorder (thrombophlebitis, cerebrovascular disease such as stroke or focal migraine with asymmetrical visual loss or other symptoms indicating transient cerebral ischemia, myocardial infarction, pulmonary embolism, and retinal thrombosis). If such are suspected, consider removal of the implant. The etonogestrel implant should be removed in the event of a thrombosis.

    Coronary artery disease, edema, heart failure, hypertension, renal disease, renal failure, renal impairment

    Hormonal contraceptives may cause some degree of fluid retention or edema; however, it is unknown if etonogestrel causes fluid retention. In patients with conditions that might be aggravated by fluid retention, such as coronary artery disease, heart failure, renal disease, and hypertension, prescribe hormone contraceptives with caution and careful monitoring. No formal data are available regarding the use of etonorgestrel in renal impairment or renal failure. In addition, women taking combination hormonal contraceptives have experienced an increase in blood pressure; this increase is more likely with continued use and with those patients who are older. Studies have shown that the incidence of hypertension increases with increasing concentrations of progestins. According to the World Health Organization Medical Eligibility Criteria (WHO MEC 2010), in patients with adequately controlled hypertension, there is no restriction for the use of etonogestrel implant, although no supportive data exist. The same recommendation is true for patients with systolic blood pressure levels of 140—159 mm Hg or diastolic blood pressure levels of 90—99 mm Hg. In patients with systolic blood pressure levels >=160 mm Hg or diastolic blood pressure levels >=100 mm Hg, the advantages of using etonogestrel implant generally outweigh the theoretical or proven risks. It should be noted that the WHO MEC 2010 recommendations for hypertension are based on the assumption that no other risk factors exist for cardiovascular disease; when multiple risk factors exist, the risk for cardiovascular disease might increase substantially. Discontinue etonogestrel in a patient who develops sustained hypertension or who does not respond to antihypertensive therapy. For most women, elevated blood pressure will return to normal after discontinuing hormonal contraceptives, and there is no difference in the occurrence of hypertension between ever- and never-users. In addition to hypertension, heart failure may be exacerbated by fluid retention. According to the WHO MEC 2010, in patients with normal or mildly impaired cardiac function (New York Heart Association Functional Class 1 or 2), there is no restriction for the use of the etonogestrel implant. In patients with moderately or severely impaired cardiac function (New York Heart Association Functional Class 3 or 4,) the advantages of using etonogestrel implant generally outweigh the theoretical or proven risks.

    Depression

    Etonogestrel should be used cautiously in patients with a history of depression. Depression has been reported in patients taking etonogestrel and, therefore, the drug may exacerbate symptoms in a patient who is already depressed. Consider discontinuing therapy with etonogestrel in patients who become significantly depressed.

    Seizure disorder

    Etonogestrel should be used cautiously in patients with a seizure disorder. Etonogestrel is not recommended for women who chronically take drugs that are potent hepatic enzyme inducers because etonogestrel levels may be substantially reduced in these women; this recommendation applies to many anti-epileptic drug therapies.

    Contact lenses

    Patients who wear contact lenses must be assessed by a ophthalmologist if they develop visual changes or changes in lens tolerance while using etonogestrel.

    Obesity

    It is possible that etonogestrel contraceptive efficacy could be reduced in women exhibiting obesity. The efficacy of etonogestrel in overweight women has not been defined because women who weighed >130% of their ideal body weight were not studied. Since serum concentrations of etonogestrel are inversely related to body weight and decrease with time after insertion, it is possible that over time etonogestrel may be less effective in women with obesity versus women who are closer to ideal body weight.

    Geriatric

    Etonogestrel has not been studied in geriatric women over 65 years of age and is not indicated in this population.

    Children, infants, neonates

    Use of etonogestrel products in neonates, infants, and children before menarche is not indicated. The safety and efficacy of etonogestrel have only been established in females of reproductive age. Safety and efficacy of etonogestrel is expected to be the same for adolescents as compared to adults; however, no clinical studies have been conducted in women under the age of 18.

    Intramuscular administration


    Intramuscular administration or other routes of deep insertion of etonogestrel implant may result in complications (e.g., neural or vascular injury), difficult localization of the implant, or result in the need for a surgical procedure in an operating room to remove the implant. Exploratory surgery without knowledge of the exact location of the implant is strongly discouraged. Etonogestrel implant should be inserted subdermally only, just under the skin to avoid the large blood vessels and nerves that lie deeper in the subcutaneous tissues in the sulcus between the triceps and biceps muscles. The implant should be palpable after insertion, and this should be confirmed by palpation immediately after insertion to ensure proper positioning. Undetected failure to insert the implant may lead to an unintended pregnancy. In rare cases, implant insertions have failed because the implant fell out of the needle or remained in the needle during insertion. Conversely, difficult or impossible removal can occur if the implant is not inserted correctly, is inserted too deeply (intramuscular or in the fascia), not palpable, encased in fibrous tissue, or has migrated. Failure to remove the implant properly may result in continued effects of etonogestrel, such as compromised fertility, ectopic pregnancy, or persistence or occurrence of a drug-related adverse event. Confirm that the entire 4 cm long implant has been removed by measuring its length. There have been reports of broken implants while in the patient’s arm. In some cases, difficult removal of the broken implant has been reported. General complications related to insertion and removal procedures may occur, including pain, paresthesias, bleeding, hematoma, scarring, or infection.

    ADVERSE REACTIONS

    Severe

    angioedema / Rapid / Incidence not known
    bronchospasm / Rapid / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    seizures / Delayed / Incidence not known
    stroke / Early / Incidence not known
    pulmonary embolism / Delayed / Incidence not known
    thrombosis / Delayed / Incidence not known

    Moderate

    vaginitis / Delayed / 14.5-14.5
    vaginal bleeding / Delayed / 11.0-11.0
    depression / Delayed / 5.5-5.5
    gastritis / Delayed / 0-5.0
    constipation / Delayed / 0-5.0
    hot flashes / Early / 0-5.0
    dysuria / Early / 0-5.0
    migraine / Early / 0-5.0
    hypertension / Early / 0-5.0
    edema / Delayed / 0-5.0
    erythema / Early / 0.3-0.3
    hematoma / Early / 0.1-0.1
    dyspnea / Early / Incidence not known
    bleeding / Early / Incidence not known
    hemoptysis / Delayed / Incidence not known

    Mild

    headache / Early / 24.9-24.9
    weight gain / Delayed / 13.7-13.7
    acne vulgaris / Delayed / 13.5-13.5
    mastalgia / Delayed / 12.8-12.8
    menstrual irregularity / Delayed / 10.8-11.0
    abdominal pain / Early / 10.9-10.9
    vaginal discharge / Delayed / 9.6-9.6
    leukorrhea / Delayed / 9.6-9.6
    dysmenorrhea / Delayed / 7.2-7.2
    dizziness / Early / 7.2-7.2
    back pain / Delayed / 6.8-6.8
    emotional lability / Early / 6.5-6.5
    nausea / Early / 6.4-6.4
    sinusitis / Delayed / 5.6-5.6
    rash / Early / 0-5.0
    injection site reaction / Rapid / 0-5.0
    pruritus / Rapid / 0-5.0
    anxiety / Delayed / 0-5.0
    libido decrease / Delayed / 0-5.0
    flatulence / Early / 0-5.0
    anorexia / Delayed / 0-5.0
    dyspepsia / Early / 0-5.0
    vomiting / Early / 0-5.0
    diarrhea / Early / 0-5.0
    weight loss / Delayed / 0-5.0
    cough / Delayed / 0-5.0
    rhinitis / Early / 0-5.0
    fever / Early / 0-5.0
    breast discharge / Delayed / 0-5.0
    pelvic pain / Delayed / 0-5.0
    breast enlargement / Delayed / 0-5.0
    vaginal irritation / Early / 0-5.0
    alopecia / Delayed / 0-5.0
    hypoesthesia / Delayed / 0-5.0
    myalgia / Early / 0-5.0
    insomnia / Early / 0-5.0
    arthralgia / Delayed / 0-5.0
    fatigue / Early / 0-5.0
    asthenia / Delayed / 0-5.0
    musculoskeletal pain / Early / 0-5.0
    amenorrhea / Delayed / 0.3-0.3
    pharyngitis / Delayed / 5.0
    infection / Delayed / 5.0
    melasma / Delayed / Incidence not known
    paresthesias / Delayed / Incidence not known
    urticaria / Rapid / Incidence not known
    hypertrichosis / Delayed / Incidence not known
    drowsiness / Early / Incidence not known

    DRUG INTERACTIONS

    Acetohexamide: (Minor) Progestins can impair glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued.
    Acitretin: (Major) Acitretin interferes with the contraceptive effect of microdose progestins ('minipill' contraceptive preparations). It is not known if acitretin also interacts with other progestational contraceptives, such as etonogestrel implants, or if this method is an adequate method of contraception during acitretin therapy. However, female patients should be advised of the possibility that any contraceptive method can fail. Since Acitretin may cause serious birth defects, the patient should use 2 forms of reliable contraception at the same time for at least 1 month before beginning acitretin therapy, during acitretin therapy, and must continue to use them for at least 3 years after acitretin treatment has stopped. It is recommended that the patient either abstain from sexual intercourse or use 2 reliable kinds of birth control at the same time to prevent unwanted pregnancy.
    Alogliptin: (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Alogliptin; Metformin: (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. (Minor) Patients receiving antidiabetic agents like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance.
    Alogliptin; Pioglitazone: (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. (Minor) Progestins can impair glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued.
    Alpha-glucosidase Inhibitors: (Minor) Progestins can impair glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued.
    Amobarbital: (Moderate) Barbiturates can accelerate the hepatic clearance of progestins. For hormonal contraceptives, this interaction could result in unintended pregnancy or breakthrough bleeding. For patients regularly taking a barbiturate, an alternative or back-up method of contraception may be advisable to ensure contraceptive reliability during the use of the barbiturate, and for 1 month following the discontinuation of barbiturate use. The exception is the use of levonorgestrel progestin IUDs, which have not been reported to interact and appear to maintain reliable efficacy. Pregnancy has been reported during therapy with both estrogen- and/or progestin-based oral contraceptives in patients receiving barbiturates (e.g., phenobarbital). For patients taking progestins for other indications, like hormone replacement, monitor the patient for signs and symptoms of reduced therapeutic efficacy or need for dosage adjustment.
    Amoxicillin; Clarithromycin; Omeprazole: (Minor) Coadministration of etonogestrel and strong CYP3A4 inhibitors such as clarithromycin may increase the serum concentration of etonogestrel.
    Amprenavir: (Major) Oral contraceptives and non-oral combination contraceptives should not be administered with amprenavir. Alternative methods of non-hormonal contraception are recommended. Clinically significant hepatic enzyme (transaminase) elevations may occur with concomitant use. Additionally, hormonal contraceptives, estrogens, and progestins may decrease the serum concentrations of amprenavir, which could lead to loss of virologic response and possible viral resistance. Additionally, data on the effects that other protease inhibitors have on the serum concentrations of estrogens and progestins are complex; some protease inhibitors increase and others decrease the metabolism of hormonal contraceptives. Coadministration of medroxyprogesterone, a CYP3A substrate with amprenavir, a strong CYP3A inhibitor should be avoided since it is expected to increase concentrations of medroxyprogesterone acetate. It is not known if amprenavir alters the metabolism of other hormonal contraceptives or other estrogen or progestin products. Because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives concurrently with protease inhibitors should use an additional barrier method of contraception such as condoms. In women receiving oral contraceptives containing the progestin drospirenone, consider monitoring serum potassium concentrations during the first month of dosing in high-risk patients who take strong CYP3A4 inhibitors concomitantly.
    Apalutamide: (Major) Progestins are susceptible to drug interactions with hepatic enzyme inducing drugs such as apalutamide. Concurrent administration of apalutamide with progestins, oral contraceptives, or non-oral combination contraceptives may reduce hormonal concentrations. Progestins are CYP3A4 substrates and apalutamide is a strong CYP3A4 inducer. If the hormone is used for contraception, an alternate or additional form of contraception should be considered. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of apalutamide. Monitor hormonal replacement therapy for loss of efficacy while on apalutamide, with dose adjustments as needed. Women taking hormonal replacement and apalutamide should report breakthrough bleeding to their prescribers. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
    Aprepitant, Fosaprepitant: (Major) If aprepitant, fosaprepitant is coadministered with hormonal contraceptives, including hormonal contraceptive devices (skin patches, implants, and hormonal IUDs), use an alternative or back-up non-hormonal method of contraception (e.g., condoms, spermicides) during treatment and for at least 1 month following the last dose of aprepitant, fosaprepitant. The efficacy of progestins may be reduced when coadministered with aprepitant, fosaprepitant and for 28 days after the last dose. The exact mechanism for this interaction has not been described. Progestins are CYP3A4 substrates and aprepitant, fosaprepitant is a CYP3A4 inducer; however, aprepitant, fosaprepitant is also a dose-dependent weak-to-moderate CYP3A4 inhibitor. When administered as an oral 3-day regimen (125mg/80mg/80mg) in combination with ondansetron and dexamethasone, aprepitant decreased trough concentrations of ethinyl estradiol and norethindrone by up to 64% for 3 weeks post-treatment. When ethinyl estradiol and norgestimate were administered on days 1 to 21 and aprepitant (40mg) give as a single dose on day 8, the AUC of ethinyl estradiol decreased by 4% on day 8 and by 29% on day 12; the AUC of norelgestromin increased by 18% on day 8, and decreased by 10% on day 12. Trough concentrations of both ethinyl estradiol and norelgestromin were generally lower after coadministration of aprepitant (40mg) on day 8 compared to administration without aprepitant. Specific studies have not been done with other hormonal contraceptives (e.g., progestins, non-oral combination contraceptives), an alternative or additional non-hormonal method of birth control during treatment and for 28 days after treatment is prudent to avoid potential for contraceptive failure. The clinical significance of this is not known since aprepitant, fosaprepitant is only used intermittently.
    Armodafinil: (Major) Armodafinil may cause failure of oral contraceptives or hormonal contraceptive-containing implants or devices due to induction of CYP3A4 isoenzyme metabolism of estrogens and/or the progestins in these products. Female patients of child-bearing potential should be advised to discuss contraceptive options with their health care provider to prevent unintended pregnancies. An alternative method or an additional method of contraception should be utilized during armodafinil therapy and continued for one month after armodafinil discontinuation.
    Artemether; Lumefantrine: (Major) Although no formal drug interaction studies have been performed, the manufacturer states that artemether; lumefantrine may reduce the effectiveness of hormonal contraceptives, including non-oral combination contraceptives, oral contraceptives, and progestin contraceptives (i.e. norgestrel, progesterone, etonogestrel, levonorgestrel, medroxyprogesterone, and norethindrone). This may be due to a CYP3A4 interaction. Artemether; lumefantrine is a substrate and ethinyl estradiol is a substrate/inhibitor of the CYP3A4 isoenzyme. Additional use of a non-hormonal method of birth control is recommended.
    Aspirin, ASA; Butalbital; Caffeine: (Moderate) Barbiturates can accelerate the hepatic clearance of progestins. For hormonal contraceptives, this interaction could result in unintended pregnancy or breakthrough bleeding. For patients regularly taking a barbiturate, an alternative or back-up method of contraception may be advisable to ensure contraceptive reliability during the use of the barbiturate, and for 1 month following the discontinuation of barbiturate use. The exception is the use of levonorgestrel progestin IUDs, which have not been reported to interact and appear to maintain reliable efficacy. Pregnancy has been reported during therapy with both estrogen- and/or progestin-based oral contraceptives in patients receiving barbiturates (e.g., phenobarbital). For patients taking progestins for other indications, like hormone replacement, monitor the patient for signs and symptoms of reduced therapeutic efficacy or need for dosage adjustment.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Moderate) Barbiturates can accelerate the hepatic clearance of progestins. For hormonal contraceptives, this interaction could result in unintended pregnancy or breakthrough bleeding. For patients regularly taking a barbiturate, an alternative or back-up method of contraception may be advisable to ensure contraceptive reliability during the use of the barbiturate, and for 1 month following the discontinuation of barbiturate use. The exception is the use of levonorgestrel progestin IUDs, which have not been reported to interact and appear to maintain reliable efficacy. Pregnancy has been reported during therapy with both estrogen- and/or progestin-based oral contraceptives in patients receiving barbiturates (e.g., phenobarbital). For patients taking progestins for other indications, like hormone replacement, monitor the patient for signs and symptoms of reduced therapeutic efficacy or need for dosage adjustment.
    Atazanavir; Cobicistat: (Major) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with etonogestrel. Insufficient data are available to make dosage recommendations, particularly when cobicistat is combined in other antiviral regimens. It is not clear how cobicistat alters various progestin-only agents used for contraception, fertility or luteal support, or for hormone replacement therapy (HRT). Instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. There is a potential for altered efficacy for combined hormonal contraceptives. Consider alternative methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When progestins are used for other purposes, monitor for altered clinical response to hormonal therapy.
    Barbiturates: (Moderate) Barbiturates can accelerate the hepatic clearance of progestins. For hormonal contraceptives, this interaction could result in unintended pregnancy or breakthrough bleeding. For patients regularly taking a barbiturate, an alternative or back-up method of contraception may be advisable to ensure contraceptive reliability during the use of the barbiturate, and for 1 month following the discontinuation of barbiturate use. The exception is the use of levonorgestrel progestin IUDs, which have not been reported to interact and appear to maintain reliable efficacy. Pregnancy has been reported during therapy with both estrogen- and/or progestin-based oral contraceptives in patients receiving barbiturates (e.g., phenobarbital). For patients taking progestins for other indications, like hormone replacement, monitor the patient for signs and symptoms of reduced therapeutic efficacy or need for dosage adjustment.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Moderate) Barbiturates can accelerate the hepatic clearance of progestins. For hormonal contraceptives, this interaction could result in unintended pregnancy or breakthrough bleeding. For patients regularly taking a barbiturate, an alternative or back-up method of contraception may be advisable to ensure contraceptive reliability during the use of the barbiturate, and for 1 month following the discontinuation of barbiturate use. The exception is the use of levonorgestrel progestin IUDs, which have not been reported to interact and appear to maintain reliable efficacy. Pregnancy has been reported during therapy with both estrogen- and/or progestin-based oral contraceptives in patients receiving barbiturates (e.g., phenobarbital). For patients taking progestins for other indications, like hormone replacement, monitor the patient for signs and symptoms of reduced therapeutic efficacy or need for dosage adjustment.
    Belzutifan: (Major) Women taking both progestins and belzutifan should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed belzutifan. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of belzutifan. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. Progestins are CYP3A4 substrates and belzutifan is a weak CYP3A4 inducer.
    Bexarotene: (Major) Bexarotene capsules may theoretically increase the rate of metabolism and reduce plasma concentrations of substrates metabolized by CYP3A4, including oral contraceptives. It is recommended that two reliable forms of contraception be used simultaneously during oral bexarotene therapy. It is strongly recommended that one of the forms of contraception be non-hormonal. Additionally, because of possible CYP3A4 induction, bexarotene may also decrease the efficacy of hormones used for hormone replacement therapy.
    Boceprevir: (Major) Use of non-oral combination contraceptives with boceprevir have not been studied and are contraindicated. Patients receiving boceprevir in combination with ribavirin (and their partners) are required to use two reliable forms of contraception, including a non-hormonal form of birth control, while on therapy and for at least 6 months after treatment. The manufacturer states that one of reliable forms of contraception can be combined oral contraceptives containing ethinyl estradiol and at least 1 mg of norethindrone. Bceprevir is a potent inhibitor of CYP3A4, has been shown to reduce the Cmax of norethindrone by 17%, a decrease which may be sufficient to reduce the effectiveness of combined oral contraceptives containing less than 1 mg of norethindrone. Additionally, ethinyl estradiol plasma concentrations may be decreased is administered with boceprevir.
    Bosentan: (Major) Hormonal contraceptives should not be used as the sole method to prevent pregnancy in patients receiving bosentan. There is a possibility of contraceptive failure when bosentan is coadministered with products containing estrogens and/or progestins. Bosentan is teratogenic. To prevent pregnancy, females of reproductive potential must use 2 acceptable contraception methods during treatment and for 1 month after discontinuation of bosentan therapy. The patient may choose 1 highly effective contraceptive form, including an intrauterine device (IUD) or tubal sterilization, a combination of a hormonal contraceptive with a barrier method, or 2 barrier methods. If a male partner's vasectomy is chosen as a method of contraception, a hormonal or barrier method must still be used by the female patient. Hormonal contraceptives, including oral contraceptives or non-oral combination contraceptives (injectable, transdermal, and implantable contraceptives) may not be reliably effective in the presence of bosentan, since many contraceptive drugs are metabolized by CYP3A4 isoenzymes and bosentan is a significant inducer of CYP3A enzymes. Decreases in hormonal exposure have been documented in drug interaction studies of bosentan with hormonal contraception. Additionally, estrogens and progestins used for hormone replacement therapy (HRT) may also be less effective; patients should be monitored for changes in efficacy such as breakthrough bleeding or an increase in hot flashes. Dosage adjustments may be necessary.
    Bromocriptine: (Minor) Bromocriptine is used to restore ovulation and ovarian function in amenorrheic women. Progestins can cause amenorrhea and, therefore, counteract the desired effects of bromocriptine. Concurrent use is not recommended; an alternate form of contraception is recommended during bromocriptine therapy.
    Butabarbital: (Moderate) Barbiturates can accelerate the hepatic clearance of progestins. For hormonal contraceptives, this interaction could result in unintended pregnancy or breakthrough bleeding. For patients regularly taking a barbiturate, an alternative or back-up method of contraception may be advisable to ensure contraceptive reliability during the use of the barbiturate, and for 1 month following the discontinuation of barbiturate use. The exception is the use of levonorgestrel progestin IUDs, which have not been reported to interact and appear to maintain reliable efficacy. Pregnancy has been reported during therapy with both estrogen- and/or progestin-based oral contraceptives in patients receiving barbiturates (e.g., phenobarbital). For patients taking progestins for other indications, like hormone replacement, monitor the patient for signs and symptoms of reduced therapeutic efficacy or need for dosage adjustment.
    Butalbital; Acetaminophen: (Moderate) Barbiturates can accelerate the hepatic clearance of progestins. For hormonal contraceptives, this interaction could result in unintended pregnancy or breakthrough bleeding. For patients regularly taking a barbiturate, an alternative or back-up method of contraception may be advisable to ensure contraceptive reliability during the use of the barbiturate, and for 1 month following the discontinuation of barbiturate use. The exception is the use of levonorgestrel progestin IUDs, which have not been reported to interact and appear to maintain reliable efficacy. Pregnancy has been reported during therapy with both estrogen- and/or progestin-based oral contraceptives in patients receiving barbiturates (e.g., phenobarbital). For patients taking progestins for other indications, like hormone replacement, monitor the patient for signs and symptoms of reduced therapeutic efficacy or need for dosage adjustment.
    Butalbital; Acetaminophen; Caffeine: (Moderate) Barbiturates can accelerate the hepatic clearance of progestins. For hormonal contraceptives, this interaction could result in unintended pregnancy or breakthrough bleeding. For patients regularly taking a barbiturate, an alternative or back-up method of contraception may be advisable to ensure contraceptive reliability during the use of the barbiturate, and for 1 month following the discontinuation of barbiturate use. The exception is the use of levonorgestrel progestin IUDs, which have not been reported to interact and appear to maintain reliable efficacy. Pregnancy has been reported during therapy with both estrogen- and/or progestin-based oral contraceptives in patients receiving barbiturates (e.g., phenobarbital). For patients taking progestins for other indications, like hormone replacement, monitor the patient for signs and symptoms of reduced therapeutic efficacy or need for dosage adjustment.
    Butalbital; Acetaminophen; Caffeine; Codeine: (Moderate) Barbiturates can accelerate the hepatic clearance of progestins. For hormonal contraceptives, this interaction could result in unintended pregnancy or breakthrough bleeding. For patients regularly taking a barbiturate, an alternative or back-up method of contraception may be advisable to ensure contraceptive reliability during the use of the barbiturate, and for 1 month following the discontinuation of barbiturate use. The exception is the use of levonorgestrel progestin IUDs, which have not been reported to interact and appear to maintain reliable efficacy. Pregnancy has been reported during therapy with both estrogen- and/or progestin-based oral contraceptives in patients receiving barbiturates (e.g., phenobarbital). For patients taking progestins for other indications, like hormone replacement, monitor the patient for signs and symptoms of reduced therapeutic efficacy or need for dosage adjustment.
    Calaspargase pegol: (Major) The concomitant use of calaspargase pegol and hormonal contraceptives may reduce the efficacy of hormonal contraceptives. Women of reproductive potential should use a non-hormonal method of birth control during therapy and for at least 3 months after the last calaspargase pegol dose due to the risk of fetal harm.
    Canagliflozin: (Minor) Progestins can impair glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued.
    Canagliflozin; Metformin: (Minor) Patients receiving antidiabetic agents like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance. (Minor) Progestins can impair glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued.
    Carbamazepine: (Major) Concomitant use of carbamazepine with hormonal products may render the hormonal product less effective. The plasma concentrations of the hormones may be decreased because carbamazepine induces the activity of hepatic metabolic enzymes. Women taking both hormones and hepatic enzyme-inducing drugs should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed hepatic enzyme inducing drugs, or higher-dose hormonal regimens may be indicated where acceptable or applicable as pregnancy has been reported in patients taking the hepatic enzyme inducing drug phenytoin concurrently with hormonal contraceptives. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of the interacting medication. Additionally, epileptic women taking both anticonvulsants and OCs may be at higher risk of folate deficiency secondary to additive effects on folate metabolism; if oral contraceptive failure occurs, the additive effects could potentially heighten the risk of neural tube defects in pregnancy. Patients taking progestins for other indications may need to be monitored for reductions in clinical effect of the progestin. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
    Cenobamate: (Major) Women taking both progestins and cenobamate should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed cenobamate. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of cenobamate. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on cenobamate, with dose adjustments made based on clinical efficacy. Progestins are CYP3A4 substrates and cenobamate is a moderate CYP3A4 inducer. Concurrent administration may increase progestin elimination.
    Chloramphenicol: (Minor) Coadministration of etonogestrel and strong CYP3A4 inhibitors such as chloramphenicol may increase the serum concentration of etonogestrel.
    Chlorpropamide: (Minor) Progestins can impair glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued.
    Cimetidine: (Minor) Coadministration of etonogestrel and moderate CYP3A4 inhibitors such as cimetidine may increase the serum concentration of etonogestrel.
    Ciprofloxacin: (Minor) Coadministration of etonogestrel and moderate CYP3A4 inhibitors such as ciprofloxacin may increase the serum concentration of etonogestrel.
    Clarithromycin: (Minor) Coadministration of etonogestrel and strong CYP3A4 inhibitors such as clarithromycin may increase the serum concentration of etonogestrel.
    Clobazam: (Major) The addition of non-hormonal forms of contraception are recommended during concurrent use of clobazam and hormonal contraceptives. Concurrent administration of clobazam, a weak CYP3A4 inducer, with progestins may increase the elimination of these hormones. The additional contraceptive agent may need to be continued for 1 month after discontinuation of the interacting medication. Patients taking these hormones for indications other than contraception may need to be monitored for reduced clinical effect while on clobazam, with dose adjustments made based on clinical efficacy.
    Cobicistat: (Major) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with etonogestrel. Insufficient data are available to make dosage recommendations, particularly when cobicistat is combined in other antiviral regimens. It is not clear how cobicistat alters various progestin-only agents used for contraception, fertility or luteal support, or for hormone replacement therapy (HRT). Instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. There is a potential for altered efficacy for combined hormonal contraceptives. Consider alternative methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When progestins are used for other purposes, monitor for altered clinical response to hormonal therapy.
    Cyclosporine: (Moderate) Coadministration may result in increased serum concentrations of cyclosporine or etonogestrel. There have been reports indicating the estrogens and/or progestins in oral contraceptives or non-oral combination contraceptives may inhibit the metabolism of cyclosporine. Delayed cyclosporine clearance and elevated cyclosporine concentrations can lead to seizures, nephrotoxicity, and/or hepatotoxicity. If etonogestrel is initiated or discontinued, the patient's cyclosporine concentrations should be monitored closely. In addition, coadministration of etonogestrel and moderate CYP3A4 inhibitors such as cyclosporine may increase the serum concentration of etonogestrel.
    Dabrafenib: (Major) Avoid concomitant use of dabrafenib and hormonal contraceptives; decreased hormonal contraceptive concentrations and loss of efficacy may occur. Use of an alternative non-hormonal contraceptive method of birth control is recommended during treatment for 2 weeks after the last dose of dabrafenib. Dabrafenib is a moderate CYP3A4 inducer and many hormonal contraceptive are CYP3A4 substrates.
    Danazol: (Minor) Coadministration of etonogestrel and moderate CYP3A4 inhibitors such as danazol may increase the serum concentration of etonogestrel.
    Dapagliflozin: (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Dapagliflozin; Metformin: (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. (Minor) Patients receiving antidiabetic agents like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance.
    Dapagliflozin; Saxagliptin: (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. (Minor) Progestins can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Darunavir: (Minor) Coadministration of etonogestrel and strong CYP3A4 inhibitors such as darunavir may increase the serum concentration of etonogestrel.
    Darunavir; Cobicistat: (Major) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with etonogestrel. Insufficient data are available to make dosage recommendations, particularly when cobicistat is combined in other antiviral regimens. It is not clear how cobicistat alters various progestin-only agents used for contraception, fertility or luteal support, or for hormone replacement therapy (HRT). Instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. There is a potential for altered efficacy for combined hormonal contraceptives. Consider alternative methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When progestins are used for other purposes, monitor for altered clinical response to hormonal therapy. (Minor) Coadministration of etonogestrel and strong CYP3A4 inhibitors such as darunavir may increase the serum concentration of etonogestrel.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with etonogestrel. Insufficient data are available to make dosage recommendations, particularly when cobicistat is combined in other antiviral regimens. It is not clear how cobicistat alters various progestin-only agents used for contraception, fertility or luteal support, or for hormone replacement therapy (HRT). Instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. There is a potential for altered efficacy for combined hormonal contraceptives. Consider alternative methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When progestins are used for other purposes, monitor for altered clinical response to hormonal therapy. (Minor) Coadministration of etonogestrel and strong CYP3A4 inhibitors such as darunavir may increase the serum concentration of etonogestrel.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Coadministration may result in an increased or decreased effect of etonogestrel. Contraceptive efficacy may be reduced. Etonogestrel is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor and CYP3A4 inducer.
    Deferasirox: (Moderate) Counsel patients to use non-hormonal methods of contraception during treatment with deferasirox. Deferasirox may induce the CYP3A4 metabolism of hormonal contraceptives; thereby decreasing their effectiveness.
    Diltiazem: (Minor) Coadministration of etonogestrel and moderate CYP3A4 inhibitors such as diltiazem may increase the serum concentration of etonogestrel.
    Dronedarone: (Minor) Coadministration of etonogestrel and moderate CYP3A4 inhibitors such as dronedarone may increase the serum concentration of etonogestrel.
    Efavirenz: (Major) Patients should be advised to use a reliable method of barrier contraception in addition to oral contraceptives or non-oral combination contraceptives, including implantable etonogestrel, while using efavirenz. Efavirenz has no effect on ethinyl estradiol concentrations, but levels of progestins (norelgestromin, levonorgestrel, and etonogestrel) can be markedly decreased. Norelgestromin Cmax and AUC decreased by 46% and 64%, respectively. Levonorgestrel Cmax and AUC decreased by 80% and 83%, respectively. Etonogestrel AUC decreased by 63% to 82%. There have been postmarketing reports of contraceptive failure with implantable etonogestrel in efavirenz-exposed patients. There are no effects of ethinyl estradiol/norgestimate on efavirenz plasma concentrations.
    Efavirenz; Emtricitabine; Tenofovir: (Major) Patients should be advised to use a reliable method of barrier contraception in addition to oral contraceptives or non-oral combination contraceptives, including implantable etonogestrel, while using efavirenz. Efavirenz has no effect on ethinyl estradiol concentrations, but levels of progestins (norelgestromin, levonorgestrel, and etonogestrel) can be markedly decreased. Norelgestromin Cmax and AUC decreased by 46% and 64%, respectively. Levonorgestrel Cmax and AUC decreased by 80% and 83%, respectively. Etonogestrel AUC decreased by 63% to 82%. There have been postmarketing reports of contraceptive failure with implantable etonogestrel in efavirenz-exposed patients. There are no effects of ethinyl estradiol/norgestimate on efavirenz plasma concentrations.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Major) Patients should be advised to use a reliable method of barrier contraception in addition to oral contraceptives or non-oral combination contraceptives, including implantable etonogestrel, while using efavirenz. Efavirenz has no effect on ethinyl estradiol concentrations, but levels of progestins (norelgestromin, levonorgestrel, and etonogestrel) can be markedly decreased. Norelgestromin Cmax and AUC decreased by 46% and 64%, respectively. Levonorgestrel Cmax and AUC decreased by 80% and 83%, respectively. Etonogestrel AUC decreased by 63% to 82%. There have been postmarketing reports of contraceptive failure with implantable etonogestrel in efavirenz-exposed patients. There are no effects of ethinyl estradiol/norgestimate on efavirenz plasma concentrations.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with etonogestrel. Insufficient data are available to make dosage recommendations, particularly when cobicistat is combined in other antiviral regimens. It is not clear how cobicistat alters various progestin-only agents used for contraception, fertility or luteal support, or for hormone replacement therapy (HRT). Instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. There is a potential for altered efficacy for combined hormonal contraceptives. Consider alternative methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When progestins are used for other purposes, monitor for altered clinical response to hormonal therapy.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with etonogestrel. Insufficient data are available to make dosage recommendations, particularly when cobicistat is combined in other antiviral regimens. It is not clear how cobicistat alters various progestin-only agents used for contraception, fertility or luteal support, or for hormone replacement therapy (HRT). Instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. There is a potential for altered efficacy for combined hormonal contraceptives. Consider alternative methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When progestins are used for other purposes, monitor for altered clinical response to hormonal therapy.
    Empagliflozin: (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Empagliflozin; Linagliptin: (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents, such as linagliptin, should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Empagliflozin; Linagliptin; Metformin: (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents, such as linagliptin, should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. (Minor) Patients receiving antidiabetic agents like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance.
    Empagliflozin; Metformin: (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. (Minor) Patients receiving antidiabetic agents like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance.
    Encorafenib: (Major) Avoid coadministration of encorafenib and hormonal contraceptives due to the potential for loss of contraceptive efficacy. Advise females of reproductive potential to use an effective, non-hormonal method of contraception during treatment and for 2 weeks after the final dose of encorafenib. Encorafenib can cause fetal harm when administered during pregnancy.
    Enzalutamide: (Major) Avoid coadministration of enzalutamide with progestins if used for contraception; consider an alternate or additional form of contraception. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of enzalutamide. Patients taking hormonal replacement therapy may need to be monitored for reduced clinical effect while on enzalutamide, with dose adjustments made based on clinical efficacy. Higher-dose hormonal regimens may be indicated where acceptable or applicable. Women taking hormonal replacement and enzalutamide should report breakthrough bleeding, hot flashes, or other symptoms to their prescribers. Progestins are substrates of CYP3A4 and enzalutamide is a strong CYP3A4 inducer. Concurrent administration of enzalutamide with progestins, oral contraceptives, or non-oral combination contraceptives may reduce hormonal concentrations. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
    Ertugliflozin: (Minor) Progestins can impair glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued.
    Ertugliflozin; Metformin: (Minor) Patients receiving antidiabetic agents like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance. (Minor) Progestins can impair glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued.
    Ertugliflozin; Sitagliptin: (Minor) Progestins can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. (Minor) Progestins can impair glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued.
    Erythromycin: (Minor) Coadministration of etonogestrel and moderate CYP3A4 inhibitors such as erythromycin may increase the serum concentration of etonogestrel.
    Erythromycin; Sulfisoxazole: (Minor) Coadministration of etonogestrel and moderate CYP3A4 inhibitors such as erythromycin may increase the serum concentration of etonogestrel.
    Etravirine: (Major) Women taking both progestins and etravirine should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed etravirine. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for one month after discontinuation of etravirine. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. Progestins are CYP3A4 substrates and etravirine is a strong CYP3A4 inducer.
    Felbamate: (Major) Based on very limited data, it appears felbamate can accelerate the clearance of the estrogen component of some oral contraceptives. Patients who experience breakthrough bleeding while receiving these drugs together should notify their prescribers. An alternate or additional form of contraception should be used during concomitant treatment. Additionally, patients taking non-oral combination contraceptives or estrogens or progestins for hormone replacement therapy may also experience reduced clinical efficacy; dosage adjustments may be necessary.
    Fluconazole: (Minor) Coadministration of etonogestrel and moderate CYP3A4 inhibitors such as fluconazole may increase the serum concentration of etonogestrel.
    Fluvoxamine: (Minor) Co-administration of etonogestrel and moderate CYP3A4 inhibitors, such as fluvoxamine, may increase the serum concentrations of progestins, including etonogestrel.
    Fosamprenavir: (Major) Oral contraceptives and non-oral combination contraceptives should not be administered with fosamprenavir. Alternative methods of non-hormonal contraception are recommended. Fosamprenavir should not be coadministered with oral contraceptives as clinically significant hepatic enzyme (transaminase) elevations may occur with concomitant use. Additionally, hormonal contraceptives, estrogens, and progestins may decrease the serum concentrations of fosamprenavir's active metabolite, amprenavir, which could lead to loss of virologic response and possible viral resistance. Additionally, data on the effects that other protease inhibitors have on the serum concentrations of estrogens and progestins are complex; some protease inhibitors increase and others decrease the metabolism of hormonal contraceptives. Coadministration of medroxyprogesterone, a CYP3A substrate with fosamprenavir, a strong CYP3A inhibitor. should be avoided since it is expected to increase concentrations of medroxyprogesterone acetate. It is not known if fosamprenavir alters the metabolism of other hormonal contraceptives or other estrogen or progestin products. Because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives concurrently with protease inhibitors should use an additional barrier method of contraception such as condoms. In women receiving oral contraceptives containing the progestin drospirenone, consider monitoring serum potassium concentrations during the first month of dosing in high-risk patients who take strong CYP3A4 inhibitors concomitantly.
    Glimepiride: (Minor) Progestins can impair glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued.
    Glimepiride; Rosiglitazone: (Minor) Progestins can impair glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. (Minor) Progestins can impair glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued.
    Glipizide: (Minor) Progestins can impair glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued.
    Glipizide; Metformin: (Minor) Patients receiving antidiabetic agents like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance. (Minor) Progestins can impair glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued.
    Glyburide: (Minor) Progestins can impair glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued.
    Glyburide; Metformin: (Minor) Patients receiving antidiabetic agents like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance. (Minor) Progestins can impair glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued.
    Grapefruit juice: (Minor) Coadministration of etonogestrel and strong CYP3A4 inhibitors such as grapefruit juice may increase the serum concentration of etonogestrel. Grapefruit juice contains a compound that inhibits CYP3A4 in enterocytes. The clinical significance of the interaction is unknown. It is possible that progestin induced side effects could be increased in some individuals. Patients should be advised to not significantly alter their grapefruit juice ingestion.
    Griseofulvin: (Major) The concurrent use of griseofulvin and oral contraceptives can reduce contraceptive efficacy and result in an unintended pregnancy and/or breakthrough bleeding. This risk is particularly serious because griseofulvin is contraindicated during pregnancy due to the risk of teratogenic and abortifacient effects. An alternate or additional form of contraception should be used during concomitant treatment and continued for 1 month after griseofulvin discontinuation. If these drugs are used together, counsel the patient about the risk of pregnancy and teratogenic effects, and instruct the patient to notify the prescriber if they experience breakthrough bleeding while receiving these drugs together. Additionally, patients taking non-oral combination contraceptives or progestins for hormone replacement therapy may also experience reduced clinical efficacy.
    Hydantoins: (Major) Drugs that can induce hepatic enzymes can accelerate the rate of metabolism of hormonal contraceptives. Pregnancy has been reported during therapy with progestin contraceptives in patients receiving hydantoins. Women taking both hormones and hepatic enzyme-inducing drugs should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed concomitant therapy with enzyme-inducing anticonvulsants, or higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for one month after discontinuation of the interacting medication. Additionally, epileptic women taking both anticonvulsants and OCs may be at higher risk of folate deficiency secondary to additive effects on folate metabolism; if oral contraceptive failure occurs, the additive effects could potentially heighten the risk of neural tube defects in pregnancy.
    Idelalisib: (Minor) Coadministration of etonogestrel and strong CYP3A4 inhibitors such as idelalisib may increase the serum concentration of etonogestrel.
    Imatinib: (Minor) Coadministration of etonogestrel and moderate CYP3A4 inhibitors such as imatinib may increase the serum concentration of etonogestrel.
    Incretin Mimetics: (Moderate) Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as progestin-only oral contraceptives. Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive (OC) at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For Lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. Additionally, progestins can impair glucose tolerance. Monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control.
    Indinavir: (Moderate) Indinavir decreases the metabolism of oral contraceptives and non-oral combination contraceptives; the AUC for ethinyl estradiol and norethindrone increased by 24+/-17% and 26+/-14%, respectively, when coadministered with indinavir. It is unknown whether this applies to etonogestrel. Women receiving hormonal contraceptives and anti-retroviral protease inhibitors (PIs), such as indinavir, should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. Because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives with PIs should use an additional barrier method of contraception such as condoms.
    Insulins: (Minor) Progestins can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Isavuconazonium: (Minor) Coadministration of etonogestrel and moderate CYP3A4 inhibitors such as isavuconazonium may increase the serum concentration of etonogestrel.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Women taking both progestins and rifampin should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed rifampin. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for one month after discontinuation of rifampin. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. Progestins are CYP3A4 substrates and rifampin is a strong CYP3A4 inducer.
    Isoniazid, INH; Rifampin: (Major) Women taking both progestins and rifampin should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed rifampin. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for one month after discontinuation of rifampin. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. Progestins are CYP3A4 substrates and rifampin is a strong CYP3A4 inducer.
    Itraconazole: (Minor) Coadministration of etonogestrel and strong CYP3A4 inhibitors such as itraconazole may increase the serum concentration of etonogestrel.
    Ivosidenib: (Major) Consider alternative methods of contraception in patients receiving ivosidenib. Coadministration may decrease the concentrations of hormonal contraceptives.
    Ketoconazole: (Minor) Coadministration of etonogestrel and strong CYP3A4 inhibitors such as ketoconazole may increase the serum concentration of etonogestrel.
    Lamotrigine: (Moderate) Hormonal contraceptives, such as etonogestrel, may affect the metabolism of lamotrigine. Consequently, plasma concentrations of lamotrigine may decrease. Patients should be monitored for loss of efficacy of lamotrigine during concurrent use of etonogestrel.
    Lansoprazole; Amoxicillin; Clarithromycin: (Minor) Coadministration of etonogestrel and strong CYP3A4 inhibitors such as clarithromycin may increase the serum concentration of etonogestrel.
    Lesinurad: (Major) Hormonal contraceptives, including combination oral contraceptives, non-oral combination contraceptives, and contraceptives containing only progestins. This includes injectable, transdermal, and implantable forms. Hormonal contraceptives may not be reliable when coadministered with lesinurad. Females should use additional, non-hormonal methods of contraception and not rely solely on hormonal contraceptive methods when taking lesinurad.
    Lesinurad; Allopurinol: (Major) Hormonal contraceptives, including combination oral contraceptives, non-oral combination contraceptives, and contraceptives containing only progestins. This includes injectable, transdermal, and implantable forms. Hormonal contraceptives may not be reliable when coadministered with lesinurad. Females should use additional, non-hormonal methods of contraception and not rely solely on hormonal contraceptive methods when taking lesinurad.
    Linagliptin: (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents, such as linagliptin, should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Linagliptin; Metformin: (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents, such as linagliptin, should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. (Minor) Patients receiving antidiabetic agents like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance.
    Lopinavir; Ritonavir: (Major) Coadministration may result in an increased or decreased effect of etonogestrel. Contraceptive efficacy may be reduced. Etonogestrel is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor and CYP3A4 inducer.
    Lorlatinib: (Major) Women taking both progestins and lorlatinib should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed lorlatinib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of lorlatinib. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. Progestins are CYP3A4 substrates and lorlatinib is a moderate CYP3A4 inducer.
    Lumacaftor; Ivacaftor: (Major) Avoid concomitant use of hormonal contraceptives and lumacaftor; ivacaftor, unless the benefits outweigh the risks. Lumacaftor; ivacaftor may decrease hormonal contraceptive exposure, reducing efficacy. When coadministered with lumacaftor; ivacaftor, hormonal contraceptives are not a reliable method of effective contraception; instruct patients on alternative methods of birth control. In addition, concomitant use may increase the incidence of menstruation-associated adverse reactions (e.g., amenorrhea, dysmenorrhea, menorrhagia).
    Meglitinides: (Minor) Progestins can impair glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued.
    Mephobarbital: (Moderate) Barbiturates can accelerate the hepatic clearance of progestins. For hormonal contraceptives, this interaction could result in unintended pregnancy or breakthrough bleeding. For patients regularly taking a barbiturate, an alternative or back-up method of contraception may be advisable to ensure contraceptive reliability during the use of the barbiturate, and for 1 month following the discontinuation of barbiturate use. The exception is the use of levonorgestrel progestin IUDs, which have not been reported to interact and appear to maintain reliable efficacy. Pregnancy has been reported during therapy with both estrogen- and/or progestin-based oral contraceptives in patients receiving barbiturates (e.g., phenobarbital). For patients taking progestins for other indications, like hormone replacement, monitor the patient for signs and symptoms of reduced therapeutic efficacy or need for dosage adjustment.
    Metformin: (Minor) Patients receiving antidiabetic agents like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance.
    Metformin; Repaglinide: (Minor) Patients receiving antidiabetic agents like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance.
    Metformin; Rosiglitazone: (Minor) Patients receiving antidiabetic agents like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance. (Minor) Progestins can impair glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued.
    Metformin; Saxagliptin: (Minor) Patients receiving antidiabetic agents like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance. (Minor) Progestins can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Metformin; Sitagliptin: (Minor) Patients receiving antidiabetic agents like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance. (Minor) Progestins can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Methohexital: (Moderate) Barbiturates can accelerate the hepatic clearance of progestins. For hormonal contraceptives, this interaction could result in unintended pregnancy or breakthrough bleeding. For patients regularly taking a barbiturate, an alternative or back-up method of contraception may be advisable to ensure contraceptive reliability during the use of the barbiturate, and for 1 month following the discontinuation of barbiturate use. The exception is the use of levonorgestrel progestin IUDs, which have not been reported to interact and appear to maintain reliable efficacy. Pregnancy has been reported during therapy with both estrogen- and/or progestin-based oral contraceptives in patients receiving barbiturates (e.g., phenobarbital). For patients taking progestins for other indications, like hormone replacement, monitor the patient for signs and symptoms of reduced therapeutic efficacy or need for dosage adjustment.
    Mifepristone: (Contraindicated) Mifepristone is a progesterone-receptor antagonist and will interfere with the effectiveness of hormonal contraceptives. Therefore, non-hormonal contraceptive methods should be used in Cushing's patients taking mifepristone.
    Mobocertinib: (Major) Women taking both progestins and mobocertinib should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed mobocertinib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for one month after discontinuation of mobocertinib. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. Progestins are CYP3A substrates and mobocertinib is a weak CYP3A inducer.
    Modafinil: (Major) Modafinil may cause failure of oral contraceptives or hormonal contraceptive-containing implants or devices due to induction of CYP3A4 isoenzyme metabolism of the progestins in these products. An alternative method or an additional method of contraception should be utilized during modafinil therapy and continued for one month after modafinil discontinuation. If these drugs are used together, monitor patients for a decrease in clinical effects; patients should report breakthrough bleeding to their prescriber. Dosage adjustments may be necessary.
    Nelfinavir: (Major) Coadministration may result in an increased or decreased effect of etonogestrel. Etonogestrel is not recommended for women who require the chronic use of drugs that are potent inducers of hepatic enzymes, as contraceptive efficacy is likely to be reduced. In addition, coadministration of etonogestrel and strong CYP3A4 inhibitors such as nelfinavir may increase the serum concentration of etonogestrel.
    Netupitant, Fosnetupitant; Palonosetron: (Minor) Coadministration of etonogestrel and moderate CYP3A4 inhibitors such as netupitant may increase the serum concentration of etonogestrel.
    Nevirapine: (Moderate) Nevirapine may decrease plasma concentrations of oral contraceptives and non-oral combination contraceptives (i.e., ethinyl estradiol and norethindrone). However despite lower exposures, literature suggests that use of nevirapine has no effect on pregnancy rates among HIV-infected women on combined oral contraceptives. Thus, the manufacturer states that no dose adjustments are needed when these drugs are used for contraception in combination with nevirapine. When these oral contraceptives are used for hormone replacement and given with nevirapine, the therapeutic effect of the hormonal therapy should be monitored.
    Nicardipine: (Minor) Coadministration of etonogestrel and moderate CYP3A4 inhibitors such as nicardipine may increase the serum concentration of etonogestrel.
    Nilotinib: (Minor) Coadministration of etonogestrel and moderate CYP3A4 inhibitors such as nilotinib may increase the serum concentration of etonogestrel.
    Octreotide: (Minor) Coadministration of etonogestrel and moderate CYP3A4 inhibitors such as octreotide may increase the serum concentration of etonogestrel.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) Coadministration may result in an increased or decreased effect of etonogestrel. Contraceptive efficacy may be reduced. Etonogestrel is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor and CYP3A4 inducer.
    Oxcarbazepine: (Major) Progestins are susceptible to drug interactions with hepatic enzyme inducing drugs such as oxcarbazepine. Concurrent administration of oxcarbazepine progestins may increase the hormone's elimination. A high percentage of breakthrough bleeding has been reported in the literature from the combined use of oxcarbazepine and oral contraceptives; the results of one study demonstrated that the mean AUC of ethinyl estradiol/levonorgestrel was decreased by 52% when coadministered with oxcarbazepine. Women taking both hormones and hepatic enzyme-inducing drugs should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed hepatic enzyme inducing drugs, or higher-dose hormonal regimens may be indicated where acceptable or applicable as pregnancy has been reported in patients taking the hepatic enzyme inducing drug phenytoin concurrently with hormonal contraceptives. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of the interacting medication. Additionally, epileptic women taking both anticonvulsants and OCs may be at higher risk of folate deficiency secondary to additive effects on folate metabolism; if oral contraceptive failure occurs, the additive effects could potentially heighten the risk of neural tube defects in pregnancy. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on oxcarbazepine, with dose adjustments made based on clinical efficacy.
    Pegaspargase: (Major) Avoid the concomitant use of pegaspargase and hormonal contraceptives due to the potential for decreased contraceptive efficacy and risk of fetal harm from pegaspargase. Women of reproductive potential should use an effective non-hormonal method of birth control during therapy and for at least 3 months after the last pegaspargase dose.
    Pentobarbital: (Moderate) Barbiturates can accelerate the hepatic clearance of progestins. For hormonal contraceptives, this interaction could result in unintended pregnancy or breakthrough bleeding. For patients regularly taking a barbiturate, an alternative or back-up method of contraception may be advisable to ensure contraceptive reliability during the use of the barbiturate, and for 1 month following the discontinuation of barbiturate use. The exception is the use of levonorgestrel progestin IUDs, which have not been reported to interact and appear to maintain reliable efficacy. Pregnancy has been reported during therapy with both estrogen- and/or progestin-based oral contraceptives in patients receiving barbiturates (e.g., phenobarbital). For patients taking progestins for other indications, like hormone replacement, monitor the patient for signs and symptoms of reduced therapeutic efficacy or need for dosage adjustment.
    Pexidartinib: (Major) Avoid the concomitant use of pexidartinib and hormone-containing contraceptives; the effectiveness of hormonal contraceptives may be decreased resulting in contraceptive failure. Females of reproductive potential should avoid pregnancy during and for 1 month after treatment with pexidartinib. Advise these patients to use an effective, non-hormonal method of contraception. Pexidartinib is a moderate CYP3A inducer and many non-oral combination contraceptives (injectable, transdermal, and implantable contraceptives) are metabolized by CYP3A.
    Phenobarbital: (Moderate) Barbiturates can accelerate the hepatic clearance of progestins. For hormonal contraceptives, this interaction could result in unintended pregnancy or breakthrough bleeding. For patients regularly taking a barbiturate, an alternative or back-up method of contraception may be advisable to ensure contraceptive reliability during the use of the barbiturate, and for 1 month following the discontinuation of barbiturate use. The exception is the use of levonorgestrel progestin IUDs, which have not been reported to interact and appear to maintain reliable efficacy. Pregnancy has been reported during therapy with both estrogen- and/or progestin-based oral contraceptives in patients receiving barbiturates (e.g., phenobarbital). For patients taking progestins for other indications, like hormone replacement, monitor the patient for signs and symptoms of reduced therapeutic efficacy or need for dosage adjustment.
    Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Moderate) Barbiturates can accelerate the hepatic clearance of progestins. For hormonal contraceptives, this interaction could result in unintended pregnancy or breakthrough bleeding. For patients regularly taking a barbiturate, an alternative or back-up method of contraception may be advisable to ensure contraceptive reliability during the use of the barbiturate, and for 1 month following the discontinuation of barbiturate use. The exception is the use of levonorgestrel progestin IUDs, which have not been reported to interact and appear to maintain reliable efficacy. Pregnancy has been reported during therapy with both estrogen- and/or progestin-based oral contraceptives in patients receiving barbiturates (e.g., phenobarbital). For patients taking progestins for other indications, like hormone replacement, monitor the patient for signs and symptoms of reduced therapeutic efficacy or need for dosage adjustment.
    Phentermine; Topiramate: (Moderate) Topiramate may increase the clearance and compromise the efficacy of progestins used in contraception or hormone replacement therapies. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. However, pregnancy has been reported in patients who are using hormonal-containing contraceptives and taking hepatic enzyme inducers like topiramate. Patients taking progestin-containing contraceptives or patients taking progestins for hormone replacement therapy (HRT) should report changes in their bleeding patterns to their prescribers. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception may also be needed.
    Pioglitazone: (Minor) Progestins can impair glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued.
    Pioglitazone; Glimepiride: (Minor) Progestins can impair glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. (Minor) Progestins can impair glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued.
    Pioglitazone; Metformin: (Minor) Patients receiving antidiabetic agents like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance. (Minor) Progestins can impair glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued.
    Pitolisant: (Major) Advise patients to use an alternative, non-hormonal contraceptive during and for at least 21 days after discontinuation of pitolisant. Pitolisant is a weak CYP3A4 inducer and may decrease the plasma exposure of hormonal contraceptives resulting in decreased efficacy.
    Posaconazole: (Minor) Coadministration of etonogestrel and strong CYP3A4 inhibitors such as posaconazole may increase the serum concentration of etonogestrel.
    Pramlintide: (Minor) Progestins can impair glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued.
    Prasterone, Dehydroepiandrosterone, DHEA (Dietary Supplements): (Moderate) Either additive or antagonistic effects could potentially occur if prasterone is combined with progestins.
    Prasterone, Dehydroepiandrosterone, DHEA (FDA-approved): (Moderate) Either additive or antagonistic effects could potentially occur if prasterone is combined with progestins.
    Primidone: (Moderate) Barbiturates can accelerate the hepatic clearance of progestins. For hormonal contraceptives, this interaction could result in unintended pregnancy or breakthrough bleeding. For patients regularly taking a barbiturate, an alternative or back-up method of contraception may be advisable to ensure contraceptive reliability during the use of the barbiturate, and for 1 month following the discontinuation of barbiturate use. The exception is the use of levonorgestrel progestin IUDs, which have not been reported to interact and appear to maintain reliable efficacy. Pregnancy has been reported during therapy with both estrogen- and/or progestin-based oral contraceptives in patients receiving barbiturates (e.g., phenobarbital). For patients taking progestins for other indications, like hormone replacement, monitor the patient for signs and symptoms of reduced therapeutic efficacy or need for dosage adjustment.
    Quinine: (Minor) Coadministration of etonogestrel and moderate CYP3A4 inhibitors such as quinine may increase the serum concentration of etonogestrel.
    Ribociclib: (Minor) Coadministration of etonogestrel and moderate CYP3A4 inhibitors such as ribociclib may increase the serum concentration of etonogestrel.
    Ribociclib; Letrozole: (Minor) Coadministration of etonogestrel and moderate CYP3A4 inhibitors such as ribociclib may increase the serum concentration of etonogestrel.
    Rifampin: (Major) Women taking both progestins and rifampin should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed rifampin. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for one month after discontinuation of rifampin. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. Progestins are CYP3A4 substrates and rifampin is a strong CYP3A4 inducer.
    Rifapentine: (Major) Women taking both progestins and rifapentine should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed rifapentine. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for one month after discontinuation of rifapentine. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. Progestins are CYP3A4 substrates and rifapentine is a strong CYP3A4 inducer.
    Ritonavir: (Major) Coadministration may result in an increased or decreased effect of etonogestrel. Contraceptive efficacy may be reduced. Etonogestrel is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor and CYP3A4 inducer.
    Rosiglitazone: (Minor) Progestins can impair glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued.
    Rufinamide: (Major) Coadministration of hormonal contraceptives with rufinamide may reduce hormone concentrations and therefore reduce the clinical efficacy of hormonal contraceptives. If coadministration is necessary, recommend patients use additional non-hormonal forms of contraception. Hormonal contraceptives are metabolized by CYP3A4 and rufinamide is a weak CYP3A4 inducer.
    Saquinavir: (Minor) Coadministration of etonogestrel and strong CYP3A4 inhibitors such as saquinavir may increase the serum concentration of etonogestrel.
    Saxagliptin: (Minor) Progestins can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Secobarbital: (Moderate) Barbiturates can accelerate the hepatic clearance of progestins. For hormonal contraceptives, this interaction could result in unintended pregnancy or breakthrough bleeding. For patients regularly taking a barbiturate, an alternative or back-up method of contraception may be advisable to ensure contraceptive reliability during the use of the barbiturate, and for 1 month following the discontinuation of barbiturate use. The exception is the use of levonorgestrel progestin IUDs, which have not been reported to interact and appear to maintain reliable efficacy. Pregnancy has been reported during therapy with both estrogen- and/or progestin-based oral contraceptives in patients receiving barbiturates (e.g., phenobarbital). For patients taking progestins for other indications, like hormone replacement, monitor the patient for signs and symptoms of reduced therapeutic efficacy or need for dosage adjustment.
    Simvastatin; Sitagliptin: (Minor) Progestins can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Sitagliptin: (Minor) Progestins can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    St. John's Wort, Hypericum perforatum: (Major) It is possible that, as with other CYP3A4 inducers, St. John's Wort could reduce the therapeutic efficacy of progestin-only contraceptives. Women should report irregular menstrual bleeding or other hormone-related symptoms to their health care providers if they are taking St. John's Wort concurrently with their hormones. Avoidance of these combinations is recommended. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
    Sugammadex: (Major) If an oral contraceptive is taken the same day sugammadex is administered, the patient must use an additional, non-hormonal contraceptive method or back-up method of contraception for the next 7 days. Sugammadex may bind to progestogen, resulting in a decrease in progestogen exposure. The administration of a bolus dose of sugammadex results in actions that are essentially equivalent to missing one or more doses of contraceptives containing estrogen or progestogen, including combination oral contraceptives, non-oral combination contraceptives, or progestins.
    Sulfonylureas: (Minor) Progestins can impair glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued.
    Tazemetostat: (Major) Women taking both progestins and tazemetostat should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed tazemetostat. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of tazemetostat. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. Progestins are CYP3A4 substrates and tazemetostat is a weak CYP3A4 inducer.
    Telithromycin: (Minor) Coadministration of etonogestrel and strong CYP3A4 inhibitors such as telithromycin may increase the serum concentration of etonogestrel.
    Thalidomide: (Moderate) Thalidomide and hormone contraceptives should be used cautiously due an increased risk of thromboembolism. The pharmacokinetic parameters of norethindrone/estradiol were not affected when a single dose of norethindrone 1 mg/estradiol 75 micrograms was administered in 10 healthy women who were receiving thalidomide 200 mg/day (at steady state levels).
    Thiazolidinediones: (Minor) Progestins can impair glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued.
    Thiopental: (Moderate) Barbiturates can accelerate the hepatic clearance of progestins. For hormonal contraceptives, this interaction could result in unintended pregnancy or breakthrough bleeding. For patients regularly taking a barbiturate, an alternative or back-up method of contraception may be advisable to ensure contraceptive reliability during the use of the barbiturate, and for 1 month following the discontinuation of barbiturate use. The exception is the use of levonorgestrel progestin IUDs, which have not been reported to interact and appear to maintain reliable efficacy. Pregnancy has been reported during therapy with both estrogen- and/or progestin-based oral contraceptives in patients receiving barbiturates (e.g., phenobarbital). For patients taking progestins for other indications, like hormone replacement, monitor the patient for signs and symptoms of reduced therapeutic efficacy or need for dosage adjustment.
    Tipranavir: (Major) Etonogestrel is not recommended for women who require the chronic use of drugs that are potent inducers of hepatic enzymes, as contraceptive efficacy is likely to be reduced. Several of the anti-retroviral protease inhibitors have been studied with co-administration of combination oral contraceptives; significant changes (increase and decrease) in the mean area under the curve (AUC) of the estrogen and progestin have been noted in some cases. The efficacy and safety of combination oral contraceptive products may be affected with co-administration of anti-HIV protease inhibitors; it is unknown whether this applies to etonogestrel. Healthcare providers should refer to the labeling of the individual anti-HIV protease inhibitors for further drug-drug interaction information. Hormonal contraceptives may decrease the serum concentrations of amprenavir and fosamprenavir, which could lead to loss of virologic response and possible viral resistance; thus, etonogestrel should not be administered with amprenavir or fosamprenavir.
    Tolazamide: (Minor) Progestins can impair glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued.
    Tolbutamide: (Minor) Progestins can impair glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued.
    Topiramate: (Moderate) Topiramate may increase the clearance and compromise the efficacy of progestins used in contraception or hormone replacement therapies. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. However, pregnancy has been reported in patients who are using hormonal-containing contraceptives and taking hepatic enzyme inducers like topiramate. Patients taking progestin-containing contraceptives or patients taking progestins for hormone replacement therapy (HRT) should report changes in their bleeding patterns to their prescribers. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception may also be needed.
    Trandolapril; Verapamil: (Minor) Coadministration of etonogestrel and moderate CYP3A4 inhibitors such as verapamil may increase the serum concentration of etonogestrel.
    Ulipristal: (Major) Avoid concurrent use of ulipristal and progestin-containing hormonal contraceptives or other progestins. Hormonal contraceptives may be started or resumed no sooner than 5 days after ulipristal treatment. Also, a reliable barrier method of contraception should be used during the same menstrual cycle in which ulipristal was administered (until the next menstrual period). Progestin-containing contraceptives may impair the ability of ulipristal to delay ovulation. Ulipristal may may reduce the effectiveness of progestin-containing hormonal contraceptives by competitively binding at the progesterone receptor.
    Verapamil: (Minor) Coadministration of etonogestrel and moderate CYP3A4 inhibitors such as verapamil may increase the serum concentration of etonogestrel.
    Voriconazole: (Minor) Coadministration of etonogestrel and strong CYP3A4 inhibitors such as voriconazole may increase the serum concentration of etonogestrel.

    PREGNANCY AND LACTATION

    Pregnancy

    Etonogestrel is contraindicated for use during pregnancy or suspected pregnancy. Remove the etonogestrel implant if pregnancy is detected. Teratology studies involving rats using oral administration up to 390 times the human etonogestrel dose and rabbits using oral administration up to 790 times the human etonogestrel dose (based upon body surface) have revealed no evidence of fetal harm due to etonogestrel exposure. In addition, studies have revealed no increased risk of birth defects in women who have used combination oral contraceptives before pregnancy or during early pregnancy; no evidence that the risk associated with etonogestrel is different from that of combination oral contraceptives exists. In women who become pregnant or complain of lower abdominal pain while using etonogestrel, the possibility of ectopic pregnancy exists. Although ectopic pregnancies should be uncommon among patients using etonogestrel, a pregnancy that occurs in a patient using etonogestrel may be more likely to be ectopic than a pregnancy occurring in a patient using no contraception. Ectopic pregnancies can cause serious internal bleeding and even death.

    MECHANISM OF ACTION

    The contraceptive effect of etonogestrel is achieved by several mechanisms that include suppression of ovulation, increased viscosity of the cervical mucus, and alterations in the endometrium.[46375] Its primary mechanism of action is that it suppresses ovulation. Ovulation is normally triggered by a spike in the amount of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) released from the pituitary gland. The contraceptive action is mediated by both processes of positive and negative feedback on the production of LH and FSH by estradiol. The positive feedback involves the stimulation of the release of LH and FSH by estradiol; however, progestins interfere with this process resulting in the absence of adequate LH surges. The negative feedback involves the inhibition of LH and FSH by estradiol; this remains undisturbed which also results in the absence of proper LH surges. This additive decrease in LH produces an altered LH/FSH ratio that leads to decreased folliculogenesis and thus, the follicles grow under abnormal gonadotropin support and the pituitary fails to provide a normal ovulatory stimulus leading to suppression of ovulation.[41710] [41677] Another mechanism of action is an increase in cervical mucus viscosity which renders the cervical mucus impenetrable to sperm.[41710]
     
    Etonogestrel also exerts complex effects on the endometrium. These include direct effects on the endometrium through endometrial progestin target sites and indirect effects through suppression of the hypothalamic-pituitary-ovarian axis. The effects are categorized by alterations in endometrial histology, endometrial thickness, dysmenorrhea, and menstrual bleeding pattern. The exact mechanism of action of progestins on the endometrium has not been determined.[41691]

    PHARMACOKINETICS

    Etonogestrel is marketed in the US as a subdermal implantable device (Implanon) for routine contraception. The apparent volume of distribution for etonogestrel averages about 201 L. Etonogestrel is approximately 32% bound to sex hormone binding globulin (SHBG) and 66% bound to albumin in blood. In vitro data shows that etonogestrel is metabolized in liver microsomes by the CYP3A4 isoenzyme; the biological activity of the drug's metabolites is unknown. Etonogestrel is marketed as a subdermal implantable device (Implanon) for routine contraception.Excretion of etonogestrel and its metabolites, either as free steroid or as conjugates, is mainly in urine and to a lesser extent in feces. The elimination half-life is roughly 25 hours.

    Other Route(s)

    Subdermal Route
    After subdermal implantation of Implanon, etonogestrel is released into the circulation and is essentially 100% bioavailable. The implant delivers 60—70 mcg/day of etonogestrel by week 5—6 and decreases to approximately 35—45 mcg/day at the end of the first year, approximately 30—40 mcg/day at the end of the second year, and then to approximately 25—30 mcg/day at the end of the third year. The mean peak serum concentrations in 3 pharmacokinetic studies ranged between 781—894 pg/mL within the first few weeks after insertion; over time the mean serum etonogestrel concentration decreases gradually to 192—261 pg/mL at 12 months (n=41), 154—194 pg/mL at 24 months (n=35), and 156—177 pg/mL at 36 months (n=17). After removal of the implant, etonogestrel concentrations decrease below sensitivity of the assay by one week.
     
    In clinical trials, pregnancies occurred as early as the first week after removal of etongestrel. Among women aged 18—35 years of age at entry, six pregnancies during 20,648 cycles of use were reported. Two pregnancies occurred in each of years 1, 2 and 3. Each conception was likely to have occurred shortly before or within two weeks after etonogestrel implant removal. Pooled data from a systematic review of published trials for implantable contraception document a failure rate for Implanon at 0/2068 (0.00) per 100 woman-years of use.
     
    The etonogestrel implant may affect certain endocrine tests. Sex hormone-binding globulin concentrations may be decreased for the first six months after insertion followed by a gradual recovery. In addition, thyroxine concentrations may initially be slightly decreased followed by gradual recovery to baseline.