Implanon

It's important to share with your doctor and pharmacist all of the medications you are taking.

This includes your prescriptions medications, over-the-counter (OTC) drugs, vitamins, nutritional supplements (nutritional shakes, protein powders, etc.), herbal remedies, and any illegal and recreational drugs.

You shouldn't use Implanon if you are taking:

• Fosamprenavir (Lexiva)
• Tranexamic acid (Lysteda, Cyklokapron)

Certain drugs weaken the effects of etonogestrel. Check with your doctor or pharmacist before Implanon insertion if you're taking any of the following drugs:

• Seizure drugs, such as carbamazepine (Carbatrol, Tegretol, Equetro), lamotrigine (Lamictal), or Dilantin or Phenytek (phenytoin)
• HIV/AIDS drugs, such as atazanavir (Reyataz, Evotaz), darunavir (Prezista), and efavirenz (Sustiva)
• Barbiturates, such as butabarbital (Butisol or in Fioricet)
• Felbamate (Felbatol)
• Topiramate (Topamax)
• Herbal supplements, such as St. John's wort and garlic
• Armodafanil (Nuvigil)
• Acitretin (Soriatane)

Certain antibiotics and blood thinners also reduce the strength of Implanon, so if you need these medications at any time, talk with your health care provider about using a back-up form of birth control.

Implanon and Alcohol

Alcohol, like etonogestrel, can alter mood and cause dizziness, nausea, and stomach pain. Drinking while an Implanon is in place can make these symptoms worse.

Limit or avoid drinking while you have the implant.

Implanon and Grapefruit Juice

Grapefruit causes the liver to break down Implanon more slowly and could cause a dangerous increase in the amount of the etonogestrel in your bloodstream.

Avoid grapefruit or grapefruit juice while you have the implant in place.

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

• Changes in Menstrual Bleeding Patterns [see WARNINGS AND PRECAUTIONS]
• Ectopic Pregnancies [see WARNINGS AND PRECAUTIONS]
• Thrombotic and Other Vascular Events [see WARNINGS AND PRECAUTIONS]
• Liver Disease [see WARNINGS AND PRECAUTIONS]

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In clinical trials including 942 women who were evaluated for safety, change in menstrual bleeding patterns (irregular menses) was the most common adverse reaction causing discontinuation of use of IMPLANON (11.1% of women).

Adverse reactions that resulted in a rate of discontinuation of ≥ 1% are shown in Table 3.

Table 3: Adverse Reactions Leading to Discontinuation of Treatment in 1% or More of Subjects in Clinical Trials of IMPLANON

Other adverse reactions that were reported by at least 5% of subjects in clinical trials of IMPLANON are listed in Table 4.

Table 4: Common Adverse Reactions Reported by ≥ 5% of Subjects in Clinical Trials with IMPLANON

Implant site complications were reported by 3.6% of subjects during any of the assessments in clinical trials. Pain was the most frequent implant site complication, reported during and/or after insertion, occurring in 2.9% of subjects. Additionally, hematoma, redness, and swelling were reported by 0.1%, 0.3%, and 0.3% of patients, respectively [see WARNINGS AND PRECAUTIONS].

Postmarketing Experience

The following additional adverse reactions have been identified during post-approval use of IMPLANON. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Gastrointestinal disorders: constipation, diarrhea, flatulence, vomiting.

General disorders and administration site conditions: edema, fatigue, implant site reaction, pyrexia.

Immune system disorders: anaphylactic reactions

Infections and infestations: rhinitis, urinary tract infection.

Investigations: clinically relevant rise in blood pressure, weight decreased.

Metabolism and nutrition disorders: increased appetite.

Musculoskeletal and connective tissue disorders: arthralgia, musculoskeletal pain, myalgia.

Nervous system disorders: convulsions, migraine, somnolence.

Pregnancy, puerperium and perinatal conditions: ectopic pregnancy.

Psychiatric disorders: anxiety, insomnia, libido decreased.

Renal and urinary disorders: dysuria.

Reproductive system and breast disorders: breast discharge, breast enlargement, ovarian cyst, pruritus genital, vulvovaginal discomfort.

Skin and subcutaneous tissue disorders: angioedema, aggravation of angioedema and/or aggravation of hereditary angioedema, alopecia, chloasma, hypertrichosis, pruritus, rash, seborrhea, urticaria.

Vascular disorders: hot flush.

Complications related to insertion or removal of the implant reported include: bruising, slight local irritation, pain or itching, fibrosis at the implant site, paresthesia or paresthesia-like events, scarring and abscess. Expulsion or migration of the implant, have been reported, including to the chest wall. In some cases implants have been found within the vasculature including the pulmonary artery. Some cases of implants found within the pulmonary artery reported chest pain and/or dyspnea; others have been reported as asymptomatic [see WARNINGS AND PRECAUTIONS]. Surgical intervention might be necessary when removing the implant.

Implanon is a medication used to prevent pregnancy for up to 3 years. Implanon belongs to a group of medications called progestin hormone which causes changes in the lining of the uterus and the cervical mucus to keep the sperm from joining an egg and therefore prevents pregnancy.

Implanon is a flexible, plastic rod that contains the hormone, etonogestrel. It is implanted just under the skin of the inner side of your upper arm by a healthcare provider.

Common side effects of Implanon include changes in periods, nausea, weight gain, and headache.

In the U.S.

• Implanon
• Nexplanon

Available Dosage Forms:

• Implant

Therapeutic Class: Contraceptive, Progestin

Pharmacologic Class: Progestin

• It is used to prevent pregnancy.

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
• Signs of liver problems like dark urine, feeling tired, not hungry, upset stomach or stomach pain, light-colored stools, throwing up, or yellow skin or eyes.
• Signs of high blood sugar like confusion, feeling sleepy, more thirst, more hungry, passing urine more often, flushing, fast breathing, or breath that smells like fruit.
• Signs of high blood pressure like very bad headache or dizziness, passing out, or change in eyesight.
• Weakness on 1 side of the body, trouble speaking or thinking, change in balance, drooping on one side of the face, or blurred eyesight.
• Shortness of breath, a big weight gain, or swelling in the arms or legs.
• Low mood (depression).
• Mood changes.
• Very bad belly pain.
• Change in eyesight, eye pain, or very bad eye irritation.
• Loss of eyesight.
• A lump in the breast or breast soreness.
• Breast pain.
• Change in how contact lenses feel in the eyes.
• Flu-like signs.
• Vaginal bleeding that is not normal.
• Call your doctor right away if you have signs of a blood clot like chest pain or pressure; coughing up blood; shortness of breath; swelling, warmth, numbness, change of color, or pain in a leg or arm; or trouble speaking or swallowing.

The following information is based on experience with either Implanon, other progestin-only contraceptives, or experience with combination (estrogen plus progestin) oral contraceptives.

Complications of Insertion and Removal

Implanon should be inserted subdermally so that it will be palpable after insertion, and this should be confirmed by palpation immediately after insertion. Failure to insert Implanon properly may go unnoticed unless it is palpated immediately after insertion. Undetected failure to insert the implant may lead to an unintended pregnancy. Complications related to insertion and removal procedures, such as pain, paresthesias, bleeding, hematoma, scarring or infection, may occur. Occasionally in post-marketing use, implant insertions have failed because the implant fell out of the needle or remained in the needle during insertion.

If Implanon is inserted deeply (intramuscular or in the fascia), neural or vascular injury may occur. To reduce the risk of neural or vascular injury, Implanon should be inserted at the inner side of the non-dominant upper arm about 8-10 cm (3-4 inches) above the medial epicondyle of the humerus. Implanon should be inserted subdermally just under the skin, avoiding the sulcus (groove) between the biceps and triceps muscles and the large blood vessels and nerves that lie there in the neurovascular bundle deeper in the subcutaneous tissues. Deep insertions of Implanon have been associated with paraesthesia (due to neural injury), migration of the implant (due to intramuscular or fascial insertion), and intravascular insertion. If infection develops at the insertion site, start suitable treatment. If the infection persists, the implant should be removed. Incomplete insertions or infections may lead to expulsion.

Implant removal may be difficult or impossible if the implant is not inserted correctly, is inserted too deeply, not palpable, encased in fibrous tissue, or has migrated.

There have been reports of migration of the implant within the arm from the insertion site, which may be related to a deep insertion. There also have been postmarketing reports of implants located within the vessels of the arm and the pulmonary artery, which may be related to deep insertions or intravascular insertion. In cases where the implant has migrated to the pulmonary artery, endovascular procedures may be needed for removal.

If at any time the implant cannot be palpated, it should be localized and removal is recommended.

Exploratory surgery without knowledge of the exact location of the implant is strongly discouraged. Removal of deeply inserted implants should be conducted with caution in order to prevent injury to deeper neural or vascular structures in the arm and be performed by healthcare providers familiar with the anatomy of the arm. If the implant is located in the chest, healthcare providers familiar with the anatomy of the chest should be consulted. Failure to remove the implant may result in continued effects of etonogestrel, such as compromised fertility, ectopic pregnancy, or persistence or occurrence of a drug-related adverse event.

Changes in Menstrual Bleeding Patterns

After starting Implanon, women are likely to have a change from their normal menstrual bleeding pattern. These may include changes in bleeding frequency (absent, less, more frequent or continuous), intensity (reduced or increased) or duration. In clinical trials, bleeding patterns ranged from amenorrhea (1 in 5 women) to frequent and/or prolonged bleeding (1 in 5 women). The bleeding pattern experienced during the first three months of Implanon use is broadly predictive of the future bleeding pattern for many women. Women should be counseled regarding the bleeding pattern changes they may experience so that they know what to expect. Abnormal bleeding should be evaluated as needed to exclude pathologic conditions or pregnancy.

In clinical studies of Implanon, reports of changes in bleeding pattern were the most common reason for stopping treatment (11.1%). Irregular bleeding (10.8%) was the single most common reason women stopped treatment, while amenorrhea (0.3%) was cited less frequently. In these studies, women had an average of 17.7 days of bleeding or spotting every 90 days (based on 3,315 intervals of 90 days recorded by 780 patients). The percentages of patients having 0, 1-7, 8-21, or >21 days of spotting or bleeding over a 90-day interval while using the Implanon implant are shown in Table 1.

Bleeding patterns observed with use of Implanon for up to 2 years, and the proportion of 90-day intervals with these bleeding patterns, are summarized in Table 2.

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

Ectopic Pregnancies

As with all progestin-only contraceptive products, be alert to the possibility of an ectopic pregnancy among women using Implanon who become pregnant or complain of lower abdominal pain. Although ectopic pregnancies are uncommon among women using Implanon, a pregnancy that occurs in a woman using Implanon may be more likely to be ectopic than a pregnancy occurring in a woman using no contraception.

Thrombotic and Other Vascular Events

The use of combination hormonal contraceptives (progestin plus estrogen) increases the risk of vascular events, including arterial events (strokes and myocardial infarctions) or deep venous thrombotic events (venous thromboembolism, deep venous thrombosis, retinal vein thrombosis, and pulmonary embolism). Implanon is a progestin-only contraceptive. It is unknown whether this increased risk is applicable to etonogestrel alone. It is recommended, however, that women with risk factors known to increase the risk of venous and arterial thromboembolism be carefully assessed.

There have been postmarketing reports of serious arterial thrombotic and venous thromboembolic events, including cases of pulmonary emboli (some fatal), deep vein thrombosis, myocardial infarction, and strokes, in women using Implanon. Implanon should be removed in the event of a thrombosis.

Due to the risk of thromboembolism associated with pregnancy and immediately following delivery, Implanon should not be used prior to 21 days postpartum. Women with a history of thromboembolic disorders should be made aware of the possibility of a recurrence.

Evaluate for retinal vein thrombosis immediately if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions.

Consider removal of the Implanon implant in case of long-term immobilization due to surgery or illness.

Ovarian Cysts

If follicular development occurs, atresia of the follicle is sometimes delayed, and the follicle may continue to grow beyond the size it would attain in a normal cycle. Generally, these enlarged follicles disappear spontaneously. On rare occasion, surgery may be required.

Carcinoma of the Breast and Reproductive Organs

Women who currently have or have had breast cancer should not use hormonal contraception because breast cancer may be hormonally sensitive [see Contraindications (4)]. Some studies suggest that the use of combination hormonal contraceptives might increase the incidence of breast cancer; however, other studies have not confirmed such findings.

Some studies suggest that the use of combination hormonal contraceptives is associated with an increase in the risk of cervical cancer or intraepithelial neoplasia. However, there is controversy about the extent to which such findings are due to differences in sexual behavior and other factors.

Women with a family history of breast cancer or who develop breast nodules should be carefully monitored.

Liver Disease

Disturbances of liver function may necessitate the discontinuation of hormonal contraceptive use until markers of liver function return to normal. Remove Implanon if jaundice develops.

Hepatic adenomas are associated with combination hormonal contraceptives use. An estimate of the attributable risk is 3.3 cases per 100,000 for combination hormonal contraceptives users. It is not known whether a similar risk exists with progestin-only methods like Implanon.

The progestin in Implanon may be poorly metabolized in women with liver impairment. Use of Implanon in women with active liver disease or liver cancer is contraindicated [see Contraindications (4)].

Weight Gain

In clinical studies, mean weight gain in US Implanon users was 2.8 pounds after 1 year and 3.7 pounds after 2 years. How much of the weight gain was related to the implant is unknown. In studies, 2.3% of the users reported weight gain as the reason for having the implant removed.

Elevated Blood Pressure

Women with a history of hypertension-related diseases or renal disease should be discouraged from using hormonal contraception. For women with well-controlled hypertension, use of Implanon can be considered. Women with hypertension using Implanon should be closely monitored. If sustained hypertension develops during the use of Implanon, or if a significant increase in blood pressure does not respond adequately to antihypertensive therapy, Implanon should be removed.

Gallbladder Disease

Studies suggest a small increased relative risk of developing gallbladder disease among combination hormonal contraceptive users. It is not known whether a similar risk exists with progestin-only methods like Implanon.

Carbohydrate and Lipid Metabolic Effects

Use of Implanon may induce mild insulin resistance and small changes in glucose concentrations of unknown clinical significance. Carefully monitor prediabetic and diabetic women using Implanon.

Women who are being treated for hyperlipidemia should be followed closely if they elect to use Implanon. Some progestins may elevate LDL levels and may render the control of hyperlipidemia more difficult.

Depressed Mood

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

Return to Ovulation

In clinical trials with Implanon, the etonogestrel levels in blood decreased below sensitivity of the assay by one week after removal of the implant. In addition, pregnancies were observed to occur as early as 7 to 14 days after removal. Therefore, a woman should re-start contraception immediately after removal of the implant if continued contraceptive protection is desired.

Fluid Retention

Hormonal contraceptives may cause some degree of fluid retention. They should be prescribed with caution, and only with careful monitoring, in patients with conditions which might be aggravated by fluid retention. It is unknown if Implanon causes fluid retention.

Contact Lenses

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

In Situ Broken or Bent Implant

There have been reports of broken or bent implants while in the patient's arm. Based on in vitro data, when the implant is broken or bent, the release rate of etonogestrel may be slightly increased.

When an implant is removed, it is important to remove it in its entirety [see Dosage and Administration (2.3)].

Monitoring

A woman who is using Implanon should have a yearly visit with her healthcare provider for a blood pressure check and for other indicated health care.

Drug-Laboratory Test Interactions

Sex hormone-binding globulin concentrations may be decreased for the first 6 months after Implanon insertion followed by a gradual recovery. Thyroxine concentrations may initially be slightly decreased followed by gradual recovery to baseline.

Implanon (etonogestrel implant) is a progestin-only, soft, flexible implant preloaded in a sterile, disposable applicator for subdermal use. The implant is off-white, non-biodegradable and 4 cm in length with a diameter of 2 mm (see Figure 22). Each implant consists of an ethylene vinylacetate (EVA) copolymer core, containing 68 mg of the synthetic progestin etonogestrel, surrounded by an EVA copolymer skin. Once inserted subdermally, the release rate is 60 to 70 mcg/day in Week 5 to 6 and decreases to approximately 35 to 45 mcg/day at the end of the first year, to approximately 30 to 40 mcg/day at the end of the second year, and then to approximately 25 to 30 mcg/day at the end of the third year. Implanon is a progestin-only contraceptive and does not contain estrogen. Implanon does not contain latex and is not radio-opaque.

Figure 22 (Not to scale)

Etonogestrel [13-Ethyl-17-hydroxy-11-methylene-18,19-dinor-17α-pregn-4-en-20-yn-3-one], structurally derived from 19-nortestosterone, is the synthetic biologically active metabolite of the synthetic progestin desogestrel. It has a molecular weight of 324.46 and the following structural formula (Figure 23).

Figure 23

Mechanism of Action

The contraceptive effect of Implanon is achieved by suppression of ovulation, increased viscosity of the cervical mucus, and alterations in the endometrium.

Pharmacodynamics

Exposure-response relationships of Implanon are unknown.

Pharmacokinetics

Absorption

After subdermal insertion of the etonogestrel implant, etonogestrel is released into the circulation and is approximately 100% bioavailable.

The mean peak serum concentrations in 3 pharmacokinetic studies ranged between 781 and 894 pg/mL and were reached within the first few weeks after insertion. The mean serum etonogestrel concentration decreases gradually over time declining to 192 to 261 pg/mL at 12 months (n=41), 154 to 194 pg/mL at 24 months (n=35), and 156 to 177 pg/mL at 36 months (n=17).

The pharmacokinetic profile of Implanon from 1 of 3 pharmacokinetic studies is shown in Figure 24.

Distribution

The apparent volume of distribution averages about 201 L. Etonogestrel is approximately 32% bound to sex hormone binding globulin (SHBG) and 66% bound to albumin in blood.

Metabolism

In vitro data shows that etonogestrel is metabolized in liver microsomes by the cytochrome P450 3A4 isoenzyme. The biological activity of etonogestrel metabolites is unknown.

Excretion

The elimination half-life of etonogestrel is approximately 25 hours. Excretion of etonogestrel and its metabolites, either as free steroid or as conjugates, is mainly in urine and to a lesser extent in feces. After removal of the implant, etonogestrel concentrations decreased below sensitivity of the assay by 1 week.

Common side effects of Implanon include: irregular menses and weight gain. Other side effects include: depression and pain. See below for a comprehensive list of adverse effects.