IMPLANON NXT Implant for subdermal use Ref.[49861] Active ingredients: Etonogestrel

If any of the conditions/risk factors mentioned below is present, the benefits of progestagen use should be weighed against the possible risks for each individual woman and discussed with the woman before she decides to start with Implanon nxt. In the event of aggravation, exacerbation or first appearance of any of these conditions, the woman should contact her HCP. The HCP should then decide on whether the use of Implanon nxt should be discontinued.

Carcinoma of the Breast

The risk for breast cancer increases in general with increasing age. During the use of (combined) oral contraceptives (OCs) the risk of having breast cancer diagnosed is slightly increased. This increased risk disappears gradually within 10 years after discontinuation of OC use and is not related to the duration of use, but to the age of the woman when using the OC. The expected number of cases diagnosed per 10,000 women who use combined OCs (up to 10 years after stopping) relative to never users over the same period have been calculated for the respective age groups to be: 4.5/4 (16-19 years), 17.5/16 (20-24 years), 48.7/44 (25-29 years), 110/100 (30-34 years), 180/160 (35-39 years) and 260/230 (40-44 years). The risk in users of contraceptive methods, which only contain progestagens is possibly of a similar magnitude to that associated with combined OCs. However, for these methods, the evidence is less conclusive. Compared to the risk of getting breast cancer ever in life, the increased risk associated with OCs is low. The cases of breast cancer diagnosed in OC users tend to be less advanced than in those who have not used OCs. The increased risk observed in OC users may be due to an earlier diagnosis, biological effects of the OC or a combination of both.

Liver Disease

When acute or chronic disturbances of liver function occur the woman should be referred to a specialist for examination and advice.

Thrombotic and Other Vascular Events

Epidemiological investigations have associated the use of combined OCs (estrogen + progestagen) with an increased incidence of venous thromboembolism (VTE, deep venous thrombosis and pulmonary embolism) and arterial thromboembolism (ATE, myocardial infarction and ischaemic stroke). The clinical relevance of these findings for etonogestrel (the biologically active metabolite of desogestrel) used as a progestagen-only contraceptive in the absence of an estrogenic component is unknown. Limited epidemiological data do not suggest an increased risk of VTE or ATE in women using the implant; however, there have been postmarketing reports of VTE and ATE, in women using etonogestrel implants. It is recommended to assess risk factors, which are known to increase the risk of VTE and ATE.

Women with a history of thromboembolic disorders should be made aware of the possibility of a recurrence. The implant should be removed in the event of a thrombosis. Removal of the implant should also be considered in the case of long-term immobilisation due to surgery or illness.

Elevated Blood Pressure

If a sustained hypertension develops during the use of Implanon nxt, or if a significant increase in blood pressure does not adequately respond to antihypertensive therapy, the use of Implanon nxt should be discontinued.

Carbohydrate Metabolic Effect

The use of progestagen-containing contraceptives may have an effect on peripheral insulin resistance and glucose tolerance. Therefore, diabetic women should be carefully monitored during the first months of Implanon nxtuse.

Chloasma

Chloasma may occasionally occur, especially in women with a history of chloasma gravidarum. Women with a tendency to chloasma should avoid exposure to the sun or ultraviolet radiation whilst using Implanon nxt.

Body Weight

The contraceptive effect of Implanon nxt is related to the plasma levels of etonogestrel, which are inversely related to body weight, and decrease with time after insertion. The clinical experience in heavier women in the third year of use is limited. Therefore it cannot be excluded that the contraceptive effect in these women during the third year of use may be lower than for women of normal weight. HCPs may therefore consider earlier replacement of the implant in heavier women.

Complications of Insertion

There have been reports of migration of the implant within the arm from the insertion site, which may be related to a deep insertion (see section 4.2 How to insert Implanon nxt), or external forces (e.g. manipulation of the implant or contact sports). There also have been rare 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 within the arm from the insertion site, localisation of the implant may be more difficult and removal may require a minor surgical procedure with a larger incision or a surgical procedure in an operating room. In cases where the implant has migrated to the pulmonary artery endovascular or surgical procedures may be needed for removal (see section 4.2 How to remove Implanon nxt). If at any time the implant cannot be palpated, it should be localised and removal is recommendedas soon as medically appropriate. If the implant is not removed, contraception and the risk of progestagen-related undesirable effects may continue beyond the time desired by the woman.

Expulsion may occur especially if the implant is not inserted according to the instructions given in section 4.2 How to insert Implanon nxt, or as a consequence of local inflammation.

Ovarian Cysts

With all low-dose hormonal contraceptives, follicular development occurs and occasionally the follicle may continue to grow beyond the size it would attain in a normal cycle. Generally, these enlarged follicles disappear spontaneously. Often, they are asymptomatic; in some cases they are associated with mild abdominal pain. They rarely require surgical intervention.

Ectopic Pregnancies

The protection with traditional progestagen-only contraceptives against ectopic pregnancies is not as good as with combined OCs, which has been associated with the frequent occurrence of ovulations during the use of these methods. Despite the fact that Implanon nxt will inhibit ovulation, ectopic pregnancy should be taken into account in the differential diagnosis if the woman gets amenorrhoea or abdominal pain.

Psychiatric Disorders

Depressed mood and depression are well-known undesirable effects of hormonal contraceptive use (see section 4.8). Depression can be serious and is a well-known risk factor for suicidal behaviour and suicide. Women should be advised to contact their physician in case of mood changes and depressive symptoms, including shortly after initiating the treatment.

Other Conditions

The following conditions have been reported both during pregnancy and during sex steroid use, but an association with the use of progestagens has not been established: jaundice and/or pruritus related to cholestasis; gallstone formation; porphyria; systemic lupus erythematosus; haemolytic uraemic syndrome; Sydenham’s chorea; herpes gestationis; otosclerosis-related hearing loss and (hereditary) angioedema. Medical examination/consultation Prior to the initiation or reinstitution of Implanon nxt a complete medical history (including family medical history) should be taken and pregnancy should be excluded. Blood pressure should be measured and a physical examination should be performed, guided by the contraindications (see section 4.3) and warnings (see section 4.4). It is recommended that the woman returns for a medical check-up three months after insertion of Implanon nxt. During this check-up, the blood pressure should be measured and the woman should be asked whether she has any questions or complaints or has experienced any undesirable effects. The frequency and nature of further periodic checks should be adapted to the individual woman, guided by clinical judgement. The implant should be palpated at each check-up visit. The woman should be instructed to contact her doctor as soon as possible if she cannot palpate her implant at any time between check-ups.

Women should be advised that Implanon nxt does not protect against HIV (AIDS) and other sexually transmitted diseases.

Reduced efficacy with concomitant medications

The efficacy of Implanon nxt may be reduced when concomitant medications that decrease the plasma concentration of etonogestrel are used (see section 4.5).

Changes in the menstrual bleeding pattern

During the use of Implanon nxt, women are likely to have changes in their menstrual bleeding pattern which are unpredictable beforehand. These may include the occurrence of an irregular bleeding pattern (absent, less frequent, more frequent or continuous), and changes in bleeding intensity (reduced or increased) or duration. Amenorrhoea was reported in about 1 of 5 women while another 1 of 5 women reported frequent and/or prolonged bleeding. The bleeding pattern experienced during the first three months is broadly predictive of future bleeding patterns for many women. Information, counselling and the use of a bleeding diary can improve the woman’s acceptance of a bleeding pattern. Evaluation of vaginal bleeding should be done on an ad hoc basis and may include an examination to exclude gynaecological pathology or pregnancy.

In situ broken or bent implant

There have been reports of broken or bent implants, which may be due to external forces applied while in the patient’s arm. There have also been reports of migration of a broken implant fragment within the arm. Based on in vitro data, when the implant is broken or bent, the release rate of etonogestrel may be slightly increased. This change is not expected to have clinically meaningful effects. However, when an implant is broken, it should be removed, and it is important to remove it in its entirety. Refer to section 4.2 for the procedures of implant removal (either palpable or non-palpable).

Note: The prescribing information of concomitant medications should be consulted to identify potential interactions.

Effects of other medicinal products on Implanon nxt

Interactions can occur with drugs that induce microsomal enzymes which can result in increased clearance of sex hormones and which may lead to menstrual bleeding and/or contraceptive failure.

Management

Enzyme induction can already be observed after a few days of treatment. Maximum enzyme induction is generally observed within a few weeks. After the cessation of drug therapy, enzyme induction may be sustained for about 4 weeks.

Women receiving hepatic enzyme-inducing drugs or herbal products should be advised that the efficacy of Implanon nxt may be reduced. Removal of the implant is not needed, but women are advised to use an additional non-hormonal contraceptive method during the time of concomitant drug administration and for 28 days after their discontinuation in order to obtain maximum protection.

The following interactions have been reported in the literature (mainly with combined contraceptives but occasionally also with progestagen-only contraceptives including Implanon NXT):

Substances increasing the clearance of hormonal contraceptives (diminished efficacy of hormonal contraceptives by enzyme-induction)

e.g: Barbiturates, bosentan, carbamazepine, phenytoin, primidone, rifampicin, and HIV/HCV medication like ritonavir, efavirenz, boceprevir, nevirapine and possibly also felbamate, griseofulvin, oxcarbazepine, topiramate and products containing the herbal remedy St. John’s Wort (hypericum perforatum).

Substances with variable effects on the clearance of hormonal contraceptives

When co-administered with hormonal contraceptives, many combinations of HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors, including combinations with HCV inhibitors, can increase or decrease plasma concentrations of progestins, including etonogestrel. The net effect of these changes may be clinically relevant in some cases.

Therefore, the prescribing information on concomitant HIV/HCV medications should be consulted to identify potential interactions and any related recommendations. In case of any doubt, an additional barrier contraceptive method should be used by women on protease inhibitor or non-nucleoside reverse transcriptase inhibitor therapy.

Substances decreasing the clearance of hormonal contraceptives (enzyme inhibitors)

Concomitant administration of strong (e.g. ketoconazole, itraconazole, clarithromycin) or moderate (e.g. fluconazole, diltiazem, erythromycin) CYP3A4 inhibitors may increase the serum concentrations of progestins, including etonogestrel.

Effects of Implanon nxt on other medicinal products

Hormonal contraceptives may affect metabolism of certain other active substances. Accordingly, plasma and tissue concentrations may either increase (e.g., ciclosporin) or decrease (e.g., lamotrigine).

Laboratory parameters

Data obtained with combined OCs have shown that contraceptive steroids may affect some laboratory parameters, including biochemical parameters of liver, thyroid, adrenal and renal function, serum levels of (carrier) proteins, e.g., corticosteroid binding globulin and lipid/lipoprotein fractions, parameters of carbohydrate metabolism and parameters of coagulation and fibrinolysis. The changes generally remain within the normal range. To what extent this also applies to progestagen-only contraceptives is not known.

Pregnancy

Implanon nxt is not indicated during pregnancy. If pregnancy occurs during use of Implanon nxt, the implant should be removed. Animal studies have shown that very high doses of progestagenic substances may cause masculinisation of female foetuses. Extensive epidemiological studies have revealed neither an increased risk of birth defects in children born to women who used OCs prior to pregnancy, nor of a teratogenic effect when OCs were inadvertently used during pregnancy. Although this probably applies to all OCs, it is not clear whether this is also the case for Implanon nxt.

Pharmacovigilance data with various etonogestrel- and desogestrel-containing products (etonogestrel is a metabolite of desogestrel) do not indicate an increased risk.

Breast-feeding

Clinical data indicate that Implanon nxt does not influence the production or the quality (protein, lactose or fat concentrations) of breast milk. However, small amounts of etonogestrel are excreted in breast milk. Based on an average daily milk ingestion of 150 ml/kg, the mean daily infant etonogestrel dose calculated after one month of etonogestrel release is approximately 27 ng/kg/day. This corresponds to approximately 2.2% of the weight-adjusted maternal daily dose and to approximately 0.2% of the estimated absolute maternal daily dose. Subsequently the milk etonogestrel concentration decreases with time during the lactation period.

Limited long-term data are available on 38 children, whose mothers had an implant inserted during the 4th to 8th week postpartum. They were breast-fed for a mean duration of 14 months and followed-up to 36 months of age. Evaluation of growth, and physical and psychomotor development did not indicate any differences in comparison to nursing infants whose mothers used an IUD (n=33). Nevertheless, development and growth of the child should be carefully followed. Based on the available data, Implanon nxt may be used during lactation and should be inserted after the 4th post partum week.

On the basis of the pharmacodynamic profile, Implanon NXT is expected to have no or negligible influence on the ability to drive or use machines.

During the use of Implanon nxt, women are likely to have changes in their menstrual bleeding pattern which are unpredictable beforehand. These may include the occurrence of an irregular bleeding pattern (absent, less frequent, more frequent or continuous), andchanges in bleeding intensity (reduced or increased) or duration. Amenorrhoea was reported in about 1 of 5 women while another 1 of 5 women reported frequent and/or prolonged bleeding. Occasionally, heavy bleeding has been reported. In clinical trials, bleeding changes were the most common reason for stopping treatment (about 11 %). The bleeding pattern experienced during the first three months is broadly predictive of future bleeding patterns for many women.

Possibly related undesirable effects reported in clinical trials have been listed in the table below:

¹ The most appropriate MedDRA term (version 10.1) to describe a certain adverse reaction is listed. Synonyms or related conditions are not listed, but should be taken into account as well.

During post marketing surveillance, a clinically relevant rise in blood pressure has been observed in rare cases. Seborrhoea has also been reported. Anaphylactic reactions, urticaria, angioedema, aggravation of angioedema and/or aggravation of hereditary angioedema may occur. Insertion or removal of the implant may cause some bruising, including haematoma in some cases, slight local irritation, pain or itching.

Fibrosis at the implant site may occur, a scar may be formed or an abscess may develop. Paraesthesia or paraesthesia-like events may occur. Expulsion or migration of the implant have been reported, including rarely to the chest wall. In rare cases, implants have been found within the vasculature including the pulmonary artery. Some cases of implants found within the pulmonary artery reported chest pain and/or respiratory disorders (such as dyspnaea, cough, haemoptysis); others have been reported as asymptomatic (see section 4.4). If instructions are not followed (see section 4.2), incorrect insertions, difficult localisations and difficult removals of the implant may occur. Surgical intervention might be necessary when removing the implant.

On rare occasions, ectopic pregnancies have been reported (see section 4.4).

In women using (combined oral) contraceptives a number of (serious) undesirable effects have been reported. These include venous thromboembolic disorders, arterial thromboembolic disorders, hormone-dependent tumours (e.g. liver tumours, breast cancer) and chloasma, some of which are discussed in more detail in section 4.4 “Special Warnings and Special Precautions for Use”.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via HPRA Pharmacovigilance, website: www.hpra.ie.

Not applicable.