JADELLE Implant Ref.[50641] Active ingredients: Levonorgestrel

Warnings

Clinical trials have shown the contraceptive efficacy of JADELLE implants to decrease after the fourth year of use. Consequently, the removal of JADELLE implants and their change into new implants could be considered after 4 years of use, especially in women weighing over 60 kg (see Pharmacodynamic properties). The serum levonorgestrel concentration is lower at the end of the implant use and it is inversely related to body weight.

The effects of JADELLE on clotting factors are varied. In patients with a history of thromboembolic disease, JADELLE should only be used if other contraceptive methods are unsuitable and after careful assessment of the risk benefit ratio. Thromboembolic and cardiovascular undesirable effects have been reported in users of other levonorgestrel implants. Cases of stroke, myocardial infarction, pulmonary embolism and deep venous thrombosis have been reported in users of other levonorgestrel implants, as they have been in users of any hormonal contraceptive method, but a causal relationship with the contraceptive method has not been established.

Patients who develop arterial or venous thrombotic or embolic disease, or suspicion thereof, should have their JADELLE implants removed (see Large and Small Surgical Procedures). Thrombophlebitis and superficial phlebitis have occurred more commonly in the arm of insertion. Some cases have been associated with trauma to that arm.

Expulsion of an implant may occur before the incision has healed if the implants have been inserted very near the skin surface or too close to the incision or when the insertion site is infected. An expelled implant must always be replaced with a new, sterile implant.

Reports have been published on slight displacement of similar levonorgestrel implants, most of which have involved minor changes in the position of the implants. Infrequent reports on significant displacement (a few to several centimetres) have been received. Some of these cases have been associated with pain or discomfort. In the event of displacement, the removal technique may have to be modified and may involve additional incisions or visits.

Altered serum lipoprotein levels have been observed in clinical trials on JADELLE. Although statistically significant decreases in total cholesterol, HDL (high-density lipoprotein), LDL (low-density lipoprotein) and triglycerides have been detected, all mean values have remained within the normal ranges. The long-term clinical significance of these changes has not been determined.

Caution should be observed in prescribing JADELLE implants for patients with recognised risk factors for, or any predisposition to arterial disease.

If a sustained hypertension develops during the use of JADELLE, or if a significant increase in blood pressure does not adequately respond to anti-hypertensive therapy, the use of JADELLE should be discontinued.

If a patient has a history of or develops focal or crescendo type migraine or exhibits worsening of such migraine during the use of JADELLE, the situation should be carefully assessed.

Contact lens wearers who develop visual changes or changes in lens tolerance should be assessed by an ophthalmologist. The patient may be advised to stop wearing contact lenses for a while or completely.

Altered glucose tolerance and insulin sensitivity in oral glucose tolerance tests has been reported in users of JADELLE in some studies. The clinical significance of these findings is unknown but diabetic patients using JADELLE should be carefully monitored. A gain in weight is possible during the use of JADELLE.

If cholestatic hepatitis or jaundice develops in a patient with JADELLE, the implants must be removed. Mild or moderate transient rise in total serum bilirubin is usual at the start of the implant use. A slightly increased risk of cholelithiasis has been reported during the use of other levonorgestrel implants of similar type. Levonorgestrel metabolism may be slower than normal in patients with impaired liver function.

Removal of JADELLE should also be considered in women who become significantly depressed, since the symptom may be hormone related. Women with a history of depression should be carefully monitored and removal of JADELLE considered if clear symptoms develop.

Steroid contraceptives may cause some degree of fluid retention, which may result in weight gain. JADELLE should be prescribed with caution to patients with conditions that might be aggravated by fluid retention, and their condition should be monitored closely during the use of JADELLE.

Idiopathic intracranial hypertension has been reported on rare occasions in users of levonorgestrel implants. Evidence is based on isolated reports only. This diagnosis should be considered if persistent headache and/or visual disturbances occur in a woman with JADELLE, particularly if the patient is obese or has recently gained weight. If idiopathic intracranial hypertension is diagnosed, JADELLE should be removed.

JADELLE implants affect the menstrual bleeding pattern in most women. Irregular, prolonged and intermenstrual bleeding, spotting and amenorrhoea have been reported. In general, such irregularities decrease with continuing use. Significant blood loss leading to anaemia is rare, and average concentrations of haemoglobin normally rise slightly in JADELLE users.

Since some users of JADELLE experience periods of amenorrhoea, missed menstrual periods should not be relied on as the sole means of diagnosing pregnancy. A pregnancy test should be performed whenever pregnancy is suspected. Six or more weeks of amenorrhoea after a period of regular menses may indicate pregnancy. The implants should be removed if pregnancy occurs.

Ectopic pregnancy occurs rarely with levonorgestrel implants: at a rate less than 1 per 1000 womanyears. If a woman using JADELLE presents with lower abdominal pain or is found to be pregnant, she should be examined to exclude ectopic pregnancy.

Follicles develop during the use of JADELLE but their atresia may be delayed and they may continue to grow beyond the normal size. In most women, such enlarged follicles will disappear spontaneously. In rare cases, however, they may twist or rupture, causing abdominal pain. Even in the presence of symptoms, conservative management is indicated but ectopic pregnancy must be excluded. Surgical intervention is rarely warranted.

In some rare cases autoimmune diseases such as scleroderma, LED (lupus erythematosus disseminata) or rheumatoid arthritis have been reported in users of levonorgestrel implants. No causal relationship to implants containing levonorgestrel has been established. Both during pregnancy and during the use of sex steroids, the following conditions have been observed, without confirmed relationship to the use of progestogens: cholestatic icterus and/or itching, cholelithiasis, haemolytic-uremic syndrome, herpes gestationis, and hearing loss associated with otosclerosis.

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 taking combined oral contraceptives (COCs), mainly taking estrogen-progestogen preparations. The excess risk gradually disappears during the course of the 10 years after cessation of COC use. Because breast cancer is rare in women under 40 years of age, the excess number of breast cancer diagnoses in current and recent COC users is small in relation to the overall risk of breast cancer. The risk of having breast cancer diagnosed in progestogen-only contraceptive users is possibly of similar magnitude to that associated with COC. However, for progestogen-only preparations, the evidence is based on much smaller populations of users and so is less conclusive than that for COCs. These studies do not provide evidence for causation. The observed pattern of increased risk may be due to an earlier diagnosis of breast cancer in OC users, the biological effects of OCs or a combination of both. The breast cancer diagnosed in OC ever-users tends to be less advanced clinically than the cancers diagnosed in neverusers.

In rare cases, benign liver tumours, and even more rarely malignant liver tumours, have been reported in users of hormonal contraceptives. In isolated cases, these tumours have led to life-threatening intra-abdominal haemorrhages. A liver tumour should be considered in the differential diagnosis when severe upper abdominal pain, liver enlargement or signs of intra-abdominal haemorrhage occur in women using JADELLE.

Medical Examination / Consultation

Before initiating or reinstituting treatment, a complete medical and family history should be taken. Blood pressure should be measured and a physical examination should be performed, guided by the contraindications and warnings for use. The woman should also be instructed to carefully read the user leaflet and to adhere to the advice given and to contact her doctor if any problems occur at the insertion area. The frequency and nature of examinations should be based on established practice guidelines and be adapted to the individual woman.

The insertion area should be examined at every control visit. If undiagnosed, persistent or recurrent vaginal bleeding occurs, appropriate measures should be taken to rule out malignancy.

Sexually Transmitted Infections including HIV infections and AIDS

JADELLE is intended to prevent pregnancy. It does not protect against sexually transmitted infections (STIs), including HIV infections (AIDS).

Large and Small Surgical Procedures

JADELLE implants do not contain estrogen and, therefore, the use of JADELLE, as well as of other similar contraceptives, may usually be continued during surgical procedures. However, if a high risk of thrombosis exists, consideration should be given to appropriate prophylactic measures. Due to a risk of thromboembolism, the removal of implants may be considered either in connection with surgery or with prolonged immobilisation for some other reason.

Instructions to the Patient

The package contains a patient information leaflet to facilitate explaining the characteristics of JADELLE to patients. A copy of the leaflet should be given to each patient. The advantages and disadvantages of JADELLE, other methods of contraception and of not using any contraceptive method should be explained thoroughly to the patient. In addition, information should be given on implant insertion and removal.

Effects of other Medicines on JADELLE

Interactions can occur with medicines that induce microsomal enzymes, which can result in increased clearance of sex hormones and which may lead to changes in the uterine bleeding profile and/or contraceptive failure.

Women on treatment with any of these medicines should temporarily use a barrier method in addition to JADELLE or choose another method of contraception. The barrier method should be used during the time of concomitant medicine administration and for 28 days after their discontinuation.

Substances increasing the clearance of levonorgestrel (diminished efficacy of JADELLE by enzymeinduction), e.g.:

Phenytoin, barbiturates, primidone, carbamazepine, rifampicin, efavirenz, and possibly also oxcarbazepine, topiramate, bosentan, felbamate, griseofulvin and products containing St. John’s Wort.

Enzyme induction can be observed after a few days of treatment.

Maximal enzyme induction is generally seen within a few weeks. After the cessation of therapy with other medicines, enzyme induction may be sustained for about 4 weeks.

Substances with variable effects on the clearance of levonorgestrel, e.g.:

When co-administered with sex hormones, many HIV/HCV protease inhibitors and nonnucleoside reverse transcriptase inhibitors can increase or decrease plasma concentrations of the progestin (decrease [e.g., nelfinavir, ritonavir, darunavir/ritonavir, (fos)amprenavir/ritonavir, lopinavir/ritonavir, and tipranavir/ritonavir, nevirapine, efavirenz] or increase [e.g., indinavir and atazanavir/ritonavir, etravirene]).

These changes may be clinically relevant in some cases.

Substances decreasing the clearance of levonorgestrel (enzyme inhibitors):

Strong and moderate CYP3A4 inhibitors such as azole antifungals (e.g. itraconazole, voriconazole, fluconazole), verapamil, macrolides (e.g. clarithromycin, erythromycin), diltiazem and grapefruit juice can increase plasma concentrations of the progestin.

Effects of JADELLE on other Medicines

JADELLE may affect the metabolism of other medicines. Accordingly, plasma and tissue concentrations may either increase (e.g. cyclosporine) or decrease (e.g. lamotrigine).

Other Forms of Interactions

Laboratory Tests

The use of contraceptive steroids may influence the results of certain laboratory tests, including biochemical parameters of liver, thyroid, adrenal and renal function, plasma levels of (carrier) proteins, e.g. corticosteroid binding globulin and lipid/lipoprotein fractions, parameters of carbohydrate metabolism and parameters of coagulation and fibrinolysis.

Changes generally remain within the normal laboratory range.

Pregnancy

The implants should be removed if pregnancy occurs during treatment with JADELLE. Extensive epidemiological studies have revealed neither an increased risk of birth defects in children born to women who used oral contraceptives containing levonorgestrel prior to pregnancy, nor of a teratogenic effect when oral contraceptives were inadvertently used during pregnancy. No studies are available on the effect of JADELLE during or prior to pregnancy.

Lactation

Levonorgestrel passes into milk but the available data show no adverse effects on infant growth and development. Levels of levonorgestrel obtained with JADELLE do not affect the quality or quantity of breast milk.

No effects on the ability to drive and use machines have been observed.

The following undesirable effects have been reported during clinical trials with JADELLE:

Very common undesirable effects (occurring in more than 10% of users): headache, nervousness, dizziness, nausea, changed menstrual bleeding (frequent, irregular or prolonged menstrual bleeding, spotting, amenorrhoea), cervicitis, vaginal discharge, genital pruritus, pelvic pain, breast pain, weight gain.

Most users of JADELLE can expect variation in menstrual bleeding patterns such as irregular menstrual bleeding, prolonged episodes of bleeding or spotting, heavy bleeding, bleeding or spotting between periods, no bleeding at all or a combination of these patterns. In a combined clinical report representing 3 clinical studies out of 1243 women 174 (14%) of the JADELLE users discontinued their treatment before 5 years due to menstrual problems.

In the same report, the following very common side effects (occurring in more than 10% of users) were reported over the first five years: headache (30.5%), vaginal discharge (30.3%), pelvic pain (24.4%), weight increase (22.4%), genital pruritus (16.3%), cervicitis (14.8%), vaginal fungal infection (14.8%), dizziness (14.5%), breast pain (12.6%), nausea (11.6%), acne (10.9%) and bleeding at the injection site (10.8%).

Expulsion or displacement of JADELLE may be possible (see Special warnings and precautions for use).

In users of similar levonorgestrel implants in various countries limited blistering, ulceration and sloughing have been observed rarely.

During the use of other levonorgestrel implants of similar type, very rare cases of cholestatic hepatitis, jaundice, bilirubinemia and thromboembolic complications have been reported (see Special warnings and precautions for use).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare professionals are asked to report any suspected adverse reactions https://nzphvc.otago.ac.nz/reporting/.

Not applicable.