Etonogestrel

Registered South African indications:

• Contraception

Contraindications

South African recommendations

• Hypersensitivity to the active substance or to any of the inactive ingredients
• Active venous or arterial thromboembolic disorders or history thereof
• Known or suspected sex-steroid sensitive malignancies such as breast and ovarian cancers 
• Presence or history of liver tumours (benign or malignant) 
• Presence or history of any hepatic disease for as long as liver function values have not returned to normal 
• Known or suspected pregnancy
• Undiagnosed vaginal bleeding

Recommendations in other jurisdictions

• Active venous thromboembolic disorder
• Known or suspected sex steroid sensitive malignancies
• Presence or history of liver tumours (benign or malignant)
• Presence or history of severe hepatic disease as long as liver function values have not returned to normal
• Undiagnosed vaginal bleeding
• Hypersensitivity to the active substance or to any of the excipients

Cautions

• Breastfeeding
• Renal impairment
• Risk factors for carcinoma of the breast
• Risk factors for or history of thromboembolic disorders
• Long term immobilisation
• Sustained hypertensionor a significant increase in blood pressure that does not adequately respond to antihypertensive therapy
• Diabetic women
• History of chloasma gravidarum
• Increased body mass index
• Migration of the implant from the insertion site (see additional prescribing points)
• Poor insertion technique
• External manipulation of the implant
• Contact sports
• In situ broken or bent implant
• Mood changes and depressive symptoms

Forms avail. in SA and covered in this monograph: imp

Dosages below include:

• South African registered indications and dosages
• Indications and dosages registered in other jurisdictions

South African registered indications and dosages

Contraception

• Subdermal (imp): 68mg (1 implant), inserted every 3 years

---

Insertion of the implant should be performed under aseptic conditions and only by a health care practitioner who is familiar with the procedure; Insertion of the implant should only be performed with the preloaded applicator (see additional prescribing points)

---

Rule out pregnancy before inserting implant

---

Timing of insertion depends on the woman's recent contraceptive history. See additional prescribing points for when to insert the etonogestrel implant

---

 Remove the implant no later than 3 years after the date of insertion. The user should be informed that she can request the removal of the implant at any time

---

Medical practitioners may consider earlier replacement of the implant in women with higher body weight

---

After the removal of the implant, immediate insertion of another implant will result in continued contraceptive protection. If the woman does not wish to continue using etonogestrel, but wants to continue preventing pregnancy, another contraceptive method should be recommended

---

Indications and dosages registered in other jurisdictions

Contraception

• Subdermal (imp): 68mg (1 implant), inserted every 3 years

---

Safety and efficacy have been established in women between 18 and 40 years of age

---

Pregnancy should be excluded before insertion of implant

---

It is strongly recommended that the implant be inserted and removed only by healthcare professionals (HCPs) who have completed training for the use of the implant applicator and the techniques for insertion and removal of the etonogestrel implant, and, where appropriate, that supervision be requested prior to inserting or removing the implant

---

If you are unsure of the necessary steps to safely insert and/or remove the implant, do not attempt the procedure

---

 The basis for successful use and subsequent removal of the etonogestrel implant is a correct and carefully performed subdermal insertion of the implant in accordance with the instructions
- If the implant is not inserted in accordance with the instructions and not on the correct day, this may result in an unintended pregnancy
- An implant inserted more deeply than subdermally (deep insertion) may not be palpable and the localisation and/or removal can be difficult 

Dosages below include:

• South African registered indications and dosages
• Indications and dosages registered in other jurisdictions

South African registered indications and dosages

Safety and efficacy of etonogestrel subdermal implant have been established in women of reproductive age
The safety and efficacy of etonogestrel subdermal implants are expected to be the same for postpubertal adolescents. However, to date, no clinical studies have been conducted in women less than 18 years of age
Any use of etonogestrel subdermal implant in women under the age of 18 years should be approved by specialists expert in the field of contraception

---

Indications and dosages registered in other jurisdictions

Not established for use in children below 18 years

Pregnancy

South African recommendations

• Contraindicated
• Pregnancy should be excluded before insertion of the etonogestrel implant
• Etonogestrel implant is contraindicated during pregnancy. If pregnancy occurs during use, the implant should be removed
• Animal studies have shown that progestagenic substances may cause masculinisation of female foetuses

Recommendations in other jurisdictions

• Not indicated for use in pregnant women
• If pregnancy occurs during use of etonogestrel, 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 etonogestrel
• Pharmacovigilance data with various etonogestrel- and desogestrel-containing products (etonogestrel is a metabolite of desogestrel) do not indicate an increased risk

Breastfeeding

• Caution
• Clinical data indicate that etonogestrel 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 breastfeeding 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 breastfed 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, the development and growth of the child should be carefully followed
• Based on the available data, etonogestrel may be used during breastfeeding and should be inserted after the 4th postpartum week

Renal Impairment

• Caution; no information available

Hepatic Impairment

• Mild to severe (Child-Pugh Classes A, B & C): Contraindicated

Elderly

• Not indicated for use in geriatric patients

Porphyria Information

• Probably porphyrinogenic (PRP)

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Affect lability
• Depressed mood
• Nervousness
• Decreased libido
• Anxiety
• Insomnia
• Headache
• Dizziness
• Migraine
• Somnolence
• Fatigue

Cardiovascular Disorders

• Increased blood pressure
• Venous thromboembolic disorders
• Arterial thromboembolic disorders

Respiratory Disorders

• Pharyngitis
• Rhinitis

Gastrointestinal Disorders

• Abdominal pain
• Nausea and vomiting
• Flatulence
• Constipation
• Diarrhoea

Genitourinary Disorders

• Vaginal infection
• Urinary tract infection
• Dysuria
• Breast tenderness
• Breast pain
• Irregular menstruation
• Dysmenorrhoea
• Amenorrhoea
• Irregular bleeding pattern
• Changes in bleeding intensity
• Changes in bleeding duration
• Ovarian cyst
• Genital discharge
• Vulvovaginal discomfort
• Genital pruritus
• Galactorrhoea
• Breast enlargement

Endocrine and Metabolic Disorders

• Increased appetite
• Increased weight
• Decreased weight
• Hot flush

Musculoskeletal Disorders

• Back pain
• Arthralgia
• Myalgia
• Musculoskeletal pain

Skin and Subcutaneous Tissue Disorders

• Acne
• Alopecia
• Hypertrichosis
• Rash
• Pruritus
• Oedema
• Pain of implant site
• Seborrhoea
• Urticaria
• Bruising, including haematoma, of implant site (on insertion or removal)
• Fibrosis of implant site
• Chloasma

Immune, Blood and Lymphatic System Disorders

• Hypersensitivity
• Fever
• Influenza-like illness
• Implant site reaction
• Anaphylactic reactions
• Angioedema
• Aggravation of angioedema or hereditary angioedema

Sensory Disorders

• Paraesthesia or paraesthesia-like events

Other

• Expulsion or migration of the implant, including to the pulmonary artery
  - Chest pain
  - Dyspnoea
  - Cough
  - Haemoptysis
• Ectopic pregnancy
• Hormone-dependent tumours
  - Hepatic tumours
  - Breast cancer

• Barbiturates
• Bosentan
• Carbamazepine
• Phenytoin
• Primidone
• Rifampicin
• HIV/HCV agents
• Protease inhibitors
• Non-nucleoside reverse transcriptase inhibitors
• Ritonavir
• Efavirenz
• Boceprevir
• Nevirapine
• Felbamate
• Griseofulvin
• Oxcarbazepine
• Topiramate
• CYP3A4 inhibitors
• Ketoconazole
• Itraconazole
• Clarithromycin
• Fluconazole
• Diltiazem
• Erythromycin
• Ciclosporin
• Lamotrigine
• Microsomal enzyme inducers

Other

• St. John's wort (hypericum perforatum)

• Pregnancy test
• Blood pressure

Specific cases may require

• Weight or BMI
• Lipid profiles
• Glycaemic control

Additional observations

• Vision changes
• Signs and symptoms of thromboembolic disorders
• Signs or symptoms of depression
• Adequate diagnostic measures to rule out malignancies in all cases of undiagnosed abnormal vaginal bleeding

How to insert the etonogestrel implant

• The basis for successful use and subsequent removal of the implant is a correct and carefully performed subdermal insertion of the implant in accordance with the instructions. If the implant is not inserted in accordance with the instructions and not on the correct day, this may result in an unintended pregnancy
• The implant should be inserted subdermally just under the skin at the inner side of the non-dominant upper arm. The insertion site is overlying the triceps muscle about 8-10 cm (3-4 inches) from the medial epicondyle of the humerus and 3-5 cm (1.25-2 inches) posterior to (below) the sulcus (groove) between the biceps and triceps muscles. This location is intended to avoid the large blood vessels and nerves lying within and surrounding the sulcus
• Immediately after insertion, the presence of the implant should be verified by palpation
• Health professionals should record the date of insertion, the arm of insertion and the intended date of removal
• The patient must be advised to occasionally gently palpate the implant to be sure that she knows its location. Patients should be instructed to contact their doctor as soon as possible if at any time they cannot feel the implant
• An implant inserted more deeply than subdermally (deep insertion) may not be palpable and the localisation and/or removal can be difficult

When to insert the etonogestrel implant

• Rule out pregnancy before inserting the implant
• Timing of the insertion depends on the woman's recent contraceptive history

No preceding hormonal contraceptives use in the past month

• The implant should be inserted between Day 1 (first day of menstrual bleeding) and Day 5 of the menstrual cycle, even if the woman is still bleeding
• If inserted as recommended, back-up contraception is not necessary. If deviating from the recommended timing of insertion, the woman should be advised to use a barrier method until 7 days after insertion. If intercourse has already occurred, pregnancy should be excluded

Switching hormonal contraceptive method to etonogestrel

• Changing from a combined hormonal contraceptive method:
  - The implant should be inserted preferably on the day after the last active tablet (the last tablet containing the active substances) of the previous combined oral contraceptive or on the day of removal of the vaginal ring or transdermal patch. At the latest, the implant should be inserted on the day following the usual tablet-free, ring-free, patch-free or placebo tablet interval of the previous combined hormonal contraceptive when the next application would have been due
  - If inserted as recommended, back-up contraception is not necessary. If deviating from the recommended timing of insertion, the woman should be advised to use a barrier method until 7 days after insertion. If intercourse has already occurred, pregnancy should be excluded
• Changing from a progestagen-only contraceptive method:
  - Progestagen-only injectable contraceptives: Insert the implant on the day the next injection is due
  - Progestagen-only pill: Initiate on any day of the month. The implant should be inserted within 24 hours after taking the last tablet
  - Implant/Intrauterine system (IUS): Insert the implant on the same day the previous implant or IUS is removed
• If inserted as recommended above, back-up contraception is not necessary. If deviating from the recommended timing of insertion, the woman should be advised to use a barrier method until 7 days after insertion. If intercourse has already occurred, pregnancy should be excluded

Initiating in special circumstances

• First trimester abortion or miscarriage: Insert implant within five days
• Second trimester abortion or miscarriage: Insert implant between 21 to 28 days following second trimester abortion or miscarriage  
• If inserted as recommended above, back-up contraception is not necessary. If deviating from the recommended timing of insertion, the woman should be advised to use a barrier method until 7 days after insertion. If intercourse has already occurred, pregnancy should be excluded
• Postpartum:
  - Not breastfeeding: The implant should be inserted between 21 to 28 days postpartum. If inserted as recommended, back-up contraception is not necessary. If the implant is inserted later than 28 days postpartum, the woman should be advised to use a barrier method until 7 days after insertion. If intercourse has already occurred, pregnancy should be excluded
  - Breastfeeding: The implant should be inserted after the fourth postpartum week. The woman should be advised to use a barrier method until 7 days after insertion. If intercourse has already occurred, pregnancy should be excluded

Migration of the implant

• There have been reports of migration of the implant within the arm from the insertion site, which may be related to a deep insertion or external forces (e.g. manipulation of the implant or contact sports). There also have been rare post-marketing 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. If at any time the implant cannot be palpated, it should be localised and removal is recommended as 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

Medical examination/consultation

• Prior to the initiation or reinstitution of the implant 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 and cautions
• It is recommended that the woman returns for a medical check-up three months after insertion. 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 the etonogestrel implant does not protect against HIV/AIDS and other sexually transmitted diseases

Changes in the menstrual bleeding pattern

• During use, 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

Safety and efficacy in adults

• Safety and efficacy have been established in women between 18 and 40 years of age (Source: SmPC - International Manufacturer information)

Etonogestrel is the biologically active metabolite of desogestrel, a progestagen widely used for contraception. It binds with high affinity to progesterone receptors in the target organs. The contraceptive effect of etonogestrel is primarily achieved by inhibition of ovulation. Besides inhibition of ovulation, etonogestrel also causes changes in the cervical mucus, which hinders the passage of spermatozoa.

Implant 68mg

• Implanon NXT ( Organon)