Goserelin

Goserelin is a synthetic analogue of natural luteinising hormone-releasing hormone (LHRH). Given continuously from a depot, it switches off the pituitary’s release of luteinising hormone (LH), which lowers serum testosterone in men and serum oestradiol in women. This removes the hormonal drive behind hormone-dependent prostate and breast cancer and shrinks hormone-sensitive gynaecological tissue. Goserelin is inactive by mouth, which is why it is given as an implant.

Mechanism of Action

• Initial stimulation: like other LHRH agonists, goserelin can briefly raise serum testosterone (men) or oestradiol (women) at the start of treatment. Some women have vaginal bleeding of variable intensity and duration early on; it is probably oestrogen withdrawal and is expected to stop by itself.
• Suppression in men: about 21 days after the first implant, testosterone falls into the castrate range and stays there while an implant is given every 28 days. This leads to regression of the prostate tumour and symptom relief in most patients.
• Suppression in women: serum oestradiol is suppressed about 21 days after the first implant and stays at levels similar to those after the menopause. This is linked to a thinner endometrium, suppressed follicle development, and a response of hormone-dependent breast cancer (oestrogen and/or progesterone receptor-positive), endometriosis and fibroids; most women stop menstruating.
• Assisted reproduction: the aim is pituitary down-regulation, defined as serum oestradiol similar to the early follicular phase (about 150 pmol/L), usually reached 7 to 21 days after starting.

Pharmacokinetics

• Absorption: rapidly absorbed after subcutaneous injection, with practically complete bioavailability from the implant. An implant every 4 weeks keeps effective concentrations without accumulating in tissue.
• Distribution: low protein binding (about 27% according to DrugBank).
• Metabolism: mainly hepatic.
• Elimination: serum half-life of 2 to 4 hours with normal kidney function (DrugBank quotes 4 to 5 hours; the SmPC value is given here). Clearance is by a mix of hepatic metabolism and urinary excretion, and over 90% of a radiolabelled subcutaneous solution dose was found in urine.
• Special populations: half-life is longer in renal impairment, but with the monthly implant this has minimal effect and no dose adjustment is needed. Pharmacokinetics do not change significantly in hepatic impairment.

The 3.6 mg implant is for adults only. The indications below follow the Spanish SmPC; national SmPCs in other member states can differ.

• Prostate cancer: advanced prostate carcinoma, when hormonal treatment is indicated.
• Breast cancer: pre- and perimenopausal women in whom hormonal treatment is appropriate.
• Endometriosis.
• Uterine fibroids.
• Endometrial thinning: reduction of endometrial thickness before endometrial ablation.
• Assisted reproduction: suppression of pituitary control in preparation for superovulation.

A 10.8 mg implant for use every 12 weeks is also marketed (Zoladex LA, Zoladex Trimestral). Its authorised indications are set out in its own national SmPC and are not reproduced here.

• Hypersensitivity to goserelin or to any of the excipients.
• Pregnancy and breastfeeding.

The SmPC lists reactions separately for women and men, from clinical trials and post-marketing use. Hot flushes, sweating and reduced libido are pharmacological effects that rarely require stopping treatment and can continue after it ends.

Very common (≥1/10)

• Women: reduced libido, hot flushes, excessive sweating, acne, vulvovaginal dryness, breast enlargement, injection-site reactions.
• Men: reduced libido, hot flushes, excessive sweating, erectile dysfunction.

Common (≥1/100 to <1/10)

• Women: mood changes and depression (long-term treatment), pins and needles (paraesthesia), headache, abnormal blood pressure (low or high), rash, hair loss, joint pain, tumour exacerbation and tumour pain, reduced bone mineral density, weight gain.
• Men: impaired glucose tolerance, mood changes and depression (long-term treatment), paraesthesia, spinal cord compression, heart failure and myocardial infarction, abnormal blood pressure, rash, bone pain, gynaecomastia, injection-site reaction, reduced bone mineral density, weight gain.

Uncommon (≥1/1,000 to <1/100)

• Women: hypersensitivity, raised blood calcium, mood changes and depression (short-term treatment).
• Men: hypersensitivity, mood changes and depression (short-term treatment), joint pain, ureteral obstruction, breast tenderness.

Rare (≥1/10,000 to <1/1,000)

• Women: anaphylactic reaction, ovarian cyst, ovarian hyperstimulation syndrome.
• Men: anaphylactic reaction.

Very rare (<1/10,000)

• Women and men: pituitary tumour, pituitary haemorrhage, psychotic disorder.

Not known

• Women: degeneration of uterine fibroids, changes in blood count, raised calcium at the start of treatment in breast cancer with metastases, nervousness, sleep disturbance, QT prolongation, peripheral oedema, pulmonary embolism, interstitial pneumonia, voice changes, nausea, vomiting, diarrhoea, constipation, abdominal discomfort, liver dysfunction, raised cholesterol, dry skin, loss of body hair, muscle pain, calf cramps, withdrawal bleeding, vaginitis, vaginal discharge, menopause (periods may not return after stopping), tiredness, temporary worsening of signs and symptoms in breast cancer.
• Men: changes in blood count, QT prolongation, pulmonary embolism, interstitial pneumonia, liver dysfunction, hair loss.

Important serious reactions are injection-site injury (very rarely vascular injury and haemorrhagic shock), depression, QT prolongation, loss of bone density and, in men, heart failure, myocardial infarction and impaired glucose tolerance.

The SmPC names one interaction group.

• Medicines that prolong the QT interval or can cause torsade de pointes: androgen deprivation can itself prolong the QT interval, so combining goserelin with such medicines needs careful assessment. The SmPC names class IA antiarrhythmics (for example quinidine, disopyramide), class III antiarrhythmics (amiodarone, sotalol, dofetilide, ibutilide), methadone, moxifloxacin and antipsychotics, among others.
• Anti-androgens: in men, starting an anti-androgen such as cyproterone acetate can be considered to cover the first rise in testosterone (see Administration and Dosage).
• Hormone replacement therapy: in women treated for endometriosis, adding hormone replacement therapy reduces bone loss and vasomotor symptoms.
• Bone-protecting medicines: preliminary data suggest that a bisphosphonate in men, or tamoxifen in women with breast cancer, may reduce the loss of bone mineral density.

Goserelin is injected by a healthcare professional as a single implant under the skin of the anterior abdominal wall, using the pre-filled syringe with its needle safety system, following the instructions in the pack. Care is needed because the inferior epigastric artery and its branches lie close beneath the injection site, and extra care applies in patients with a low body mass index or on full-dose anticoagulants.

Recommended Dose

• 3.6 mg implant: one implant every 28 days (4 weeks), for adults.
• Endometriosis: treatment should not exceed 6 months, as there are no clinical data for longer periods, and courses should not be repeated because of the loss of bone mineral density.
• Uterine fibroids: women with anaemia from fibroids are advised to take iron supplements with goserelin for at least 3 months before surgery.
• Endometrial thinning before ablation: 4 or 6 weeks of treatment; a second implant may be needed with a large uterus or to give flexibility in timing the operation.
• Assisted reproduction: given to reach pituitary down-regulation (oestradiol about 150 pmol/L), usually within 7 to 21 days. Controlled ovarian stimulation with gonadotropins follows; at the right stage of follicle development the gonadotropins are stopped and human chorionic gonadotropin (hCG) is given to trigger ovulation. Monitoring, egg retrieval and fertilisation follow normal practice, and treatment is given only under the supervision of a specialist experienced in this field.
• 10.8 mg implant: one implant every 12 weeks; use and indications follow its own national SmPC.

Starting Treatment in Men

In men at risk of ureteral obstruction or spinal cord compression, goserelin needs careful consideration and close observation during the first month. An anti-androgen (for example cyproterone acetate 300 mg daily, from 3 days before to 3 weeks after the first implant) can be considered to prevent the effects of the initial testosterone rise.

Special Populations

• Elderly: no dose adjustment.
• Renal impairment: no dose adjustment.
• Hepatic impairment: no dose adjustment.
• Children and adolescents: not indicated; safety and efficacy have not been established.

Injection-Site Injury

Pain, bruising, bleeding and vascular injury have been reported at the injection site. Patients should be watched for signs of abdominal bleeding. In very rare cases a faulty injection caused vascular injury and haemorrhagic shock requiring transfusion and surgery.

Depression and Mood Changes

LHRH agonists carry an increased risk of depression, which can be severe. Patients should be told of this and treated if symptoms appear. Patients with known depression, and those with high blood pressure, need appropriate monitoring.

QT Prolongation

Androgen deprivation can prolong the QT interval. In patients with a history of or risk factors for QT prolongation, or taking medicines that may prolong it, the doctor should weigh the benefit against the risk of torsade de pointes before starting.

Bone Mineral Density

• Men: LHRH agonists can reduce bone mineral density. Special caution applies with other risk factors for osteoporosis, such as chronic heavy alcohol use, smoking, long-term anticonvulsants or corticosteroids, or a family history.
• Breast cancer: after 2 years of treatment for early breast cancer the average loss was 6.2% at the femoral neck and 11.5% at the lumbar spine. It was partly reversible one year after stopping (recovery of 3.4% to 6.4% from baseline, from limited data).
• Benign gynaecological conditions: the average loss is probably about 1% a month over six months, and each 10% loss raises fracture risk about two to three times. In most women the bone recovers after treatment. For women with established osteoporosis or risk factors, treatment is considered individually, started only if the benefits clearly outweigh the risks, and combined with measures against bone loss.

Additional Points for Men

• Impaired glucose tolerance can appear as diabetes or loss of glycaemic control, so blood glucose monitoring should be considered.
• A pharmacoepidemiological study of LHRH agonists in prostate cancer found myocardial infarction and heart failure; the risk appears higher when combined with anti-androgens.

Additional Points for Women

• Withdrawal bleeding: vaginal bleeding may occur in the first month; if it continues, the cause should be investigated.
• Duration: there are no clinical data on treating benign gynaecological conditions beyond 6 months.
• Cervical resistance: goserelin may make the cervix more resistant, so take care when dilating it.
• Assisted reproduction: ovarian hyperstimulation syndrome has been reported with gonadotropins, so the cycle is monitored closely and hCG is withheld if possible when the risk is present. Use with caution in polycystic ovary syndrome, because follicle recruitment may increase.

Anti-Doping Tests

Treatment can cause positive results in anti-doping tests.

Pregnancy, Breastfeeding and Fertility

• Pregnancy: goserelin must not be given in pregnancy, because LHRH agonists carry a theoretical risk of miscarriage or foetal abnormality. Pre-menopausal women are examined carefully before treatment to exclude pregnancy, and pregnancy is excluded before use in assisted reproduction (no causal link to later problems has been shown there).
• Contraception: women must use non-hormonal contraception during treatment, until periods return after it stops.
• Breastfeeding: not recommended, and contraindicated.

Effect on Driving

There is no evidence that goserelin affects the ability to drive or use machines.

Do not store above 25 °C. No refrigeration is needed. The implant is supplied in a sealed sachet with a desiccant, inside a single-dose pre-filled syringe with a needle safety system (red safety clip). Keep out of the sight and reach of children.

3 years. Do not use after the expiry date on the pack.

Prescription only (Rx). Goserelin is not self-administered: a healthcare professional injects it, so it is supplied to the doctor, clinic or hospital that administers it. Use in assisted reproduction is supervised by a specialist experienced in that field.