Buserelin

Buserelin is a synthetic analogue of natural gonadotropin-releasing hormone (gonadorelin; GnRH, LHRH) with a markedly stronger biological activity. Replacing glycine at position 6 with D-serine and ending the chain with an ethylamide gives a nonapeptide whose effect on LH and FSH release is reported to be about 20 to 170 times that of natural LHRH, with a longer duration of action (DrugBank).

Mechanism of Action

• Initial stimulation: the first pharmacological effect is stimulation of gonadotropin release and testosterone secretion, followed by a progressive fall of testosterone to castration levels.
• Pituitary desensitisation: with continued dosing the pituitary GnRH receptors become desensitised and gonadotropin release is suppressed. In men this lowers the synthesis and secretion of testosterone; in women it inhibits oestrogen secretion.
• Dose dependence: the suppressive effect depends on the daily dose, the frequency of administration and the duration of treatment. Even when serum buserelin falls below the detection limit, gonadotropin release stays limited for about 3 hours because of sustained binding to receptors in the anterior pituitary.
• Selectivity: other pituitary hormones (growth hormone, prolactin, ACTH, TSH) are not directly affected, and adrenal steroid secretion remains unchanged.
• Prostate cancer: by removing testosterone stimulation of the tumour, buserelin is as effective as orchidectomy, with the advantage that the process is reversible.

Pharmacokinetics

• Absorption: water-soluble and well absorbed after subcutaneous injection (DrugBank gives a bioavailability of about 70%).
• Distribution: circulates mainly unchanged in serum, about 15% bound to proteins. It accumulates preferentially in the liver, the kidneys and the anterior pituitary, its target organ.
• Metabolism: inactivated by peptidases (pyroglutamyl peptidase and chymotrypsin-like endopeptidases) in the liver, the kidneys and the gastrointestinal tract; receptor-bound buserelin in the pituitary is inactivated by membrane enzymes.
• Elimination: buserelin and its inactive metabolites leave through the kidneys and in bile; in men about 50% is excreted unchanged in the urine. The elimination half-life is 50–80 minutes after intravenous and about 80 minutes after subcutaneous administration. A small part of the dose passes into breast milk, and current clinical data indicate no hormonal effect on the infant.

• Advanced hormone-dependent prostate cancer: treatment of advanced hormone-dependent prostate carcinoma. It does not apply after bilateral orchidectomy, because no further reduction in testosterone would be obtained.
• Preparation for ovulation induction: in women, pituitary desensitisation to prepare for ovulation induction, given together with gonadotropins.

• Hypersensitivity to buserelin or to any of the excipients.
• Pregnancy, when buserelin is used to prepare for ovulation induction: it must not be given to pregnant women.
• Breastfeeding, when used to prepare for ovulation induction: the SmPC refers to its pregnancy and lactation section, which advises avoiding breastfeeding during treatment.
• Tumour disease with proven hormone insensitivity.
• Buserelin is also not recommended after bilateral orchidectomy, since no further fall in testosterone is expected.

Most effects are directly or indirectly caused by the suppression of testosterone (androgen deficiency) in men or of oestrogen in women. Where the SmPC gives no frequency, the frequency is not known.

Common (≥1/100 to <1/10): mood changes and depression (long-term treatment); headache (in women rarely migraine-like); pain or local reactions at the injection site.

Uncommon (≥1/1,000 to <1/100): hypersensitivity reactions (skin redness, itching, rash including urticaria); mood changes and depression (short-term treatment); somnolence, vertigo; constipation; tiredness; raised liver enzymes (for example transaminases); weight gain or loss.

Rare (≥1/10,000 to <1/1,000): allergic asthma with dyspnoea, in isolated cases leading to anaphylactic or anaphylactoid shock; nervousness, emotional instability, anxiety; sleep disturbances, memory and concentration disturbances; palpitations; worsening blood pressure in hypertensive patients; nausea, vomiting, diarrhoea; increase or decrease of scalp and body hair.

Very rare (<1/10,000): pituitary adenoma; thrombocytopenia and leucopenia; increased thirst, changes in appetite and reduced glucose tolerance (which can worsen metabolic control in diabetic patients); visual disturbances (for example blurred vision) and a feeling of pressure behind the eyes; tinnitus and hearing disturbances; musculoskeletal discomfort and pain.

Not known: QT prolongation (post-marketing); degeneration of uterine fibroids; reduced bone density, osteoporosis and bone fractures, with the fracture risk rising with the duration of therapy; changes in serum lipids and raised bilirubin; in men, a possible rise in the risk of cardiovascular disease, diabetes mellitus and anaemia from androgen deprivation.

In prostate cancer, the testosterone level rises transiently at the start of treatment and can temporarily activate the tumour: new or worse bone pain in patients with bone metastases; signs of neurological deficit from tumour compression (for example leg weakness); urinary disturbances, hydronephrosis and lymphostasis; thrombosis with pulmonary embolism. A concomitant antiandrogen largely prevents these, although some patients may still have a mild, transient increase in tumour pain and a poorer sense of wellbeing. Hot flushes, testicular atrophy, impotence and loss of libido (mostly from the hormone suppression), occasional painless gynaecomastia and mild oedema of the ankles and lower legs may also occur.

In preparation for ovulation induction, oestrogen suppression causes uterine bleeding (a period) in the first weeks in most patients, and occasionally later. Menopause-like symptoms can follow: hot flushes, increased sweating, vaginal dryness, painful intercourse, reduced libido and, after several months, loss of bone mass. Other reactions that cannot be clearly attributed to hormone suppression include changes in breast size with discomfort, brittle nails, acne, dry skin, vaginal discharge, face and limb oedema, milk secretion, stomach or bowel pain, paraesthesia and dry eyes. Ovarian cysts may develop early in treatment, with no reported harm to the stimulation. Assisted-reproduction programmes carry their own risks, such as ectopic pregnancy, miscarriage and multiple pregnancy, including when buserelin is used as adjuvant therapy, and combining buserelin with gonadotropins raises the risk of ovarian hyperstimulation syndrome (see Special Instructions).

• Antidiabetic medicines: their effect may be weakened during treatment with buserelin.
• Medicines that prolong the QT interval or can cause Torsade de Pointes: androgen deprivation can itself prolong the QT interval, so combining buserelin with such medicines needs careful evaluation. The SmPC names class IA antiarrhythmics (quinidine, disopyramide), class III antiarrhythmics (amiodarone, sotalol, dofetilide, ibutilide), methadone, moxifloxacin and antipsychotics, among others.
• Sex hormones: in preparation for ovulation induction, the dose is set so that the overall therapeutic effect is not affected.

Buserelin solution for injection is given subcutaneously, into the tissue just under the outer layer of the skin. For greater efficacy, patients should be advised to space the daily injections at regular intervals through the day.

Prostate Cancer

• Daily dose: 1.5 mg of buserelin regardless of body weight, given as 3 subcutaneous injections of 0.5 mL at regular intervals. The injection solution is used to start the hormone suppression.
• Continuation: from the eighth day of treatment, treatment continues with the nasal form of buserelin.
• Antiandrogen: an antiandrogen is recommended as adjuvant therapy, starting 5 days before the first injection and continued alongside buserelin for the first 3–4 weeks, by which time buserelin has lowered testosterone to the desired level.
• After orchidectomy: not recommended after bilateral orchidectomy.

Preparation for Ovulation Induction

• Daily dose: 0.6 mg of buserelin regardless of body weight, given as 2 subcutaneous injections of 0.3 mL.
• Start: in the early follicular phase (day 1 or 2 of the cycle) or, once pregnancy has been excluded (do a pregnancy test if there is any doubt), in the middle of the luteal phase (about day 21).
• Stop: on the first day of human chorionic gonadotropin (hCG) administration.
• Gonadotropin stimulation: ovarian stimulation with gonadotropins should start only once oestradiol release has fallen enough, which takes 2–3 weeks in most patients.

Special Populations

• Children: must not be used; safety and efficacy have not been established.
• Other groups: the SmPC gives no separate dosing for elderly patients or for renal or hepatic impairment.

Cardiovascular Disease, Diabetes and Blood Pressure

Published epidemiological studies suggest a link between treatment with GnRH agonists and a higher risk of cardiovascular disease (such as myocardial infarction, sudden cardiac death and stroke) and of diabetes mellitus. These risks should be assessed before treatment starts and during it, and patients monitored and treated accordingly. Blood pressure should be checked regularly in patients with hypertension, and blood glucose in diabetic patients, because glucose tolerance can change and metabolic control can worsen.

QT Prolongation

Androgen deprivation can prolong the QT interval. In patients with a history of, or risk factors for, QT prolongation, and in patients taking medicines that can prolong it, the benefit and risk (including the potential risk of Torsade de Pointes) should be weighed before starting buserelin.

Depression

GnRH agonists such as buserelin carry an increased risk of depression, which can be severe. Patients should be informed and treated appropriately if symptoms appear. Those with a history of depression or active depression need close monitoring because of the risk of recurrence or worsening.

Anaemia and Bone Density

• Anaemia: because testosterone is suppressed, GnRH agonists may increase the risk of anaemia; assess the risk and monitor accordingly.
• Bone density: LHRH agonists may reduce bone density and lead to osteoporosis and more fractures. Take special care when there are extra risk factors (chronic alcohol abuse, smoking, long-term anticonvulsants or corticosteroids, a family history of osteoporosis). Bone mineral density should be checked periodically and preventive measures used.

Prostate Cancer: Tumour Flare and Monitoring

• An antiandrogen is strongly recommended as additional medication from 5 days before the first injection and for the first 3–4 weeks. Buserelin can first raise serum testosterone, and an antiandrogen prevents the effect of that initial rise.
• Without it, about 10% of patients with bone metastases may develop new or worse bone pain. Adjuvant antiandrogen therapy is also indispensable in patients with known metastases, for example in the spine, to prevent the initial complications of temporary tumour activation such as spinal cord compression and paralysis.
• Response can be followed by serum testosterone and prostate-specific antigen (PSA). Testosterone rises at the start, then falls progressively over 2 weeks and reaches castration levels after 2 to 4 weeks.

Ovulation Induction: Ovarian Hyperstimulation

• Adding buserelin to gonadotropins carries a higher risk of ovarian hyperstimulation syndrome (OHSS) than gonadotropins alone. Caution is needed in women with polycystic ovary syndrome, who are more prone to it.
• Possible signs include abdominal pain, tension or increased abdominal girth, ovarian cysts, nausea, vomiting, enlarged ovaries, dyspnoea, diarrhoea, reduced urine output, haemoconcentration and increased clotting tendency. An acute abdomen can result from ovarian torsion or rupture, serious thromboembolic events can occur, and a fatal outcome is possible.
• Each ovarian stimulation cycle must be monitored closely so that affected patients are identified early, and human chorionic gonadotropin (hCG) should be available if needed.
• A pregnancy test is recommended before starting. Ovulation induction for in vitro fertilisation must be done under strict medical supervision.

Pregnancy and Breastfeeding

• Pregnancy: buserelin solution for injection must not be given to pregnant women (a contraindication when it is used for ovulation induction).
• Breastfeeding: buserelin passes into breast milk in small amounts. No harmful effects have been seen in the infant, but breastfeeding should be avoided during treatment.

Excipients

Each mL contains 10 mg of benzyl alcohol, which can cause allergic reactions. Large amounts can accumulate in the body and cause metabolic acidosis, especially in pregnant or breastfeeding women and in patients with liver or kidney impairment. The product contains less than 1 mmol (23 mg) of sodium per mL, so it is essentially sodium-free.

Effect on Driving

No study of the effects on driving and using machines has been done. Some adverse events (for example vertigo) can impair reaction time or concentration and so are a risk when driving or using machines; patients should be warned.

Store below 25 °C. Do not freeze. Keep the vial in the outer carton to protect it from light. The solution is supplied in clear type I glass vials with a dark grey rubber stopper, an aluminium cap and a plastic button; each box holds 2 multidose vials of 5.5 mL (1 mg/mL).

2 years.

Prescription only (Rx). Buserelin is injected subcutaneously several times a day, so it is supplied to the patient or to the treating clinic on prescription. It does not need refrigeration (store below 25 °C).