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buserelin
buserelin
SYNONYM(S): ICI 123215
COMMON TRADE NAME(S): Suprefact® (Sanofi-Aventis); Suprefact Depot® (Sanofi-Aventis); Suprefact Nasal Spray® (Sanofi-Aventis)
Buserelin is a synthetic analog of natural gonadotropin-releasing hormone (GnRH/LHRH). The effects of buserelin on follicle stimulating hormone (FSH) and luteinizing hormone (LH) release are 20 to 170 times greater than those of LHRH. Chronic administration of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis, reduced circulating levels of gonadotropin and gonadal steroids.
Oral: Not absorbed
Nasal: 1-3%
SC: 70% at 200 mcg
Well distributed to liver, kidneys, anterior pituitary lobe; trace present in breast milk
| Cross blood brain barrier? | No information found |
| PPB | 15% |
Metabolized and inactivated by peptidases in liver, kidneys, GI tract, pituitary gland
| Active metabolites | None known |
| Inactive metabolites | Buserelin (5-9) pentapeptide and others |
Mainly via kidney, some biliary
| Urine | 44% intact drug |
| Half-life |
SC: 80 min (20-30 days for 2-month depot implants) |
- Palliative treatment of patients with advanced castrate-resistant prostate cancer (stage D) (SC formulation)
- Palliative treatment of patients with advanced castrate-resistant prostate cancer (stage D) (Nasal solution, for maintenance treatment only)
(Refer to the product monograph for other non-cancer indications approved by Health Canada.)
Emetogenic Potential:
Extravasation Potential: None
The following table contains adverse effects reported mainly in prostate cancer patients and reported for depot buserelin ± cyproterone.
| ORGAN SITE | SIDE EFFECT* (%) | ONSET** | |||
|---|---|---|---|---|---|
| Cardiovascular | Heart failure (<1%) | E | |||
| Hypertension (9%) (may be severe) | E | ||||
| Palpitations (5%) | E | ||||
| QT interval prolonged (rare) | E | ||||
| Venous thromboembolism (<1%) | E | ||||
| Dermatological | Rash (<1%) | D | |||
| Gastrointestinal | Constipation (<1%) | E | |||
| Diarrhea (<1%) | E | ||||
| Dry mouth (2%) (nasal route) | I | ||||
| Nausea, vomiting (5%) | I | ||||
| Weight changes (<1%) | D | ||||
| General | Edema (1%) | E | |||
| Fatigue (14%) | E | ||||
| Tumour flare (1%) (disease flare including urinary retention) | E | ||||
| Hematological | Myelosuppression (anemia, mild) | D | |||
| Hypersensitivity | Hypersensitivity (rare) | I | |||
| Injection site | Injection site reaction (5%) (transient) | I E D | |||
| Metabolic / Endocrine | Hyperglycemia (<1%) | E | |||
| Hyperlipidemia (rare) | E | ||||
| Other (pituitary adenoma- rare) | L | ||||
| Musculoskeletal | Musculoskeletal pain (5%) | E | |||
| Osteopenia (may be severe) | D L | ||||
| Neoplastic | Other (<1%) (myeloid metaplasia) | E | |||
| Nervous System | Headache (29%) (nasal route) | E | |||
| Insomnia (5%) | D | ||||
| Mood changes (2%) | D | ||||
| Renal | Creatinine increased (rare) | E | |||
| Reproductive and breast disorders | Androgen deprivation symptoms (Up to 23%) | E | |||
| Respiratory | Dyspnea (<1%) | I | |||
| Nasal irritation (13%) (nasal route) | I | ||||
* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare"
may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,
isolated data or anecdotal
reports.
Dose-limiting side effects are underlined.
** I = immediate (onset in hours to days)
E = early (days to weeks)
D = delayed (weeks to months)
L = late (months to years)
The most common side effects are expected pharmacologic effects such as androgen withdrawal symptoms, fatigue and injection site reactions. The reactions at the injection site include pain, irritation, swelling and urticaria. None of these reactions required discontinuation of therapy.
In non-orchidectomized patients, the initial stimulation of the pituitary caused by buserelin produces an acute increase in the concentration of testosterone, usually during the first week of treatment. This is accompanied by disease flare in <10% of patients. Increased bone pain and less frequently, neuropathy, symptoms of urinary tract obstruction (e.g. renal failure) and/or spinal cord compression (e.g. weakness of lower extremities) occur. Patients with metastatic vertebral lesions and/or with urinary tract obstruction should begin buserelin therapy under close supervision. Alternatively, cyproterone 100 mg bid, flutamide 250 mg tid, bicalutamide 50mg daily or nilutamide 150mg daily may be given concurrently with the first administration of buserelin in prostate cancer patients. Since the danger of a flare reaction abates in the second week following buserelin administration, there is no strong reason for continuing antiandrogens much beyond this time.
Long-term use results in hypogonadism; it is unknown whether this is reversible.
Bone loss may occur during the hypoandrogenic state caused by long-term use of buserelin. Risk factors such as older age, pre-existing osteopenia, family history of osteoporosis, chronic use of corticosteroids, anticonvulsants, or other drugs that may lead to osteoporosis or chronic alcohol/tobacco abuse should be carefully considered before starting treatment.
Androgen deprivation may increase cardiovascular risk (MI, sudden death, stroke) in men with prostate cancer since it can adversely affect cardiovascular risk factors, such as increased body weight, reduced insulin sensitivity and/or dyslipidemia. QTc prolongation has been described and buserelin should be used with caution in patients with other risk factors such as congenital long QT syndrome, abnormal electrolytes and concomitant medications which prolong QTc. Reduction in glucose tolerance and increased risk of developing diabetes have been reported in men treated androgen deprivation therapy. Anemia is also a known physiologic effect of testosterone suppression.
Hypertensive crises have been reported in patients with hypertension.
There is an increased risk of depression in patients on GnRH agonist treatment. Worsening of depression, including suicidal attempts, have been reported.
Pituitary apoplexy has been reported rarely in patients using GHRH agonists, usually in patients with pre-existing adenomas. Most occurred within 2 weeks of the first dose, and some within the first hour. Symptoms include sudden headache, vomiting, visual changes, altered mental status and sometimes cardiovascular collapse.
Hypersensitivity reaction and anaphylaxis have been described. Patients who experience anaphylaxis or anaphylactoid shock while on the depot formulation may require surgical removal of the implant.
Refer to protocol by which patient is being treated.
Prostate Cancer:
Subcutaneous: 500 mcg q8h x 7 days
Subcutaneous: 200 mcg Daily
Intranasal: 400 mcg (200 mcg in each nostril) q8h (TID)
Subcutaneous: 6.3 mg (depot injection) Every 2 months
Subcutaneous: 9.45 mg (depot injection) Every 3 months
Dosage in myelosuppression: No adjustment required
No adjustment required; no studies conducted.
No adjustment required; no studies conducted.
Safety and efficacy have not been established.
- Subcutaneous injection of depot at Cancer Centre or physician's office; supplied by outpatient prescription.
- Subcutaneous: Rotate injection sites
- Solution for SC injection: Store at room temperature. May be kept up to 14 days after the first opening when stored at room temperature. Protect from light.
- Intranasal solution: Store at room temperature. May be kept up to 5 weeks after the first opening when stored at room temperature. Protect from light.
- DEPOT formulation for SC injection:
o Store at room temperature. Protect from light.
o Applicator containing implant rods should be kept horizontal before injection.
o Before the injection, a local anesthetic may be used if needed.
o Inject SC into the lateral abdominal wall.
- patients who have a hypersensitivity to this drug or any of its components
- in patients who have undergone orchiectomy or who have non-hormone dependent prostate cancer
- Use with caution in patients with osteoporosis (or risk factors for osteoporosis), diabetes, risk factors for QT prolongation, history of depression, cardiovascular disease, metastatic vertebral lesions and/or urinary tract obstruction due to the risk of disease flare
Other Drug Properties:
-
Carcinogenicity:
Very rare cases of pituitary tumours have been observed in humans with buserelin use.
-
Mutagenicity:
No
-
Fetotoxicity:
Yes
Buserelin is CONTRAINDICATED for use in pregnancy. Adequate non-hormonal contraception should be used by both sexes during treatment, and for at least 6 months after the last dose (general recommendation). -
Breastfeeding:
Contraindicated
Buserelin is secreted into breast milk. -
Fertility effects:
Probable
| AGENT | EFFECT | MECHANISM | MANAGEMENT |
|---|---|---|---|
| Antidiabetic agents | ↓ effect | Unknown | Caution |
| Drugs that may prolong QT (i.e. Amiodarone, procainamide, sotalol, venlafaxine, amitriptyline, sunitinib, methadone, chloroquine, clarithromycin, haloperidol, fluconazole, moxifloxacin, domperidone, ondansetron, etc) | QTc prolongation, torsades de pointes | Additive | Caution |
| Monitor Type | Monitor Frequency |
|---|---|
| Blood pressure monitoring in patients with hypertension | regular |
| Blood glucose/HbA1c levels | baseline and periodic, especially in diabetic patients |
| EKG, Electrolytes, (including K, Ca, Mg) | baseline, also regular for at risk patients |
| PSA | baseline and periodic |
Clinical assessment of disease flare, local reactions, thromboembolism, cardiovascular effects, osteoporosis, psychiatric effects, hot flashes |
regular |
Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version
| Monitor Type | Monitor Frequency |
|---|---|
ECG for patients at risk of QTc prolongation |
baseline and as clinically indicated |
Product Monograph: Suprefact® (buserelin). Sanofi-aventis Canada, August 10, 2010.
Product Monograph: Suprefact® Depot (buserelin). Sanofi-aventis Canada, August 10, 2010.
Product Monograph: Suprefact®. Sanofi-aventis (New Zealand), October 2012.
October 2017 Modified adverse effects, special precautions and monitoring sections
Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.
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