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buserelin

( byoo-SE-rel-in )
Funding:
ODB - General Benefit
  • buserelin
Other Name(s): Suprefact® (Sanofi-Aventis), Suprefact Depot® (Sanofi-Aventis), Suprefact Nasal Spray® (Sanofi-Aventis)
Appearance: White-cream coloured cylindrical rod-shaped implants
A - Drug Name

buserelin

SYNONYM(S):   ICI 123215

COMMON TRADE NAME(S):   Suprefact® (Sanofi-Aventis); Suprefact Depot® (Sanofi-Aventis); Suprefact Nasal Spray® (Sanofi-Aventis)

 
B - Mechanism of Action and Pharmacokinetics

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.



Absorption

Oral: Not absorbed
Nasal: 1-3%
SC: 70% at 200 mcg


Distribution

Well distributed to liver, kidneys, anterior pituitary lobe; trace present in breast milk

Cross blood brain barrier? No information found
PPB 15%
Metabolism

Metabolized and inactivated by peptidases in liver, kidneys, GI tract, pituitary gland

Active metabolites None known
Inactive metabolites Buserelin (5-9) pentapeptide and others
Elimination

Mainly via kidney, some biliary

Urine 44% intact drug
Half-life

SC: 80 min (20-30 days for 2-month depot implants)
Intranasal: 1-2 h

 
C - Indications and Status
Health Canada Approvals:

  • 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.)



 
D - Adverse Effects

Emetogenic Potential:  

Not applicable

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.

 
E - Dosing

Refer to protocol by which patient is being treated.



Adults:

Prostate Cancer:

Induction:

Subcutaneous: 500 mcg q8h x 7 days

Maintenance:
Subcutaneous: 200 mcg Daily

Maintenance:
Intranasal: 400 mcg (200 mcg in each nostril) q8h (TID)

Maintenance:
Subcutaneous: 6.3 mg (depot injection) Every 2 months

Maintenance:
Subcutaneous: 9.45 mg (depot injection) Every 3 months

Dosage with Toxicity:

Dosage in myelosuppression:  No adjustment required



Dosage with Hepatic Impairment:

No adjustment required; no studies conducted.



Dosage with Renal Impairment:

No adjustment required; no studies conducted.



Children:

Safety and efficacy have not been established.

 



 
F - Administration Guidelines

  • 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.



 
G - Special Precautions
Contraindications:

  • 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

Other Warnings/Precautions:

  • 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.

     

Pregnancy and Lactation:
  • 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
 
H - Interactions

 

 

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
 
I - Recommended Clinical Monitoring
Recommended Clinical Monitoring

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



Suggested Clinical Monitoring

Monitor Type Monitor Frequency

ECG for patients at risk of QTc prolongation

baseline and as clinically indicated
 
J - Supplementary Public Funding

ODB - General Benefit (

)
  • buserelin ()

 
K - References

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

 
L - Disclaimer

Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.

The information set out in the drug monographs, regimen monographs, appendices and symptom management information (for health professionals) contained in the Drug Formulary (the "Formulary") is intended for healthcare providers and is to be used for informational purposes only. The information is not intended to cover all possible uses, directions, precautions, drug interactions or adverse effects of a particular drug, nor should it be construed to indicate that use of a particular drug is safe, appropriate or effective for a given condition. The information in the Formulary is not intended to constitute or be a substitute for medical advice and should not be relied upon in any such regard. All uses of the Formulary are subject to clinical judgment and actual prescribing patterns may not follow the information provided in the Formulary.

The format and content of the drug monographs, regimen monographs, appendices and symptom management information contained in the Formulary will change as they are reviewed and revised on a periodic basis. The date of last revision will be visible on each page of the monograph and regimen. Since standards of usage are constantly evolving, it is advised that the Formulary not be used as the sole source of information. It is strongly recommended that original references or product monograph be consulted prior to using a chemotherapy regimen for the first time.

Some Formulary documents, such as the medication information sheets, regimen information sheets and symptom management information (for patients), are intended for patients. Patients should always consult with their healthcare provider if they have questions regarding any information set out in the Formulary documents.

While care has been taken in the preparation of the information contained in the Formulary, such information is provided on an “as-is” basis, without any representation, warranty, or condition, whether express, or implied, statutory or otherwise, as to the information’s quality, accuracy, currency, completeness, or reliability.

CCO and the Formulary’s content providers shall have no liability, whether direct, indirect, consequential, contingent, special, or incidental, related to or arising from the information in the Formulary or its use thereof, whether based on breach of contract or tort (including negligence), and even if advised of the possibility thereof. Anyone using the information in the Formulary does so at his or her own risk, and by using such information, agrees to indemnify CCO and its content providers from any and all liability, loss, damages, costs and expenses (including legal fees and expenses) arising from such person’s use of the information in the Formulary.