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leuprolide

( LOO-pro-lied )
Funding:
ODB - General Benefit
  • leuprolide - long-acting formulation
Other Name(s): Lupron® (AbbVie), Lupron Depot® (AbbVie), Eligard® (Sanofi Aventis)
Appearance: suspension or solution for injection
A - Drug Name

leuprolide

SYNONYM(S):   TAP-144; A43818

COMMON TRADE NAME(S):   Lupron® (AbbVie); Lupron Depot® (AbbVie); Eligard® (Sanofi Aventis)

 
B - Mechanism of Action and Pharmacokinetics

Leuprolide is a synthetic analog of gonadotropin releasing hormone (GnRH) acting mainly on the pituitary gland in humans.  Continuous treatment produces initial stimulation of FSH and LH (3-4 days), then suppression, with reduction of gonadal hormones to castrate or post-menopausal levels.  In males, the net effect is a reduction of testosterone to castration levels within two to four weeks.  In females, both ovarian estrogen and androgen synthesis are inhibited.



Absorption
Destroyed in gastrointestinal tract
Distribution

Undetermined. There was no evidence of accumulation after repeated administration.

Cross blood brain barrier? yes
PPB 43-49%  (in vitro)
Metabolism

Extensive, by peptidases, to inactive peptides.

Active metabolites none reported
Inactive metabolites yes
Elimination
Urine < 5 %, parent and main inactive metabolite
Half-life 3 hours (after 1mg IV dose).
 
C - Indications and Status
Health Canada Approvals:

  • Advanced (stage D2) prostate cancer (hormone-dependent)


Other Uses:

  • Breast cancer 
 
D - Adverse Effects

Emetogenic Potential:  

Not applicable

Extravasation Potential:   None

The following table contains adverse effects reported in prostate cancer patients.

ORGAN SITE SIDE EFFECT* (%) ONSET**
Auditory Hearing impaired (<5%) E
Cardiovascular Arrhythmia (<5%) E
Arterial thromboembolism (<5%) E
Cardiotoxicity (<5%) E  D
Hypertension (<5%) E
Hypotension (<5%) E
QT interval prolonged E
Venous thromboembolism (<5%) E
Dermatological Alopecia (<5%) E
Hypertrichosis (<5%) E
Photosensitivity E
Rash (12%) E
Gastrointestinal Appetite changes (<5%) E
Constipation (<5%) E
Dysphagia (<5%) E
GI hemorrhage (<5%) E
GI obstruction (<5%) E
GI ulcer (<5%) E
Nausea, vomiting (5%) I
Weight changes (<5%) E
General Edema (21%) E
Fatigue (12%) I  E
Tumour flare (including pain) E
Hematological Myelosuppression (<5%) (mild) E
Hepatobiliary ↑ LFTs (<5%) (may be severe) E
Hypersensitivity Hypersensitivity (rare) I
Injection site Injection site reaction (38%) E
Metabolic / Endocrine Abnormal electrolyte(s) (increased/decreased Na, PO4, K, Ca) E
Hyperglycemia (5%) E
Hyperlipidemia (5%) D
Pituitary apoplexy / adenoma (rare) I  E
Musculoskeletal Musculoskeletal pain (33%) E
Osteoporosis D
Nervous System Anxiety (<5%) E
Dizziness (8%) E
Headache (10%) E
Mood changes (<5%) (including depression, may be severe) E
Paresthesia (8%) E
Seizure (<5%) E
Sleep disorder (9%) E
Ophthalmic Eye disorders (<5%) (and abnormal vision) E
Renal Creatinine increased (<5%) I  E
Reproductive and breast disorders Androgen deprivation symptoms and hypogonadism (59%) E
Respiratory Cough, dyspnea (5%) E
Pneumonitis (<5%) E  D
Urinary Urinary symptoms (<5%) E


* "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)

 

Leuprolide-induced hot flashes range in severity from mild to severe, with frequent sweating.  They usually decrease with continued therapy and do not usually require treatment discontinuation. Adverse CNS effects occur in 3% or more of patients and include dizziness, pain, headache and paresthesia.

In non-orchidectomized patients, the initial stimulation of the pituitary caused by leuprolide produces an acute increase in the concentration of testosterone, usually during the first week of treatment.  This is accompanied by disease flare in 5-10% of patients and transient prostatic enlargement in 30-50%.  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 leuprolide 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 leuprolide in prostate cancer patients.  Since the danger of a flare reaction abates in the second week following leuprolide administration, there is no strong reason for continuing antiandrogens much beyond this time. 

Bone loss may occur during the hypoandrogenic state caused by long-term use of leuprolide. 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 leuprolide 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.

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. Long-term use results in hypogonadism; it is unknown whether this is reversible.  Second malignancies have been described but the relationship to leuprolide is unclear.

Rare cases of serious hepatotoxicity, including fatal cases, have been described.

 

 
E - Dosing

Refer to protocol by which patient is being treated. Do not use formulations for shorter or longer periods (for e.g., dividing 3-monthly dose between more than one patient monthly or using 3 x monthly preparations q3m) as the pharmacokinetics are quite different. Delays of 14 days or more (for the monthly dose) will result in increased testosterone levels, so the schedule must be maintained.



Adults:

Daily schedule:  1 mg (0.2 mL of leuprolide 5mg/mL injection) subcutaneously
Use for about 2 weeks prior to beginning monthly treatments in those patients at risk of worsening signs and symptoms.

Long-acting:     
Route of administration varies depending on brand and formulation*
Monthly SR: 7.5 mg

3-monthly SR: 22.5mg

4-monthly SR: 30mg

6-monthly SR: 45mg

* NOTE:  Eligard® 7.5mg, 22.5mg, 30mg, and 45mg are for Subcutaneous use only.
Lupron Depot® 7.5mg, 22.5mg and 30mg are for Intramuscular use only.  
 
 
 
 

Dosage with Toxicity:

Toxicity
Dose modification
Myelosuppression

No dose reduction needed

↑ LFTs

Hold until ≤ grade 1. If no recovery then discontinue

Arterial and venous thromboembolism

Discontinue
Pituitary apoplexy
Discontinue
Pneumonitis
Discontinue


Dosage with Hepatic Impairment:

No adjustment required. See table above for management of drug-related hepatotoxicity.

 



Dosage with Renal Impairment:

No adjustment required.



Dosage in the elderly:

No adjustment required



Children:

No oncologic indications. Safety and efficacy have not been established.



 
F - Administration Guidelines

  • Outpatient prescription; administer in Cancer Centre or physician’s office
  • Vary injection site
  • For long-acting preparations, reconstitute with supplied diluent immediately before injection as directed (see product monograph). 
  • Do not give multiple monthly injections together to make up a q3 or q4 month dose, as the release characteristics are different

Lupron® 5mg/mL injection:

  • For Subcutaneous use only.
  • Usual sites of injection include the abdomen and anterior thigh.
  • Keep refrigerated.

Lupron Depot® 7.5mg, 22.5mg and 30mg:

  • For Intramuscular use only. 
  • Usual sites of injection include the anterior thigh, gluteal area or deltoid.  Vary injection sites.
  • Store at room temperature.

Eligard® 7.5mg, 22.5mg, 30mg, and 45mg:

  • For Subcutaneous use only.  Choose an injection site on the abdomen, upper buttocks, or anywhere with adequate amounts of subcutaneous tissue. 
  • Keep refrigerated, or may be stored at room temperature in original packaging for a period of 8 weeks before administration.
  • Allow product to reach room temperature before using.


 
G - Special Precautions
Contraindications:

Leuprolide is contraindicated in patients with hypersensitivity to the drug, its components or similar nonapeptides; Lupron® contains benzyl alcohol and may cause local reactions.

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, and in patients at risk of convulsions.

Pregnancy and Lactation:
  • Breastfeeding: Contraindicated
    Although leuprolide is not mutagenic, it is fetotoxic and teratogenic and causes adenomas in the pituitary, pancreas and testes in animals.  It is contraindicated in pregnancy as spontaneous abortions may occur.  Adequate contraception (with non-hormonal methods) should be used by both sexes during treatment and up to 6 months after leuprolide cessation.  Leuprolide may suppress fertility and this may or may not be reversible. 
 
H - Interactions

Leuprolide may interfere with diagnostic tests of pituitary-gonadal function; these tests should be conducted at more than 8 weeks after discontinuing treatment.

 

AGENT EFFECT MECHANISM MANAGEMENT
Drugs that increase QT interval ↑ risk of QT prolongation or Torsades de pointes Additive Caution
 
I - Recommended Clinical Monitoring

Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.

Recommended Clinical Monitoring

Monitor Type Monitor Frequency
Blood glucose levels/HbA1c baseline and periodic, especially in diabetic patients
PSA baseline and periodic
EKG, Electrolytes, (including K, Ca, Mg) baseline, also regular for at risk patients
Liver function tests periodic

Clinical assessment of disease flare, local reactions, thromboembolism, cardiovascular effects, osteoporosis, psychiatric effects, hot flashes and injection site reactions

At each visit

Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version



Suggested Clinical Monitoring

Monitor Type Monitor Frequency
Renal function tests periodic
 
J - Supplementary Public Funding

ODB - General Benefit (

)
  • leuprolide - long-acting formulation ()

 
K - References

Leuprolide acetate [Internet]; 2012 [cited 2012 September 4].  Available from http://www.ahfsdruginformation.com

NCI Drug Dictionary [Internet] [cited 2012 September 4].  Available from  http://www.cancer.gov/drugdictionary

Prescribiing Information:  Lupron® Depot (leuprolide). Abbvie Inc. (US), June 2014.

Product Monograph: Eligard® (leuprolide). Sanofi-aventis Canada Inc. May 31, 2011.

Product Monograph : Lupron® / Lupron® depot (leuprolide). AbbVie Corporation, August 9, 2013.

 

 

 


October 2017 added other indication

 
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.

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