Leuprolide Acetate

Registered South African indications:

• Advanced hormone-dependent prostate carcinoma
• Palliative treatment of advanced prostate cancer
• Endometriosis
• Leiomyoma uteri (uterine fibroids)
• Breast carcinomas
• Central precocious puberty

Registered South African contraindications

3.75mg, 11.25mg injection

• Hypersensitivity to the active ingredient or any of its excipients
• Hypersensitivity to similar nanopeptides
• Hypersensitivity to synthetic gonadotropin releasing hormone (GnRH) or GnRH derivatives (11.25mg)
• Children demonstrating hypersensitivity to GnRH (3.75mg)
• Women who are or may become pregnant while taking the medication
• Breastfeeding women
• Undiagnosed, abnormal vaginal bleeding
• In the context of pre- and perimenopausal breast cancer initiating aromatase inhibitor treatment before achieving adequate ovarian suppression with leuprolide (11.25mg)

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Isolated cases of anaphylaxis have been reported with the monthly depot formulation

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5mg implant

• Hypersensitivity to the active ingredient or any of its excipients
• Hypersensitivity to other gonadotropin releasing hormone agonist analogues or to poly(D,L-lactide)
• Not indicated in cases where carcinomas are shown to be hormonally independent
• After surgical castration, leuprolide does not cause any further reduction in testosterone levels

7.5mg, 22.5mg & 45mg injection

• Hypersensitivity to the active ingredient or any of its excipients
• Hypersensitivity to other gonadotropin releasing hormone (GnRH) analogues
• Pregnancy
• Lactation
• Women
• Paediatric patients
• In patients who previously underwent orchiectomy (as with other GnRH agonists, leuprolide does not result in further decrease of serum testosterone in case of surgical castration)
• As sole treatment in prostate cancer patients with spinal cord compression or evidence of spinal metastases

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Anaphylactic reactions to synthetic GnRH or GnRH agonist analogues have been reported in the literature

Contraindications registered in other jurisdictions

• Hypersensitivity to the active ingredient or any of its excipients
• Hypersensitivity to other synthetic gonadotropin releasing hormone analogues or GnRH derivatives
• Women who are or may become pregnant while taking the medication
• Breastfeeding women
• Undiagnosed, abnormal vaginal bleeding
• In the pre- and perimenopausal breast cancer setting: Initiation of aromatase inhibitor treatment before adequate ovarian suppression with
  leuprolide has been achieved
• The are no other known contraindications to the use of leuprolide in men
• In girls with central precocious puberty:
  - Pregnancy and breastfeeding
  - Undiagnosed vaginal bleeding
• Porphyria

• Renal impairment
• Hepatic impairment
• Diabetes mellitus
• High risk or history of for cardiovascular disease
• High risk for metabolic disease
• Risk of ureteric obstruction or spinal cord compression
• Risk factors for osteoporosis
• Risk factors for seizures
• History of or risk factors for QT prolongation 
• Prolonged use
• Women with submucous fibroids
• Women on effective treatment with persistent menstruation  
• Vaginal bleeding beyond the first/second month of treatment 
• Major risk factors for decreased bone mineral content 
• Uterine cervical resistance
• Men with urinary obstruction
• Men with metastatic vertebral lesions
• Girls with central precocious puberty
• Children with progressive brain tumours 
• Current or history of depression
• Pituitary adenomas
• History of seizures
• May impair the ability to drive and operate machinery

Forms avail. in SA and covered in this monograph: imp, inj

South African registered indications and dosages

Used for the treatment of

Advanced hormone-dependent prostatic carcinoma

• SC (imp): 5mg, once every 12 weeks

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Intended only for use in male patients

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If, in exceptional cases, the date of administration is postponed by up to 4 weeks, the therapeutic effect should not be impaired in the majority of patients

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Application should be performed by a medical practitioner experienced in tumour therapy. The implant is inserted subcutaneously into the abdominal skin. Refer to product professional information for administration directions

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Palliative treatment of advanced prostate cancer

• SC: 7.5mg: 1 injection, every month
• SC: 22.5mg: 1 injection, every 3 months
• SC: 45mg: 1 injection, every 6 months

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The injection delivers the dose of leuprolide acetate incorporated in a polymer formulation

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Once mixed, leuprolide must be administered within 30 minutes. The injection site should be changed with each injection

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The injection site should be an area with sufficient soft or loose subcutaneous tissue. Avoid areas with brawny or fibrous subcutaneous tissue or sites that could be rubbed or compressed (i.e with a belt or clothing waistband). In clinical trials, the injection was in the upper- or mid-abdominal area

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Refer to product professional information for administration directions

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Palliative treatment of advanced prostate cancer
- Alternative treatment of prostatic cancer when orchiectomy or estrogen administration is either not indicated or unacceptable to the patient

• SC: 3.75mg: 1 injection, once a month
• SC/IM: 11.25mg: 1 injection, every 3 months

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For 3.75mg prostate cancer: In patients treated with GnRH analogues for prostate cancer, treatment is usually continued upon development of castration-resistant prostate cancer. Reference should be made to relevant guidelines

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Breast carcinomas
- As adjuvant therapy to surgery

• SC/IM: 3.75mg: 1 injection, every 4 weeks
• SC/IM: 11.25mg: 1 injection, every 3 months

Endometriosis
- As sole therapy or as an adjunct to surgery

• SC/IM: 11.25mg: 1 injection, every 3 months; Treatment duration: Up to 6 months

- Management of endometriosis, including pain relief and reduction of endometriotic lesions

• SC/IM: 3.75mg: 1 injection; Treatment duration: Up to 6 months

Leiomyoma uteri (uterine fibroids)
- As preoperative therapy prior to myomectomy or hysterectomy, or it may provide symptomatic relief for the perimenopausal woman who does not desire surgery

• SC/IM: 11.25mg: 1 injection, every 3 months; Treatment duration: Up to 6 months 

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Leuprolide 11.25mg must be administered under the supervision of a medical practitioner

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The reconstituted suspension of leuprolide 11.25mg should be used immediately after preparation and any unused reconstituted suspension should be discarded, as the product has not been shown to be stable for 24 hours after reconstitution. The injection sites should be varied periodically. Refer to product professional information for administration directions

Forms avail. in SA and covered in this monograph: inj

South African registered indications and dosages

Used for the treatment of

Central precocious puberty

• SC/IM: 3.75mg: Initial: 0.3mg/kg (min. 7.5mg), for 4 weeks (see table below); Maintenance: If total downregulation is not achieved: Titrate upward by 3.75mg at intervals of 4 weeks and this dose will be considered the maintenance dose

The starting dose will be dictated by the child’s weight as follows

Child's Weight	Actual Dosage	Number of Injections	Total Dosage
≤25.0kg	3.75mgx2	1	7.5mg
25.0–37.5kg	3.75mgx3	2	11.25mg
>37.5kg	3.75mgx4	2	15.0mg

Note: When two injections are required to achieve the desired total dosage, they should be administered at the same time

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Leuprolide 3.75mg must be administered under the supervision of a medical practitioner

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The recommended dose for the treatment of children with central precocious puberty must be individualised for each child based on a mg/kg ratio of medicine to body weight. Younger children require higher doses on a mg/kg ratio

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For each dosage form, after 1-2 months of initiating therapy or changing doses, the child must be monitored with a GnRH stimulation test, determination of sex steroids and Tanner staging to confirm downregulation
Measurements of bone age for advancement should be monitored every 6-12 months
The dose should be titrated upward until no progression of the condition is noted either clinically and/or by laboratory parameters. The first dose found to result in adequate downregulation can probably be maintained for the duration of therapy in most children. However, there are insufficient data to guide dosage adjustment as patients move into higher weight categories after beginning therapy at very young ages and low dosages

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It is recommended that adequate downregulation be verified in such patients whose weight has increased significantly while on therapy. Discontinuation of leuprolide 3.75mg should be considered before age 11 for females and age 12 for males

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The following physiologic effects have been noted with the chronic administration of leuprolide acetate in this patient population:
1. Skeletal growth: A measurable increase in body length can be noted, since the epiphyseal plates will not close prematurely
2. Organ growth: Reproductive organs will return to a prepubertal state
3. Menses: Menses, if present, will cease

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Leuprolide 7.5mg, 22.5mg and 45mg is contraindicated in paediatrics

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No information available (11.25mg inj, 5mg imp)

Pregnancy

South African recommendations

5mg implant

• Not indicated for use in women

3.75mg injection

• Contraindicated
• The safety of leuprolide acetate in pregnancy has not been established. Pregnancy must be excluded before starting with treatment
• When used monthly at the recommended dose, leuprolide 3.75mg usually inhibits ovulation and stops menstruation. However, taking leuprolide 3.75mg does not ensure contraception
• Therefore, patients should use non-hormonal methods of contraception. Patients should be advised to see their doctor if they believe they may be pregnant. If a patient becomes pregnant during treatment, leuprolide 3.75mg must be discontinued
• The patient must be apprised of the potential risk of the foetus. During the early phase of therapy in endometriosis, sex steroids temporarily rise above baseline because of the physiologic effect of leuprolide 3.75mg. Therefore, an increase in the clinical signs and symptoms may be observed during the initial days of therapy, but these dissipate with continued therapy at adequate doses

7.5mg, 22.5mg & 45mg injection

• Contraindicated
• Leuprolide was not studied in women or children and can cause foetal harm when administered to pregnant women
• Major foetal abnormalities were observed in rabbits, but not in rats, after administration of leuprolide acetate throughout gestation. Increased foetal mortality and decreased foetal weights were noted in both rats and rabbits
• The effects on foetal mortality are anticipated due to the hormonal level alterations caused by leuprolide
• There's a potential risk of spontaneous abortion

11.25mg injection

• Contraindicated
• The safe use of leuprolide 11.25mg in pregnancy has not been established clinically. Studies in animals have shown reproductive toxicity
• Before starting treatment with leuprolide, pregnancy must be excluded. There have been reports of foetal malformation when leuprolide has been given during pregnancy
• When used 3-monthly at the recommended dose, leuprolide usually inhibits ovulation and stops menstruation. Contraception is not ensured by taking leuprolide; therefore, patients should use non-hormonal methods of contraception during treatment
• Patients should be advised that if they miss successive doses of leuprolide, breakthrough bleeding or ovulation may occur with the potential for conception. Patients should be advised to see their medical practitioner if they believe they may be pregnant
• If a patient becomes pregnant during treatment, the medicine must be discontinued. The patient must be apprised of this evidence and the potential for an unknown risk to the foetus

Recommendations in other jurisdictions

• Contraindicated
• Leuprolide must not be used in women who are pregnant
• Safe use of leuprolide in pregnancy has not been established clinically
• Studies in animals have shown reproductive toxicity. Before starting treatment with leuprolide, pregnancy must be excluded. There have been reports of foetal malformation when leuprolide has been given during pregnancy  
• When used at the recommended dose (monthly for leuprolide 3.75mg and 3-monthly for leuprolide 11.25mg), leuprolide usually inhibits ovulation and stops menstruation. Contraception is not ensured, however, by taking leuprolide and therefore patients should use non-hormonal methods of contraception during treatment and after cessation of treatment until the return of menses
• Patients should be advised that if they miss successive doses of leuprolide, breakthrough bleeding or ovulation may occur with the potential for conception. Patients should be advised to see their physician if they believe they may be pregnant. If a patient becomes pregnant during treatment, the drug must be discontinued. The patient must be apprised of this evidence and the potential for an unknown risk to the foetus

Breastfeeding

South African recommendations

• Not indicated for use in women (imp)
• Contraindicated (inj)
• It is not known whether leuprolide is excreted in human milk. Therefore, leuprolide should not be used in women who are breastfeeding

Recommendations in other jurisdictions

• Contraindicated
• Leuprolide must not be used in women who are breastfeeding

Fertility

South African recommendations

• Studies in adults with leuprolide acetate and similar analogues have shown full reversibility of fertility suppression when the medicine is discontinued after continuous administration for periods of up to 24 weeks (3.75mg, 11.25mg)
• No information available (7.5mg, 22.5mg & 45mg inj & 5mg imp)

Recommendations in other jurisdictions

• No information available

Recommendations below are applicable to South Africa and other jurisdictions

• Caution; no information available

Recommendations below are applicable to South Africa and other jurisdictions

• Caution; no information available

Recommendations below are applicable to South Africa and other jurisdictions

• No dose adjustment recommended

Central Nervous System Disorders

• Dizziness
• Parasthesiae
• Pituitary apoplexy
• Headache
• Insomnia
• Mood changes 
• Depression
• Fatigue
• Paralysis
• Seizures

Cardiovascular Disorders

• Hypotension
• Palpitations
• Electrocardiogram QT prolongation
• Hypertension
• Hypotension
• Angina pectoris
• Dysrhythmia

Respiratory Disorders

• Interstitial lung disease
• Dyspnoea
• Haemoptysis

Gastrointestinal Disorders

• Diarrhoea
• Nausea and vomiting

Hepatobiliary Disorders

• Abnormal hepatic function
• Abnormal liver function test
• Jaundice

Genitourinary Disorders

• Vulvovaginal dryness
• Urinary tract infections
• Nocturia
• Dysuria
• Haematuria
• Pollakiuria
• Micturition urgency
• Testicular pain

Endocrine and Metabolic Disorders

• Anorexia
• Diabetes mellitus
• Weight fluctuation
• Decreased appetite
• Abnormal lipids
• Abnormal glucose tolerance
• Decreasde libido
• Erectile dysfunction
• Testicular atrophy
• Testicular disorder
• Gynaecomastia
• Breast tenderness
• Breast atrophy  

Musculoskeletal Disorders

• Muscle weakness
• Bone pain
• Arthralgia
• Myalgia
• Weakness of lower extremities
• Spinal fracture

Skin and Subcutaneous Tissue Disorders

• Hyperhidrosis
• Hair loss
• Pruritus
• Dermatitis
• Skin reaction
• Abnormal hair growth

Immune, Blood and Lymphatic System Disorders

• Anaemia
• Thrombocytopaenia
• Leucopenia
• Hypersensitivity reactions
  - Rash
  - Pruritus
  - Urticaria
  - Wheezing
  - Interstitial pneumonitis
  - Anaphylactic reactions
• Hot flush
• Pulmonary embolism
• Vaginal haemorrhage
• Pyrexia
• Chills

Sensory Disorders

• Visual impairment

Others

• Peripheral Oedema
• Injection site reaction 
• Increased testosterone, dihydrotestosterone and acid phosphatase in men

• QT prolonging agents
• Class IA antiarrhythmic agents
  - Quinidine
  - Disopyramide
• Class III antiarrhythmic agents
  - Amiodarone
  - Sotalol
  - Dofetilide
  - Ibutilide
• Antipsychotic agents
• Methadone
• Moxifloxacin

• Bone mineral density

Specific cases may require

• Luteinizing hormone
• Follicle-stimulating hormone
• Serum testosterone
• Prostate-specific antigen
• Blood glucose
• HBA1c
• Full blood count
• ECG
• Electrolytes
• Renal function
• Gonadotropin-releasing hormone
• Oestradiol
• Pregnancy test
• Prolactin
• Testosterone
• Blood pressure
• Acid phosphate

Leuprolide acetate is a synthetic nonapeptide analogue of naturally occurring gonadotropin releasing hormone (GnRH or LH-RH). The analogue possesses greater potency than the natural hormone. Leuprorelin acetate is a peptide and therefore unrelated to the steroids. Chronic administration results in an inhibition of gonadotrophin production and subsequent suppression of ovarian and testicular steroid secretion.

Implant 5mg

• Leuprolide Hexal 5 (Sandoz)

Injection (per vial) 3.75mg

• Lucrin Depot (AbbVie)

Injection (per ml) 5mg

• Lucrin (AbbVie)

Injection (per syringe) 7.5mg

• Eligard (Key Oncologics) originator

Injection (per vial) 11.25mg

• Lucrin Depot  (AbbVie)

Injection (per syringe) 22.5mg

• Eligard (Key Oncologics) originator

Injection (per syringe) 45mg

• Eligard (Key Oncologics) originator