Luprodex 3.75 Injection

Indications

• Advanced prostate cancer
• Endometriosis
• Uterine leiomyomata (fibroids)
• Precocious puberty

Dosage

Adults: Refer to BNF for specific dosing guidelines based on the condition being treated.

Mechanism of action

Leuprorelin binds to gonadotropin-releasing hormone receptors (GnRHRs) on the anterior pituitary gland, leading to an initial release of LH and FSH. However, continuous administration results in feedback inhibition and significant downregulation of these hormones, resulting in decreased synthesis and release of sex hormones such as testosterone and estradiol, which is beneficial for treating hormone-sensitive conditions.

Pharmacodynamics

As a GnRH analogue, leuprorelin initially stimulates steroid production, resulting in temporary increases in testosterone and estradiol levels. Prolonged use, however, leads to a significant decrease in circulating steroid levels, mimicking the effects of androgen-deprivation therapy. The drug can have various adverse effects, including loss of bone mineral density and exacerbation of depressive symptoms in susceptible individuals. In women, initial increases in estradiol may worsen symptoms related to endometriosis or uterine fibroids.

Pharmacokinetics

Leuprorelin is administered via subcutaneous or intramuscular injection, leading to systemic absorption. Its pharmacokinetic profile is characterized by a prolonged duration of action due to its depot formulation, allowing for sustained release. The drug is metabolized in the liver and excreted primarily through the urine. Its half-life allows for dosing schedules that can range from daily to monthly, depending on the formulation used.

Contra-indications

• Pregnancy
• Known hypersensitivity to leuprolide or any of its components
• Pre-existing pituitary disorders

Adverse effects

• Hot flashes
• Mood changes
• Decreased libido
• Erectile dysfunction
• Vaginal dryness
• Osteoporosis
• Fatigue
• Injection site reactions
• Nausea
• Headache
• Abdominal pain
• Vision changes

Interactions

• Norethisterone may increase the risk of severe adverse effects such as vision loss, thrombophlebitis, and pulmonary embolism
• Medications affecting hormonal levels may alter the efficacy of leuprolide

Precautions

• Monitor bone mineral density during long-term therapy
• Assess patients for history of depression and monitor for recurrence of symptoms
• Consider potential cardiovascular risks in patients with a history of cardiovascular disease
• Caution in patients with a history of seizures

Pregnancy

Leuprolide is contraindicated during pregnancy due to potential harm to the fetus.

Breast-feeding

Leuprolide is not recommended for use during breastfeeding as it may affect milk production and composition.

Storage

Store at room temperature, away from light and moisture. Do not freeze.

Formulations

• Leuprolide acetate injection
• Leuprolide acetate implant

Indications

• Prostate cancer
• Endometriosis
• Pre- and perimenopausal breast cancer
• Management of uterine fibroids
• Preservation of ovarian function

Dosage

Children: Refer to the BNF for Children for pediatric dosing information

Adults: For prostate cancer, 11.25 mg every 3 months. For endometriosis, 3.75 mg every month for 3-4 months. For breast cancer, 3.75 mg every month. For fibroids, 3.75 mg for a single dose, administered between day 3 and 5 of the menstrual cycle.

Mechanism of action

Leuprorelin acetate acts by binding to the GnRH receptors in the pituitary gland, mimicking the action of natural GnRH. Initially, it stimulates the release of LH and FSH, leading to increased levels of sex steroids. However, with continuous administration, it causes down-regulation of GnRH receptors, ultimately reducing the secretion of gonadotropins and lowering sex steroid levels.

Pharmacodynamics

Leuprorelin acetate exhibits dose-dependent effects on gonadotropin release. Its initial stimulatory phase is followed by a decrease in pituitary responsiveness due to receptor down-regulation. This leads to a decrease in testosterone in men and estrogen in women, which is beneficial in the management of hormone-sensitive tumors and conditions such as endometriosis.

Pharmacokinetics

Leuprorelin is administered via subcutaneous or intramuscular injection, with a bioavailability of nearly 100%. It has a half-life of approximately 3 hours and is primarily metabolized in the liver. The drug exhibits a gradual release profile, allowing for once-monthly or once-every-three-months dosing regimens depending on the formulation used.

Contra-indications

• Undiagnosed vaginal bleeding
• Use longer than 6 months for endometriosis

Adverse effects

• Alopecia
• Arthralgia
• Bone pain
• Breast abnormalities
• Depression
• Glucose tolerance impaired
• Gynaecomastia
• Headache
• Heart failure
• Hot flush
• Hyperhidrosis
• Mood altered
• Myocardial infarction complications
• Paraesthesia
• Sexual dysfunction
• Skin reactions
• Spinal cord compression
• Tumour flare
• Abdominal cramps
• Body hair change
• Sleep disorder
• Endometrial thinning
• Voice alteration
• Vomiting
• Vulvovaginal infection
• Withdrawal bleed

Precautions

• Use with caution in patients with risk of myocardial infarction
• Monitor for signs of tumour flare in men during the first month of treatment
• Non-hormonal barrier contraceptive methods recommended during treatment
• Pregnancy should be excluded before treatment initiation

Pregnancy

Avoid.

Breast-feeding

Avoid.

Storage

Store in a refrigerator (2°C to 8°C). Protect from light.

Formulations

• Leuprorelin acetate 3.75 mg injectable solution (subcutaneous or intramuscular)
• Leuprorelin acetate 11.25 mg injectable solution (subcutaneous or intramuscular)
• Leuprorelin acetate 10.72 mg injectable solution (subcutaneous or intramuscular)

Mechanism of action

Gonadotropin-releasing hormone (GnRH) is a naturally occurring decapeptide that modulates the hypothalamic-pituitary-gonadal (HPG) axis. GnRH binds to corresponding receptors (GnRHRs) on the anterior pituitary gonadotropes, which in turn release luteinizing hormone (LH) and follicle-stimulating hormone (FSH); these, in turn, affect the downstream synthesis and release of the sex hormones testosterone, dihydrotestosterone, estrone, and estradiol. Despite the variety of conditions indicated for treatment with leuprolide, the mechanism of action underlying efficacy is the same in all cases. As a GnRHR agonist, leuprolide binds to and initially activates downstream LH and FSH release; this initial spike in gonadotropin levels is responsible for some of the adverse effects associated with treatment. After 2-4 weeks of treatment, continuous stimulation of GnRHR results in feedback inhibition and significant downregulation of LH, FSH, and their corresponding downstream effects, producing a therapeutic benefit. These effects are reversible upon treatment discontinuation. Like naturally occurring luteinizing hormone-releasing hormone, initial or intermittent administration of leuprolide stimulates release of luteinizing hormone and follicle-stimulating hormone from the anterior pituitary. Luteinizing hormone and follicle-stimulating hormone release from the anterior pituitary transiently increases testosterone concentration in males. However, continuous administration of leuprolide in the treatment of prostatic carcinoma suppresses secretion of gonadotropin-releasing hormone, with a resultant fall in testosterone concentrations and a "medical castration". Initial stimulation of gonadotropins form the anterior pituitary is followed by prolonged suppression. Gonadotropin release from the anterior pituitary transiently increases estrone and estradiol concentrations in females. However, continuous administration of leuprolide in the treatment of endometriosis produces a fall in estrogens to postmenopausal levels. As a consequence of suppression of ovarian function, both normal and ectopic endometrial tissues become inactive and atrophic. As a result, amenorrhea occurs.

Pharmacodynamics

Leuprolide is a gonadotropin-releasing hormone (GnRH) analogue that functions as a GnRH receptor superagonist. After an initial spike in GnRH-mediated steroidal production, including testosterone and estradiol, prolonged use results in a significant drop in circulating steroid levels, in line with those produced through other forms of androgen-deprivation therapy (ADT). The corresponding hormonal/steroidal changes produce specific adverse effects in different patient populations. In women undergoing treatment for endometriosis or uterine leiomyomata, careful consideration regarding pregnancy status is advised. The initial increase in estradiol levels may worsen symptoms such as pain and bleeding. Long-term use of leuprolide is associated with loss of bone mineral density. Patients co-administered with [norethisterone] may experience sudden vision loss, proptosis, diplopia, migraine, thrombophlebitis, and pulmonary embolism and may also be at higher risk of cardiovascular disease. Patients with a history of depression may experience severe recurrence of depressive symptoms. In men undergoing palliative treatment for advanced/metastatic prostate cancer, short-term spikes in testosterone levels may cause tumour flare and associated symptoms such as bone pain, hematuria, neuropathy, bladder and/or ureteral obstruction, and spinal cord compression. In addition, patients are at increased risk of developing hyperglycemia, diabetes, and cardiovascular disease, which may manifest through myocardial infarction, stroke, cardiac death, or prolonged QT/QTc interval. In addition, Leuprolide may cause convulsions and embryo-fetal toxicity. In pediatric patients undergoing treatment for central precocious puberty (CPP), the initial steroidal spike may be associated with increased clinical signs of puberty within 2-4 weeks of treatment initiation. In addition, leuprolide may cause convulsions and psychiatric symptoms, including irritability, impatience, aggression, anger, and crying.