Luprodex

Luprodex

leuprorelin

Manufacturer:

Bharat

Distributor:

Sandoval

Marketer:

BSV Bioscience Phils
Full Prescribing Info
Contents
Leuprorelin acetate.
Description
Leuprorelin Acetate (Luprodex) 3.75 mg Depot is a sterile lyophilized powder containing Leuprolide Acetate formulated as Microspheres.
Leuprorelin Acetate (Luprodex) 3.75 mg Depot is to be reconstituted with accompanying diluent which forms a uniform suspension, intended for intramuscular or subcutaneous injection to be administered once every month.
Leuprorelin Acetate (Luprodex) 3.75 mg Depot is a synthetic nonapeptide analog of naturally occurring gonadotropin-releasing hormone (GnRH or LH-RH). The analog possesses greater potency than the natural hormone.
Leuprorelin Acetate (Luprodex) 3.75 mg Depot: Each vial contains (As lyophilized powder): Leuprorelin B.P. (As acetate) 3.75 mg.
Excipients: Poly (D,L-lactide-co-glycolide) Biodegradable Polymer, D-Mannitol B.P.
Ampoule of diluent for reconstitution: Each mL contains: D-Mannitol B.P. 50 mg, Water for Injection U.S.P. q.s.
Action
Pharmacology: Leuprolide Acetate, a GnRH agonist, acts as a potent inhibitor of gonadotropin secretion when given continuously and in therapeutic doses. Human studies indicate that following an initial stimulation of gonadotropins, chronic stimulation with Leuprolide Acetate results in suppression or "down-regulation" of these hormones and consequent suppression of ovarian and testicular steroidogenesis. These effects are reversible on discontinuation of drug therapy.
Pharmacodynamics: Administration of Leuprorelin acetate results in an initial increase in circulating levels of luteinising hormone (LH) and follicle stimulating hormone (FSH), leading to a transient increase in levels of the gonadal steroids, both in females and males. Continuous administration of Leuprorelin acetate results in decreased levels of LH and FSH. In men serum testosterone levels, initially raised in response to early luteinising hormone (LH) release, fall to castrate levels in about 2-4 weeks. Estradiol levels will decrease to postmenopausal levels in premenopausal women within one month of initiating treatment.
No pharmacodynamic studies have been conducted for Leuprorelin Acetate (Luprodex) 3.75 mg Depot from the literature following data were obtained.
Leuprorelin acetate when administered in males, testosterone is reduced to below castrate threshold (≤ 50 ng/dL). These decreases occur within three to five weeks after initiation of treatment. In a study, mean testosterone levels at six months was 10.1 (± 0.7) ng/dL, comparable to levels following bilateral orchiectomy. All patients who received the full dose of 22.5 mg Leuprorelin reached castrate levels at 5 weeks; 99 % had reached this by day 28. In the vast majority of patents, the testosterone levels seen were below 20 ng/dL. Prostate specific antigen (PSA) levels decreased by 98% over six months.
A study compared the efficacy and safety of the 3.75 mg and 11.25 mg depots of Leuprorelin acetate in advance and metastatic prostate cancer. Mean serum testosterone level fell below the threshold for chemical castration (0.5 ng/ml) at one month of treatment, continuing to decrease thereafter and stabilising at a value below the castration threshold. The decline in serum PSA mirrored that of serum testosterone in both groups. Long-term studies have shown that continuation of therapy maintains testosterone below the castrate level for up to seven years, and presumably indefinitely.
A long-term efficacy and safety of Leuprorelin acetate was assessed in patients with metastatic prostate cancer. Testosterone levels were maintained below the castrate threshold over the 63-month follow up period. Median survival time exceeded 42.5 months for those receiving monotherapy and 30.9 months for those receiving Leuprorelin acetate in combination with anti-androgens (this difference relating to baseline differences between groups).
Pharmacokinetics: Leuprorelin Acetate is not active when given orally.
Absorption: Intramuscular injection of the depot formulation provides plasma concentrations of Leuprorelin over a period of one month.
Distribution: Distributed to kidney, liver, pineal and pituitary tissues.
Metabolism: It is metabolized to its metabolites in hypothalamus and anterior pituitary gland.
Elimination: Leuprorelin is eliminated by enzymatic breakdown and renal excretion.
No pharmacokinetic studies have been conducted for Leuprorelin Acetate (Luprodex) 3.75 mg Depot.
Literature data indicates that Leuprorelin acetate is well absorbed after subcutaneous and intramuscular injections. Leuprorelin acetate binds to the LHRH receptors and is rapidly degraded. An initially high plasma level of Leuprorelin acetate peaks at around 3 hours after a subcutaneous injection, followed by a decrease to maintenance levels in 7 to 14 days. Leuprorelin acetate provides continuous plasma levels for up to 117 days resulting in suppression of testosterone to below castration level within 4 weeks of the first injection in the majority of patients. The metabolism, distribution and excretion of Leuprorelin acetate in humans have not been fully determined.
A study which included 3.75, 7.5, 11.25, 15 and 30 mg depots of Leuprorelin Acetate showed that a mean Cmax of 13.1, 20.8 to 21.8, 47.4, 54.5 and 53 mcg/L, respectively, occur within 1 to 3 hours of depot subcutaneous administration. The plasma concentration was maintained between 0.4 and 1.4 mcg/L over 28 days after single 3.75, 7.5 or 15 mg depot injections.
A significant dose-related increase in the AUC from 0 to 35 days was noted after depot injection of Leuprorelin 3.75, 7.5 and 15 mg. Mean volume of distribution of Leuprorelin is was 36, 33 and 27 L after depot administration of 3.75, 7.5 and 15 mg, respectively. Total body clearance is 9.1 L/h and elimination half-life 3.6 hours after a subcutaneous 1 mg injection; corresponding values after intravenous injection are 8.3 L/h and 2.9 hours.
In Children: The Leuprorelin serum levels in children during the first 6 months of treatment following s.c. administration of Leuprorelin acetate 3-month depot (two injections) showed following results.
From the first injection, the Leuprorelin serum levels increase reaching maximal serum levels at month 4 (294.79 pg/ml ± 105.42) and slightly decrease until month 6 (229.02 pg/ml ± 103.33).
Indications/Uses
Endometriosis: Leuprorelin Acetate (Luprodex) 3.75 mg Depot is indicated in the treatment of endometriosis, including pain relief and reduction of endometriosis lesions. Duration of initial treatment or retreatment should be limited to 6 months.
Leuprorelin Acetate (Luprodex) 3.75 mg Depot can be used as sole therapy where it may provide symptomatic relief for women close to menopause who do not desire surgery, or as an adjunct to surgery.
Uterine Leiomyomata (Fibroids): Leuprorelin Acetate (Luprodex) 3.75 mg Depot concomitantly with iron therapy is indicated for the preoperative hematologic improvement of patients with anemia caused by uterine leiomyomata.
Leuprorelin Acetate (Luprodex) 3.75 mg Depot may be added if the response to iron alone is considered inadequate. Recommended duration of therapy with Leuprorelin Acetate (Luprodex) 3.7 mg Depot is up to six months.
Advanced Prostate Cancer (Palliative Treatment): Leuprorelin Acetate (Luprodex) 3.75 mg Depot is indicated in the treatment of advanced prostatic cancer. It offers an alternative treatment of prostatic cancer when orchidectomy or estrogen administration are either not indicated or unacceptable to the patient.
Central Precocious Puberty (CPP): Leuprorelin Acetate (Luprodex) 3.75 mg Depot is indicated in the treatment of children with Central Precocious Puberty (CPP).
Children should be selected using the following criteria: Clinical diagnosis of CPP (idiopathic or neurogenic) with onset of secondary sexual characteristics earlier than 8 years in girls and less than 9 years in boys.
Clinical diagnosis should be confirmed prior to initiation of therapy as follows: Confirmation of diagnosis by a pubertal response to a GnRH stimulation test and Bone age advanced one year beyond the chronological age.
Other evaluation and assessments should also include: Height and weight measurements.
Sex steroid levels.
Adrenal steroid level to exclude congenital adrenal hyperplasia.
Beta HCG level to rule out a chorionic gonadotropin secreting tumor.
Pelvic/adrenal/testicular ultrasound to rule out a steroid secreting tumor.
Computerized tomography of the head to rule out intracranial tumor.
Dosage/Direction for Use
Leuprorelin acetate (Luprodex) 3.75 mg Depot must be administered under the supervision of a physician.
Endometriosis: The recommended duration of treatment with Leuprorelin acetate (Depot) as a single subcutaneous or intramuscular injection or in combination with norethindrone acetate every month for a period of 6 months only. The initial dose should be given during the first 5 days of menstrual cycle.
In women, the addition of hormone replacement therapy (estrogen and progestogen) would be useful to reduce bone mineral density loss and vasomotor symptoms.
If the symptoms of endometriosis recur after a course of therapy, retreatment with a six-month course of Leuprorelin acetate monthly and norethindrone acetate daily may be considered. Retreatment beyond this one six-month course cannot be recommended. It is recommended that bone density be assessed before retreatment begins to ensure that value are within normal limits. If norethindrone acetate is contraindicated for the individual patient, then retreatment is not recommended.
Uterine Leiomyomata (Fibroids): Recommended duration of therapy with Leuprorelin acetate (Depot) is up to 3 months. The symptoms associated with uterine leiomyomata will recur following discontinuation of therapy. If additional treatment with Leuprorelin acetate is contemplated, bone density should be assessed prior to initiation of therapy.
The initial dose should be given during the first 5 days of menstrual cycle. For endometrial preparation prior to intrauterine surgery, 3.75 mg leuprorelin acetate single dose may be given subcutaneous or intramuscular injection 5-6 weeks prior to surgery.
Prostate cancer: Administered monthly as a single intramuscular injection of 3.75 mg depot every month. Therapy should not be discontinued when remission or improvement occurs. This treatment is usually continued upon development of castrate-resistant prostate cancer.
Central Precocious Puberty (CPP): Leuprorelin Acetate (Luprodex) 3.76 mg Depot must be administered under the supervision of a paediatrician.
The dose of Leuprorelin acetate must be individualised for each child. The dose is based on a mg/kg ratio of drug to body weight. Younger children may require higher doses on a mg/kg ratio. After 1-2 months of initiating therapy or changing doses, the child must be monitored with a GnRH stimulation test, sex steroids, and Tanner staging to confirm down regulation. 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 down regulation can probably be maintained for the duration of therapy in most children however, there are insufficient data to guide dosage adjustment as patients move to higher weight categories after beginning therapy at very young ages and low dosages. It is recommended that adequate down regulation be verified in such patient whose weight has increased significantly while on therapy. Discontinuation of leuprorelin acetate should be considered before age 11 for girls and age 12 for boys.
The recommended starting dose is 0.3 mg/kg/4 weeks (minimum 7.5 mg) administered as a single intramuscular injection or subcutaneously. The starting dose will be dictated by the child's weight as follows: See Table 1.

Click on icon to see table/diagram/image

If a total down regulation is not achieved, the dose should be titrated upward in increment of 3.75 mg every 4 weeks. This dose will be considered the maintenance dose.
When two injections are required to achieve the desired total dosage, they should be administered at one site, however more than two injections should be administered at different injection sites.
Reconstitution & Administration for Leuprorelin acetate (Depot): Use Aseptic precautions throughout.
Do not substitute saline or sterile water for diluent.
1. Ensure that the diluent fluid is at bottom section of the ampoule of diluent. Open the ampoule from the tip.
2. Using a syringe with 22-gauge needle, withdraw 1 ml of diluent from the ampoule. (Extra Diluent is provided, any remaining unused portion should be discarded.)
3. Remove the plastic seal cap from the vial.
4. Inject the Diluent from the syringe into the glass vial.
5. Shake well for thorough dispersion of particles to obtain uniform suspension. (The suspension will appear milky.)
6. Withdraw entire contents from the vial into the syringe.
7. Inject intramuscularly/subcutaneously.
8. Discard the unused product remaining in the vial along with unused diluent remaining in the ampoule.
Overdosage
No cases of overdose have been reported. In cases of overdose, the patients should be monitored closely and management should be symptomatic and supportive. In rats subcutaneous administration of 250 to 500 times the recommended human dose, expressed on a per body weight basis, resulted in dyspnea, decreased activity and local irritation at the injection site. There is no evidence that there is clinical counterpart of this phenomenon. In early clinical trials using daily subcutaneous Leuprorelin Acetate in patients with prostate cancer, doses as high as 20 mg/day for up to two years caused no adverse effects differing from those observed with the 1 mg/day dose.
Contraindications
Hypersensitivity to GnRH, GnRH agonist analogs or its diluent.
Undiagnosed abnormal vaginal bleeding.
Leuprorelin Acetate (Luprodex) 3.75 mg Depot is contraindicated in women who are pregnant while receiving the drug. Leuprorelin Acetate (Luprodex) 3.75 mg Depot may cause fetal harm when administered to a pregnant woman.
Use in women who are breast-feeding.
Special Precautions
Cardiovascular disease: In patients with a history of or risk factors for QT prolongation and in patients receiving concomitant medicinal products that might prolong the QT interval physicians should assess the benefit risk ratio. Patients receiving GnRH agonists should be monitored for symptoms and signs suggestive of development of cardiovascular disease and be managed according to current clinical practice.
Androgen deprivation therapy may prolong the QT interval: In patients with a history of or risk factors for QT prolongation and in patients receiving concomitant medicinal products that might prolong the QT interval physicians should assess the benefit risk ratio.
Transient testosterone flare: Leuprorelin acetate causes a transient increase in serum concentrations of testosterone, dihydrotestosterone and acid phosphatase during the first week of treatment. Patients may experience worsening of symptoms or onset of new symptoms, including bone pain, neuropathy, haematuria, or ureteral or bladder outlet obstruction. These symptoms usually subside on continuation of therapy.
Bone density: Decreased bone density has been reported in the medical literature in men who have had orchiectomy or who have been treated with GnRH agonists. The risk for fractures owing to osteoporosis is generally higher than the risk for pathological fractures.
Pituitary apoplexy has been reported after the administration of GnRH-agonists and was presented as sudden headache, vomiting, visual changes, ophthalmoplegia, altered mental status, and sometimes cardiovascular collapse. Immediate medical attention is required.
Hyperglycemia and diabetes: Hyperglycemia and an increased risk of developing diabetes have been reported after receiving GnRH agonists.
Convulsions: Post marketing reports of convulsions have been observed in patients on leuprorelin acetate with or without a history of predisposing factors.
Hepatic dysfunction and jaundice with elevated liver enzyme have been reported. Therefore, close observation should be made and appropriate measures taken if necessary.
Spinal fracture, paralysis and hypotension have been reported.
There is an increased risk of incident depression (which may be severe) in patients undergoing treatment with GnRH agonists, such as leuprorelin. Patients should be informed accordingly and treated as appropriate if symptoms occur.
When considering the preoperative treatment of fibroids it is mandatory to confirm the diagnosis of fibroids and exclude an ovarian mass, either visually by laparoscopy or by ultrasonography or other investigative technique, as appropriate, before administering Leuprorelin acetate.
The patients should be warned of severe bleeding following the administration of Leuprorelin acetate as a consequence of the acute degeneration of the fibroids.
Leuprorelin acetate may cause an increase in uterine cervical resistance, which may result in difficulty in dilating the cervix for intrauterine surgical procedure.
Men: Patients with urinary obstruction and patients with metastatic vertebral lesions should begin Leuprorelin acetate therapy under close supervision for the first few weeks of treatment.
Women: Since menstruation should stop with effective doses of Leuprorelin acetate, the patient should notify her physician if regular menstruation persists.
In girls with central precocious puberty: Before starting the therapy, a precise diagnosis of idiopathic and/or neurogenic central precocious puberty is necessary.
Pediatric Use: Experience with Leuprorelin acetate (Depot) for treatment of endometriosis has been limited to women 18 years of age and older.
Adverse Reactions
Adverse events are mainly subject to the specific pharmacological action of Leuprorelin acetate, namely increases and decreases in certain hormone levels. The most commonly reported adverse reactions are hot flashes, nausea, malaise and fatigue and transient local irritation at the site of injection. Mild hot flashes occur in approximately 58% of patients.
The following adverse events are from literature. Adverse events are classified, by frequency, as very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1,000, <1/100), rare (≥1/10,000, <1/1,000), and very rare (<1/10,000), not known (cannot be estimated from the available data). (See Table 2.)

Click on icon to see table/diagram/image

Other adverse events which have been reported in general are: peripheral oedema, pulmonary embolism, palpitations, myalgia, muscle weakness, an alteration in the skin sensation, chills, rash, amnesia and visual disturbances, muscular atrophy, pituitary apoplexy, thrombocytopenia, leucopenia, convulsions. Decreased bone density has been reported in literature who have been treated with GnRH analogues.
In men cases where a "tumour flare" occurs after leuprorelin acetate therapy, an exacerbation may occur in any symptoms or signs due to disease, for example, bone pain, urinary obstruction, weakness of the lower extremities and paraesthesia. These symptoms subside on continuation of therapy.
In women, adverse events are associated with hypo-estrogenism; the most frequently reported are hot flushes, mood swings including depression (occasionally severe), and vaginal dryness. Estrogen levels return to normal after treatment is discontinued.
Drug Interactions
Studies for interaction with drugs or any other forms of interactions have not been done.
Administration of Leuprorelin Acetate (Luprodex) 3.75 mg Depot in therapeutic doses results in suppression of the pituitary-gonadal system. Normal function is usually restored within three months after treatment is discontinued. Therefore, diagnostic tests of pituitary gonadotropic and gonadal functions conducted during treatment and for up to three months after discontinuation of Leuprorelin Acetate (Luprodex) 3.75 mg Depot may be misleading.
Low HDL-cholesterol (<40 mg/dL) and elevated LDL-cholesterol (>160 mg/dL) are recognized risk factors for cardiovascular disease. The longterm significance of the observed treatment related changes in serum lipids in women with endometriosis is unknown. Therefore, assessment of cardiovascular risk factors should be considered prior to initiation of concurrent treatment with Leuprorelin acetate (Depot) and norethindrone acetate.
If additional treatment (duration longer than 3 months) with Leuprorelin acetate (Depot) is contemplated, bone density should be assessed prior to initiation of therapy to ensure that values are within normal limits.
Since androgen deprivation treatment may prolong the QT interval, the concomitant use of Leuprorelin acetate with medicinal products known to prolong the QT interval or medicinal products able to induce Torsade de pointes such as class IA (e.g. quinidine, disopyramide) or class III (e.g. amiodarone, sotalol, dofetilide, ibutilide) antiarrhythmic medicinal products, methadone, moxifloxacin, antipsychotics, etc. should be carefully evaluated.
Caution For Usage
Procedure for Reconstitution: Use Aseptic Technique Throughout.
Do not use Sterile Water for Injection or Sodium Chloride Injection (Saline) for reconstitution in place of the recommended diluent provided in the pack.
1. Visually inspect the vial. Vial should not be used if clumping or caking is evident. A thin layer of powder on the wall of the vial is considered normal. The diluent in the ampoule should appear clear.
Ensure that the fluid is at the bottom section of the ampoule (flick or tap lightly if need be).
Hold the ampoule and snap open the ampoule.
2. Use luer lock syringe with 22 gauge needle provided in the pack.
Fix needle in luer lock till it rotates no more.
Withdraw 1 ml of diluent from the ampoule.
3. Remove plastic seal cap of vial by flicking it off.
4. Inject diluent into the vial.
5. Shake well the contents of vial for thorough Dispersion.
The suspension will appear uniformly milky.
6. Withdraw entire contents of the vial back in the syringe.
Inject intramuscularly/subcutaneously.
Discard the remainder of the diluent, the ampoule and the vial.
Storage
Store at temperatures not exceeding 30°C. Do not Freeze.
After Reconstitution: Once reconstituted with the sterile diluent, the suspension should be administered immediately and remaining should be discarded. However, the suspension is considered stable for up to 24 hrs at 25°C.
ATC Classification
L02AE02 - leuprorelin ; Belongs to the class of gonadotropin releasing hormone analogues. Used in endocrine therapy.
Presentation/Packing
Lyo powd for inj (vial) 3.75 mg [+ 2 mL amp diluent + 2 (22 G) needles + 3 mL syringe + 2 alcohol swabs] x 1's.
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