Lucrin Depot Paediatric 30 mg Injection: Indications, Dosage, Precautions, Adverse Effects
Россия
  • Россия
  • Украина

Lucrin Depot Paediatric 30 mg Injection - Product Information

Manufacture: AbbVie
Country: Australia
Condition: Breast Cancer, Endometriosis, Hysterectomy, Prostate Cancer, Precocious Puberty, Uterine Leiomyomata, Uterine Fibroids
Class: Gonadotropin releasing hormones, Gonadotropin-releasing hormone antagonists
Form: Liquid solution, Intravenous (IV), Powder
Ingredients: Leuprorelinacetate, polylactic acid, mannitol, carmellose sodium, polysorbate 80, water for injections, glacial acetic acid

Name of the Medicine

Leuprorelin acetate

Chemical Structure

CAS Number

74381-53-6

Description

Leuprorelin 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 acts as an inhibitor of gonadotropin production and is chemically unrelated to the steroids. The chemical name is 5-oxo-L-prolyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl-D-leucyl-L-leucyl-L-arginyl-N-ethyl-L-prolinamide acetate (salt).

Leuprorelin acetate is a hygroscopic, white or almost white powder. It has a molecular formula of C59H84N16O12sub>.C2H4O2 and a molecular weight of 1269.47. The solubility of leuprorelin acetate in water is more than 75% and less than 0.0001% in ether and hexane.

Lucrin Depot Paediatric 30 mg 3-Month PDS Injection is available as sterile lyophilised microspheres, which, when mixed with diluent, becomes a suspension, for administration as a single intramuscular injection every three months.

Lucrin Depot Paediatric 30 mg 3-Month PDS Injection contains leuprorelin acetate (30 mg), polylactic acid (264.8 mg) and mannitol (51.9 mg). The accompanying diluent contains carmellose sodium (7.5 mg), mannitol (75 mg), polysorbate 80 (1.5 mg), water for injections USP (1.5 mL) and glacial acetic acid USP (0-0.075 mg) to control pH.

Pharmacology

Leuprorelin acetate acts as a potent inhibitor of gonadotropin secretion when given continuously and in therapeutic doses. Animal and human studies indicate that following an initial stimulation, chronic administration of leuprorelin acetate results in suppression of ovarian and testicular steroidogenesis.

Administration of leuprorelin acetate has resulted in inhibition of the growth of certain hormone-dependent tumours (prostatic tumours in noble and dunning male rats and DMBA-induced mammary tumours in female rats) as well as atrophy of the reproductive organs.

In humans, administration of leuprorelin acetate results in an initial increase in circulating levels of luteinizing hormone (LH) and follicle stimulating hormone (FSH), leading to a transient increase in levels of the gonadal steroids (testosterone and dihydrotestosterone in males and oestrone and oestradiol in pre-menopausal females). However, continuous administration of leuprorelin acetate results in decreased levels of LH and FSH. In males, androgens are reduced to castrate or pre-pubertal levels. In pre-menopausal females, oestrogens are reduced to post-menopausal levels. These decreases occur within a month of initiating treatment and are maintained as long as treatment continues.

Leuprorelin acetate is not active when given orally.

Pharmacokinetics

Absorption

Following a single Lucrin Depot Paediatric 30 mg for 3-month administration to children with CPP, the mean peak leuprorelin plasma concentration was 52.5 ng/mL. The concentrations then declined to 0.25 ng/mL at 2 weeks after dosing. Mean leuprorelin plasma concentration remained constant from month 1 to month 3. The mean leuprorelin concentrations 3 months after the first and second injections were similar indicating no accumulation of leuprorelin from repeated administration.

Distribution

The mean steady-state volume of distribution of leuprorelin following intravenous bolus administration to healthy male volunteers was 27 L. In vitro binding to human plasma proteins ranged from 43% to 49%.

Metabolism

In healthy male volunteers, a 1 mg bolus of leuprorelin administered intravenously, revealed that the mean systemic clearance was 7.6 L/h, with a terminal elimination half-life of approximately three hours based on a two compartment model.

Animal studies have shown 14C-labelled leuprorelin was metabolised into smaller peptides, a pentapeptide (Metabolite I), tripeptides (Metabolites II and III) and a dipeptide (Metabolite IV). These fragments may be further metabolised.

Special Populations

The pharmacokinetics of Lucrin Depot Paediatric 30 mg in hepatic-and renal-impaired patients has not been determined.

Clinical Trials

In children with central precocious puberty (CPP), stimulated and basal gonadotropins are reduced to prepubertal levels. Testosterone and oestradiol are reduced to prepubertal levels in males and females respectively.

Lucrin Depot Paediatric 11.25 mg or 30 mg For 3-Month Administration

In a randomised, open-label clinical study (L-CP07-167) of Lucrin Depot Paediatric 3 month formulations, 84 subjects (76 female, 8 male), with a mean age of 7.8 years (range 1 to 11 years), received the 11.25 mg and 30 mg formulation as a single intramuscular injection every 3 months.

Each dose group had an equal number of treatment-naïve patients who had pubertal LH levels and patients previously treated with GnRHa therapies who had prepubertal LH levels at the time of study entry. The percentage of subjects with suppression of peak-stimulated LH to < 4.0 mIU/mL, as determined by assessments at months 2, 3 and 6, was 78.6% in the 11.25 mg dose group and 95.2% as shown in Table 1.

Table 1: Suppression of Peak-Stimulated LH from Month 2 through Month 6
  Lucrin Depot Paediatric
30mg every 3 Months
Parameter Naïve
N = 21
Previously
Treated a
N = 21
Total
N = 42
Percent with Suppression 90.5 100 95.2
2-sided 95% CI 69.6, 98.8 83.9, 100 83.8, 99.4
a. Previously treated with GnRHa for at least 6 months prior to enrolment in pivotal
Study L-CP07-167

The mean peak stimulated LH levels for all visits are shown by dose and subgroup (naïve vs. previously treated subjects) in Figures 1.

Figure 1: Mean Peak Stimulated LH for Lucrin Depot Paediatric 3 Month 30 mg Paediatric

Indications

Lucrin Depot Paediatric 30 mg 3-Month PDS Injection is indicated in the treatment of children with central precocious puberty (CPP).

Contraindications

Hypersensitivity to GnRH, GnRH agonists or any of the excipients in LUCRIN DEPOT PAEDIATRIC 30 MG. There have been reports of anaphylactic reactions to GnRH agonists (including the monthly formulation of leuprorelin).

Although not expected to be relevant to the approved indication, LUCRIN DEPOT PAEDIATRIC 30 MG is contraindicated when the patient is pregnant or may become pregnant due to embryotoxic effects and in nursing mothers (see Precautions – Use in pregnancy; Use in lactation).

Precautions

Initial Rise of Gonadotropins and Sex Steroid Levels

During the early phase of therapy, gonadotropins and sex steroids rise above baseline because of the natural stimulatory effect of the drug. Therefore, an increase in clinical signs and symptoms of puberty may be observed (see Pharmacology).

Pituitary Apoplexy

During post-marketing surveillance, rare cases of pituitary apoplexy (a clinical syndrome secondary to infarction of the pituitary gland) have been reported after the administration of gonadotropin-releasing hormone agonists. In a majority of these cases, a pituitary adenoma was diagnosed, with a majority of pituitary apoplexy cases occurring within 2 weeks of the first dose, and some within the first hour. In these cases, pituitary apoplexy has presented as sudden headache, vomiting, visual changes, ophthalmoplegia, altered mental status, and sometimes cardiovascular collapse. Immediate medical attention has been required.

Convulsions

Postmarketing reports of convulsions have been observed in patients on leuprorelin acetate therapy. These included patients in the female and paediatric populations, patients with a history of seizures, epilepsy, cerebrovascular disorders, central nervous system anomalies or tumours, and in patients on concomitant medications that have been associated with convulsions such as bupropion and SSRIs. Convulsions have also been reported in patients in the absence of any of the conditions mentioned above.

Depression and Mood Changes

Depression has been reported in adults who have used leuprorelin for other indications. In children, emotional lability and tearfulness have been reported (see Adverse Effects).

Effects on Fertility

Following subcutaneous administration of Lucrin Depot to male and female rats before mating there was atrophy of the reproductive organs and suppression of reproductive performance. Cessation of oestrous cycling was seen in female rats at 2.4 mg/kg/month and reduced fertility was seen in male rates at ≥ 0.8 mg/kg/month. A no effect dose level was not established. These effects were reversed after a long treatment-free period.

In a clinical study of the 1-month formulation, data to assess reproductive function was collected in a post-study survey of 20 girls who reached adulthood (ages 18-26): menstrual cycles were reported to be normal in 80% of women; 12 pregnancies were reported for a total of 7 of the 20 subjects, including multiple pregnancies for 4 subjects. There are no data in humans relating to male fertility following treatment with leuprorelin acetate.

Use in Pregnancy (Category D)

Lucrin Depot Paediatric 30 mg is contraindicated in patients who are or may become pregnant while receiving the drug. (See Contraindications.)

Safe use of leuprorelin acetate in pregnancy has not been established in clinical studies. Before starting and during treatment with leuprorelin acetate, it is advisable to establish whether the patient is pregnant. Leuprorelin acetate is not a contraceptive. If contraception is required, a non-hormonal method of contraception should be used.

When Lucrin Depot Paediatric 30 mg was administered subcutaneously to groups of rabbits as one time dosing on day 6 of pregnancy at test dosages of 0.00024, 0.0024, and 0.024 mg/kg (1/1900 to 1/19 of the human paediatric dose) it produced a dose-related increase in major fetal abnormalities. Similar studies in rats failed to demonstrate an increase in fetal malformations. There was increased fetal mortality and decreased fetal weights with the two higher doses of Lucrin Depot Paediatric 30 mg in rabbits and with the highest dose in rats. No fetal malformations but increase in fetal resorptions and mortality were observed in rat and rabbit when the daily injection formulation of leuprorelin acetate was dosed subcutaneously once daily at lower doses (0.1-1 mcg/kg/day in rabbit; 10 mcg/kg/day in rat) during the period of organogenesis. The effects on fetal mortality are logical consequences of the alterations in hormonal levels brought about by this drug. Therefore, the possibility exists that spontaneous abortion may occur if the drug is administered during pregnancy.

Use in Lactation

Lucrin Depot Paediatric 30 mg should not be administered to a nursing mother, as it is not known whether leuprorelin acetate is excreted into human milk. (See Contraindications.)

Paediatric Use

Safety and efficacy in paediatric patients below the age of 2 years have not been established. The use of Lucrin Depot Paediatric 30 mg in children under 2 years is not recommended.

Noncompliance with drug regimen or inadequate dosing may result in inadequate control of the pubertal process with gonadotropins and/or sex steroids increasing above prepubertal levels.

CPP is defined as early onset of secondary sexual characteristics (generally earlier than 8 years of age in girls and 9 years of age in boys) associated with pubertal pituitary gonadotropin activation. It may show a significantly advanced bone age that can result in diminished adult height.

Prior to initiation of treatment a clinical diagnosis of CPP should be confirmed by measurement of blood concentrations of luteinizing hormone (LH) (basal or stimulated with a GnRH analog), sex steroids, and assessment of bone age versus chronological age. Baseline evaluations should include height and weight measurements, diagnostic imaging of the brain (to rule out intracranial tumour), pelvic/testicular/adrenal ultrasound (to rule out steroid secreting tumours), human chorionic gonadotropin levels (to rule out a chorionic gonadotropin secreting tumour), and adrenal steroid measurements to exclude congenital adrenal hyperplasia.

Genotoxicity

Genotoxicity studies have been performed with leuprorelin acetate using bacterial and mammalian systems. These studies provided no evidence of a genotoxic potential.

Carcinogenicity

A two-year carcinogenicity study was conducted in rats and mice. In rats, a dose-related increase of benign pituitary hyperplasia and benign pituitary adenomas was noted at 24 months when the drug was administered subcutaneously at high daily doses (0.6 to 4 mg/kg). In mice, no pituitary abnormalities were observed at a dose as high as 60 mg/kg for two years and no pituitary nor pancreatic changes were found in cynomolgus monkeys treated for 12 months with 10 mg/kg daily.

Effect on Laboratory Tests

Response to Lucrin Depot Paediatric 30 mg should be monitored with a GnRH stimulation test, basal LH or serum concentration of sex steroid levels at months 2-3, month 6 and further as judged clinically appropriate, to ensure adequate suppression. Additionally, height (for calculation of growth rate) and bone age should be assessed every 6 to 12 months.

Once a therapeutic dose has been established, gonadotropin and sex steroid levels will decline to prepubertal levels.

Interactions With Other Medicines

No pharmacokinetic-based drug-drug interaction studies have been conducted with Lucrin Depot Paediatric 30 mg. However, because leuprorelin acetate is a peptide that is primarily degraded by peptidase and the drug is only about 46% bound to plasma proteins, drug interactions would not be expected to occur.

Adverse Effects

Note: To provide a complete safety profile of leuprorelin acetate in the CPP population, adverse events for all doses studied in patients with CPP are outlined below. However, the only dosage for the treatment of CPP currently available in Australia is the 30mg 3-month formulation.

The most common adverse reactions with GnRH agonists including Lucrin Depot Paediatric 30mg for 3 month administration are injection site reactions/pain including abscess, general pain, headache, emotional lability and hot flushes/sweating.

During the early phase of therapy, gonadotropins and sex steroids rise above baseline because of the initial stimulatory effect of the drug (hormonal flare effect). Therefore, an increase in clinical signs and symptoms of puberty may be observed. (See Precautions.)

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.

Table 2: Percentage of Patients with Treatment-Emergent Adverse Reactions
Occurring in ≥2 Paediatric Patients Receiving Lucrin Depot Paediatric 7.5mg,
11.25mg or 15mg for 1 Month Administration
  Number of Patients (N = 421)
  N %
Body as a Whole    
Injection Site Reactions Including Abscess* 37 (9)
General Pain 12 (3)
Headache 11 (3)
Cardiovascular System    
Vasodilation 9 (2)
Integumentary System (Skin and Appendages)    
Acne/Seborrhea 13 (3)
Rash Including Erythema Multiforme 12 (3)
Nervous System    
Emotional Lability 19 (5)
Urogential System    
Vagintits/Vaginal Bleeding/Vaginal Discharge 13 (3)
* Most events were mild or moderate in severity.

Less Common Adverse Reactions With 1-Month Formulations

The following treatment-emergent adverse reactions were reported in less than 2% of the patient and are listed below by body system:

Body as a Whole: Aggravation of pre-existing tumour and decreased vision, allergic reaction, body odour, fever, flu syndrome, hypertrophy, infection

Cardiovascular System: Bradycardia, hypertension, peripheral vascular disorder, syncope

Digestive System: Constipation, dyspepsia, dysphagia, gingivitis, increased appetite, nausea/vomiting

Endocrine System: Accelerated sexual maturity, feminisation, goiter

Hemic and Lymphatic System: Purpura

Metabolic and Nutritional Disorders: Growth retarded, peripheral oedema, weight gain

Musculoskeletal System: Arthralgia, Joint disorder, myalgia, myopathy

Nervous System: Depression, hyperkinesia, nervousness, somnolence

Respiratory System: Asthma, epistaxis, pharyngitis, rhinitis, sinusitis

Integumentary System (Skin and Appendages): Alopecia, hair disorder, hirsutism, leukoderma, nail disorder, skin hypertrophy

Urogenital System: Cervix disorder/neoplasm, dysmenorrhoea, gynecomastia/breast disorders, menstrual disorders, urinary incontinence

Laboratory: The following laboratory events were reported as adverse reactions: antinuclear antibody present and increased sedimentation rate.

Table 3: Percentage of Patients with Treatment-Emergent Adverse Reactions
Occurring in ≥2 Paediatric Patients Receiving Lucrin Depot Paediatric
11.25mg or 30mg for 3 Month Administration
  11.25mg every 3 Months N=42 30mg every 3 Months N=42
  N % N %
Injection site pain 8 (19) 9 (21)
Weight increased 3 (7) 3 (7)
Headache 1 (2) 3 (7)
Mood altered 2 (5) 2 (5)
Injection site swelling 1 (2) 1 (2)

Less Common Adverse Reactions With 3-Month Formulations

The following treatment-emergent adverse reactions were reported in one patient and are listed below by system organ class:

Gastrointestinal Disorders – abdominal pain, nausea

General Disorders and Administration Site Conditions – asthenia, gait disturbance, injection site abscess sterile, injection site hematoma, injection site induration, injection site warmth, irritability

Metabolic and Nutritional Disorders – decreased appetite, obesity

Musculoskeletal and Connective Tissue Disorders - musculoskeletal pain, pain in extremity

Nervous System Disorders – crying, dizziness

Psychiatric Disorders – tearfulness

Respiratory, Thoracic and Mediastinal Disorders – cough

Skin and Subcutaneous Tissue Disorders – hyperhidrosis,

Vascular Disorders – pallor

Postmarketing

The following adverse events have been observed with this or other formulations of leuprorelin acetate injection. As leuprorelin has multiple indications, and therefore patient populations, some of these adverse events may not be applicable to every patient.

Allergic reactions (anaphylactic, rash, urticaria, and photosensitivity reactions) have also been reported.

Gastrointestinal Disorders: nausea, abdominal pain, vomiting

General Disorders and Administration Site Conditions: chest pain, injection site reactions including induration and abscess have been reported

Investigations: decreased WBC, weight increased

Metabolism and Nutrition Disorders: diabetes mellitus

Musculoskeletal and Connective Tissue Disorders: tenosynovitis-like symptoms

Nervous System Disorders: neuropathy peripheral, convulsion, spinal fracture/paralysis

Psychiatric Disorders: Insomnia

Skin and Subcutaneous Tissue Disorders: hot flush, flushing, hyperhidrosis

Reproductive System and Breast Disorders: prostate pain

Vascular Disorders: hypertension, hypotension

See other Lucrin Depot and Lucrin Injection package inserts for other events reported in different patient populations.

Dosage and Administration

LUCRIN DEPOT PAEDIATRIC 30mg 3-MONTH PDS injection must only be prescribed after initial assessment by a paediatric endocrinologist, who is experienced in the diagnosis and management of central precocious puberty; and with the ongoing supervision of such a specialist.

Lucrin Depot Paediatric 30 mg 3-Month PDS Injection should be administered once every three months (12 weeks) as a single intramuscular injection. The goal of therapy is to suppress pituitary gonadotropins and peripheral sex steroids, and to arrest progression of secondary sexual characteristics. Hormonal and clinical parameters should be monitored during treatment, for instance at month 2-3, month 6 and further as judged clinically appropriate, to ensure adequate suppression. In case of inadequate suppression, treatment with Lucrin should be discontinued, and other treatment options for CPP should be considered.

Do not use partial syringes or a combination of syringes to achieve a particular dose.

Lucrin Depot Paediatric 30 mg 3-Month PDS Injection treatment should be discontinued at the appropriate age of onset of puberty at the discretion of the physician. The recommended age at which therapy for CPP should be ceased is at 11 or 12 years of age, for girls and boys respectively.

Lucrin Depot Paediatric 30 mg 3-Month PDS Injection must not be injected intra-arterially or intravenously. It is to be used as an intramuscular injection.

For optimal performance of the prefilled dual-chamber syringe (PDS) read and follow the following instructions:

  1. To prepare for injection screw the white plunger into the end stopper until the stopper begins to turn.
  2. Hold the syringe UPRIGHT. Release the diluent by SLOWLY PUSHING (6-8 seconds) the plunger until the first stopper is at the blue line in the middle of the barrel.
  3. Keep the syringe UPRIGHT. Gently mix the microspheres (particles) thoroughly to form a uniform suspension. The suspension will appear milky. DO NOT USE if any of the powder has not gone into suspension.
  4. Hold the syringe UPRIGHT. With the opposite hand pull the needle cap upward without twisting.
  5. Keep the syringe UPRIGHT. Advance the plunger to expel the air from the syringe.
  6. Inject the entire contents of the syringe intramuscularly at the time of the reconstitution. The suspension settles very quickly following reconstitution; therefore, Lucrin Depot Paediatric 30 mg should be mixed and used immediately. Re-shake the suspension if settling occurs.

NOTE: Aspirated blood would be visible just below the luer lock connection if the blood vessel is accidentally penetrated. If present, blood can be seen through the transparent hub of the needle.

Although the solution has been shown to be stable for 24 hours following reconstitution, the suspension should be discarded if not used immediately, as the product does not contain a preservative.

As with other drugs administered by injection, the injection site should be varied periodically.

Product contains no antimicrobial agent. Product is for single use in one patient only. Discard any residue.

Overdosage

In early clinical trials with 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.

In rats, subcutaneous administration of leuprorelin acetate as a single dose 225 times the recommended human paediatric dose, expressed on a per body weight basis, resulted in dyspnoea, decreased activity, and local irritation at the injection site. There is no evidence at present that there is a clinical counterpart of this phenomenon.

In cases of overdosage, standard of care monitoring and management principles should be followed.

For advice on the management of overdose please contact the Poisons Information Centre, phone 131126.

Presentation and Storage Conditions

Lucrin Depot Paediatric 30 mg 3-Month Prefilled Dual-Chamber Syringe (PDS) Injection is available in a single dose procedure pack of a dual chamber syringe containing sterile lyophilised microspheres of leuprorelin acetate in the front chamber and 1.5 mL of diluent in the rear chamber. When the contents of the chambers are mixed, Lucrin Depot Paediatric 30 mg 3-month PDS is administered as a single intramuscular injection every three months.

Lucrin Depot Paediatric 30 mg 3-Month PDS Injection may be stored in a cool dry place where the room temperature stays below 25oC. Protect from light.

Name and Address of the Sponsor

AbbVie Pty Ltd

241 O’Riordan Street

Mascot NSW 2020

Australia

Poison Schedule of the Medicine

S4

Date of First Iinclusion in the Australian Register of Therapeutic Goods (the Artg)

13 October 2014

Date of Most Recent Amendment

12 December 2014