LUPRON DEPOT-PED- leuprolide acetate
AbbVie Inc.
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HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use LUPRON DEPOT-PED safely and effectively. See full prescribing information for LUPRON DEPOT-PED.
LUPRON DEPOT-PED (leuprolide acetate for depot suspension) Injection, Powder, Lyophilized, For Suspension Initial U.S. Approval: 1993 INDICATIONS AND USAGELUPRON DEPOT-PED 11.25 mg or 30 mg for 3-month administration is a gonadotropin releasing hormone (GnRH) agonist indicated in the treatment of children with central precocious puberty. (1) DOSAGE AND ADMINISTRATIONDOSAGE FORMS AND STRENGTHS11.25 mg or 30 mg intramuscular injection in a kit with prefilled dual chamber syringe. (3) WARNINGS AND PRECAUTIONS
ADVERSE REACTIONS
To report SUSPECTED ADVERSE REACTIONS, contact AbbVie Inc. at 1-800-633-9110 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. USE IN SPECIFIC POPULATIONS
See 17 for PATIENT COUNSELING INFORMATION. Revised: 06/2013 |
LUPRON DEPOT-PED 11.25 mg or 30 mg for 3-month administration is indicated in the treatment of children with central precocious puberty (CPP).
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 tumor), pelvic/testicular/adrenal ultrasound (to rule out steroid secreting tumors), human chorionic gonadotropin levels (to rule out a chorionic gonadotropin secreting tumor), and adrenal steroid measurements to exclude congenital adrenal hyperplasia.
LUPRON DEPOT-PED 11.25 mg or 30 mg for 3-month administration must be administered under the supervision of a physician.
LUPRON DEPOT-PED 11.25 mg or 30 mg for 3-month administration should be administered once every three months (12 weeks) as a single intramuscular injection. Regardless of the dose chosen, 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, other available GnRH agonists indicated for the treatment of CPP should be considered.
Each LUPRON DEPOT-PED 11.25 mg or 30 mg for 3-month administration strength and formulation has different release characteristics. Do not use partial syringes or a combination of syringes to achieve a particular dose.
LUPRON DEPOT-PED 11.25 mg or 30 mg for 3-month administration treatment should be discontinued at the appropriate age of onset of puberty at the discretion of the physician.
For optimal performance of the prefilled dual chamber syringe (PDS), read and follow the instructions in Section 2.2.
NOTE: Aspirated blood would be visible just below the luer lock connection if a blood vessel is accidentally penetrated. If present, blood can be seen through the transparent LuproLoc® safety device. If blood is present remove the needle immediately. Do not inject the medication.
LUPRON DEPOT-PED 11.25 mg or 30 mg for 3-month administration is supplied in a prefilled dual chamber syringe.
During the early phase of therapy, gonadotropins and sex steroids rise above baseline because of the initial stimulatory effect of the drug. Therefore, an increase in clinical signs and symptoms of puberty may be observed [see Clinical Pharmacology (12.3)].
Postmarketing reports of convulsions have been observed in patients on leuprolide acetate therapy. These included patients with a history of seizures, epilepsy, cerebrovascular disorders, central nervous system anomalies or tumors, and 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.
Response to LUPRON DEPOT-PED 11.25 mg or 30 mg for 3-month administration should be monitored with a GnRHa 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 6-12 months.
Once a therapeutic dose has been established, gonadotropin and/or sex steroid levels will decline to prepubertal levels. Gonadotropins and/or sex steroids may increase or rise above prepubertal levels if the dose is inadequate. 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 [see Clinical Studies (14) and Adverse Reactions (6)].
The most common adverse reactions with GnRH agonists including LUPRON DEPOT-PED 11.25 mg or 30 mg 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 Warnings and Precautions (5.1)].
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 1. Percentage of Patients with Treatment-Emergent Adverse Reactions Occurring in ≥2 Pediatric Patients Receiving LUPRON DEPOT-PED 11.25 mg or 30 mg for 3-Month Administration. | ||||||
11.25 mg every 3 Months
N=42 | 30 mg every 3 Months
N=42 | Overall N = 84 |
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N | % | N | % | N | % | |
Injection site pain | 8 | (19) | 9 | (21) | 17 | (20) |
Weight increased | 3 | (7) | 3 | (7) | 6 | (7) |
Headache | 1 | (2) | 3 | (7) | 4 | (5) |
Mood altered | 2 | (5) | 2 | (5) | 4 | (5) |
Injection site swelling | 1 | (2) | 1 | (2) | 2 | (2) |
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.
The following adverse events have been observed with this or other formulations of leuprolide acetate injection. As leuprolide 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;
Skin and Subcutaneous Tissue Disorders: hot flush, flushing, hyperhidrosis;
Reproductive System and Breast Disorders: prostate pain;
Vascular Disorders: hypertension, hypotension.
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.
See other LUPRON DEPOT and LUPRON Injection package inserts for other events reported in different patient populations.
No pharmacokinetic-based drug-drug interaction studies have been conducted; however, drug interactions are not expected to occur [see Clinical Pharmacology (12.3)].
Administration of LUPRON DEPOT-PED 11.25 mg or 30 mg for 3-month administration in therapeutic doses results in suppression of the pituitary-gonadal system. Therefore, diagnostic tests of pituitary gonadotropic and gonadal functions conducted during treatment and up to six months after discontinuation of LUPRON DEPOT-PED 11.25 mg or 30 mg for 3-month administration may be affected. Normal pituitary-gonadal function is usually restored within six months after treatment with LUPRON DEPOT-PED 11.25 mg or 30 mg for 3-month administration is discontinued.
LUPRON DEPOT-PED 11.25 mg or 30 mg for 3-month administration is contraindicated in women who are or may become pregnant while receiving the drug [see Contraindications (4) and Clinical Pharmacology (12.1)].
Safe use of leuprolide acetate in pregnancy has not been established in clinical studies. Before starting and during treatment with leuprolide acetate, it is advisable to establish whether the patient is pregnant. Leuprolide acetate is not a contraceptive. If contraception is required, a non-hormonal method of contraception should be used.
When LUPRON DEPOT 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 pediatric 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 LUPRON DEPOT 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 leuprolide 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.
It is not known whether leuprolide acetate is excreted in human milk. LUPRON DEPOT-PED 11.25 mg or 30 mg for 3-month administration should not be used by nursing mothers.
In early clinical trials using leuprolide acetate in adult patients, 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 leuprolide acetate as a single dose 225 times the recommended human pediatric dose, expressed on a per body weight basis, resulted in dyspnea, 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.
Leuprolide acetate is a synthetic nonapeptide analog of naturally occurring gonadotropin-releasing hormone (GnRH or LH-RH). The analog possesses greater potency than the natural hormone. 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) with the following structural formula:
LUPRON DEPOT-PED 11.25 mg or 30 mg for 3-month administration is available in a prefilled dual-chamber syringe containing sterile lyophilized microspheres which, when mixed with diluent, become a suspension intended as an intramuscular injection to be given ONCE EVERY THREE MONTHS.
The front chamber of LUPRON DEPOT-PED–11.25 mg for 3-month administration prefilled dual-chamber syringe contains leuprolide acetate (11.25 mg), polylactic acid (99.3 mg) and D-mannitol (19.45 mg). The second chamber of diluent contains carboxymethylcellulose sodium (7.5 mg), D-mannitol (75.0 mg), polysorbate 80 (1.5 mg), water for injection, USP, and glacial acetic acid, USP to control pH.
The front chamber of LUPRON DEPOT-PED–30 mg for 3-month administration prefilled dual-chamber syringe contains leuprolide acetate (30 mg), polylactic acid (99.3 mg) and D-mannitol (19.45 mg). The second chamber of diluent contains carboxymethylcellulose sodium (7.5 mg), D-mannitol (75.0 mg), polysorbate 80 (1.5 mg), water for injection, USP, and glacial acetic acid, USP to control pH.
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 "downregulation" of these hormones and consequent suppression of ovarian and testicular steroidogenesis. These effects are reversible on discontinuation of drug therapy.
Following a single LUPRON DEPOT-PED 11.25 mg or 30 mg for 3-month administration to children with CPP, leuprolide concentrations increased with increasing dose with mean peak leuprolide plasma concentration of 19.1 and 52.5 ng/mL at 1 hour for the 11.25 and 30 mg dose levels, respectively. The concentrations then declined to 0.08 and 0.25 ng/mL at 2 weeks after dosing for the 11.25 and 30 mg dose levels. Mean leuprolide plasma concentration remained constant from month 1 to month 3 for both 11.25 and 30 mg doses. The mean leuprolide concentrations 3 months after the first and second injections were similar indicating no accumulation of leuprolide from repeated administration.
The mean steady-state volume of distribution of leuprolide following intravenous bolus administration to healthy male volunteers was 27 L. In vitro binding to human plasma proteins ranged from 43% to 49%.
In healthy male volunteers, a 1 mg bolus of leuprolide administered intravenously revealed that the mean systemic clearance was 7.6 L/h, with a terminal elimination half-life of approximately 3 hours based on a two compartment model.
In rats and dogs, administration of 14C-labeled leuprolide was shown to be metabolized to smaller inactive peptides, a pentapeptide (Metabolite I), tripeptides (Metabolites II and III) and a dipeptide (Metabolite IV). These fragments may be further catabolized.
The major metabolite (M-I) plasma concentrations measured in 5 prostate cancer patients reached maximum concentration 2 to 6 hours after dosing and were approximately 6% of the peak parent drug concentration. One week after dosing, mean plasma M-I concentrations were approximately 20% of mean leuprolide concentrations.
Following administration of LUPRON DEPOT 3.75 mg to 3 adult patients, less than 5% of the dose was recovered as parent and M-I metabolite in the urine.
The pharmacokinetics of the drug has not been determined in patients with hepatic and renal impairment.
No pharmacokinetic-based drug-drug interaction studies have been conducted with LUPRON DEPOT-PED 11.25 mg or 30 mg for 3-month administration. However, because leuprolide acetate is a peptide that is primarily degraded by peptidase and not by cytochrome P-450 enzymes as noted in specific studies, and the drug is only about 46% bound to plasma proteins, drug interactions are not expected to occur.
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). There was a significant but not dose-related increase of pancreatic islet-cell adenomas in females and of testicular interstitial cell adenomas in males (highest incidence in the low dose group). In mice, no leuprolide acetate-induced tumors or pituitary abnormalities were observed at a dose as high as 60 mg/kg for two years. Adult patients have been treated with leuprolide acetate for up to three years with doses as high as 10 mg/day and for two years with doses as high as 20 mg/day without demonstrable pituitary abnormalities.
Following subcutaneous administration of LUPRON DEPOT to male and female rats before mating there was atrophy of the reproductive organs and suppression of reproductive performance.
Following a study with leuprolide acetate, immature male rats demonstrated tubular degeneration in the testes even after a recovery period. In spite of the failure to recover histologically, the treated males proved to be as fertile as the controls. Also, no histologic changes were observed in the female rats following the same protocol. In both sexes, the offspring of the treated animals appeared normal. The effect of the treatment of the parents on the reproductive performance of the F1 generation has been evaluated using LUPRON DEPOT formulation to groups of rats as one-time subcutaneous dose of 0.024 mg/kg (1/19 of the pediatric dose) on Day 15 of gestation or dosing on parturition day at doses up to 8 mg/kg (18 fold of the pediatric dose). There was no effect on growth, morphological development and reproductive performance of F1 generation.
In a randomized, open-label clinical study of LUPRON DEPOT-PED-3 Month formulations, 84 subjects (76 female, 8 male) between 1 and 11 years of age received the LUPRON DEPOT-PED 11.25 mg or 30 mg for 3-month administration formulation. 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 is 78.6% in the 11.25 mg dose and 95.2% in the 30 mg dose as shown in Table 2.
Table 2. Suppression of Peak-Stimulated LH from Month 2 Through Month 6 | ||||||
LUPRON DEPOT-PED 11.25 mg every 3 Months | LUPRON DEPOT-PED
30 mg every 3 Months |
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Parameter | Naïve N = 21 | Prev Trta
N = 21 | Total N = 42 | Naïve N = 21 | Prev Trta
N = 21 | Total N = 42 |
Percent with Suppression | 76.2 | 81.0 | 78.6 | 90.5 | 100 | 95.2 |
2-sided 95% CI | 52.8, 91.8 | 58.1, 94.6 | 63.2, 89.7 | 69.6, 98.8 | 83.9, 100 | 83.8, 99.4 |
a. Previously treated with GnRHa for at least 6 months prior to enrollment 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 and 2.
Figure 1. Mean Peak Stimulated LH for LUPRON DEPOT-PED 11.25 mg for 3-Month Administration
Figure 2. Mean Peak Stimulated LH for LUPRON DEPOT-PED 30 mg for 3-Month Administration
For the LUPRON DEPOT-PED 3 Month 11.25 mg dose, 93% (39/42) of subjects and for LUPRON DEPOT-PED 3 Month 30 mg dose 100% (42/42) of subjects had sex steroid (estradiol or testosterone) suppressed to prepubertal levels at all visits. Clinical suppression of puberty in female patients was observed in 29 of 32 (90.6%) and 28 of 34 (82.4%) of patients in the 11.25 mg and 30 mg groups, respectively, at month 6. Clinical suppression of puberty in males was observed in 1 of 2 (50.0%) and 2 of 5 (40.0%) patients in the 11.25 mg and 30 mg groups, respectively, at month 6. In subjects with complete data for bone age, 29 of 33 (87.9 %) in the 11.25 mg group and 30 of 40 in the 30 mg group (75.0% ) had a decrease in the ratio of bone age to chronological age at month 6 compared to screening.
LUPRON DEPOT-PED 11.25 mg or 30 mg for 3-Month Administration is packaged as follows: | ||
3 Month Kit with prefilled dual-chamber syringe | 11.25 mg | NDC 0074-3779-03 |
3 Month Kit with prefilled dual-chamber syringe | 30 mg | NDC 0074-9694-03 |
Each syringe contains sterile lyophilized microspheres of leuprolide acetate incorporated in a biodegradable lactic acid/glycolic acid copolymer. When mixed with 1.5 milliliter of accompanying diluent, LUPRON DEPOT-PED 11.25 mg or 30 mg for 3-month administration is administered as a single intramuscular injection.
Store at 25°C (77°F); excursions permitted to 15–30°C (59–86°F) [See USP Controlled Room Temperature].
Prior to starting therapy with LUPRON DEPOT-PED 11.25 mg or 30 mg for 3-month administration, patients should be informed that:
Manufactured for
AbbVie Inc.
North Chicago, IL 60064
by Takeda Pharmaceutical Company Limited
Osaka, Japan 540-8645
PEDIATRIC USE ONLY 11.25 mg for 3 – month administration
Do not remove from clamshell until ready to use.
Single Dose Administration Kit with prefilled dual-chamber syringe.
Includes: One prefilled dual-chamber syringe containing 1 1/2 inch needle with Luproloc™ safety device, one plunger, two alcohol swabs
LUPRON DEPOT-PED® (Leuprolide Acetate for Depot Suspension) 11.25 mg for 3 - month administration
PEDIATRIC USE ONLY 30 mg for 3 — month administration
Do not remove from clamshell until ready to use.
Single Dose Administration Kit with prefilled dual-chamber syringe.
Includes: One prefilled dual-chamber syringe containing 1 1/2 inch needle with Luproloc™ safety device, one plunger, two alcohol swabs
LUPRON DEPOT-PED® (Leuprolide Acetate for Depot Suspension) 30 mg 3 — month administration
LUPRON DEPOT-PED
leuprolide acetate kit |
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LUPRON DEPOT-PED
leuprolide acetate kit |
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Labeler - AbbVie Inc. (078458370) |