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Leuprolide acetate is a synthetic nonapeptide analog of naturally occurring gonadotropin-releasing hormone (GnRH). 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-leucylL-arginyl-N-ethyl-L-prolinamide acetate (salt) with the following structural formula:
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LUPRON DEPOT 7.5 mg for 1-month administration is available in a prefilled dual-chamber syringe containing sterile lyophilized microspheres which, when mixed with diluent, becomes a suspension intended as a monthly intramuscular injection.
The front chamber of LUPRON DEPOT 7.5 mg for 1-month administration prefilled dual-chamber syringe contains leuprolide acetate (7.5 mg), purified gelatin (1.3 mg), DL-lactic and glycolic acids copolymer (66.2 mg), and D-mannitol (13.2 mg). The second chamber of diluent contains carboxymethylcellulose sodium (5 mg), D-mannitol (50 mg), polysorbate 80 (1 mg), water for injection, USP, and glacial acetic acid, USP to control pH.
LUPRON DEPOT 22.5 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 12 WEEKS.
The front chamber of LUPRON DEPOT 22.5 mg for 3-month administration prefilled dual-chamber syringe contains leuprolide acetate (22.5 mg), polylactic acid (198.6 mg) and Dmannitol (38.9 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.
LUPRON DEPOT 30 mg for 4-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 16 WEEKS.
The front chamber of LUPRON DEPOT 30 mg for 4-month administration prefilled dual-chamber syringe contains leuprolide acetate (30 mg), polylactic acid (264.8 mg) and D-mannitol (51.9 mg). The second chamber of diluent contains carboxymethylcellulose sodium (7.5 mg), Dmannitol (75.0 mg), polysorbate 80 (1.5 mg), water for injection, USP, and glacial acetic acid, USP to control pH.
LUPRON DEPOT 45 mg for 6-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 24 WEEKS.
The front chamber of LUPRON DEPOT 45 mg for 6-month administration prefilled dual-chamber syringe contains leuprolide acetate (45 mg), polylactic acid (169.9 mg), D-mannitol (39.7 mg), and stearic acid (10.1 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.
LUPRON DEPOT-PED is indicated for the treatment of pediatric patients with central precocious puberty (CPP).
Table 1. Dosage Recommendations Based on Body Weight for LUPRON DEPOT-PED for 1-Month Administration
| Body Weight | Once Monthly Recommended Dosage |
| Less than or equal to 25 kg | 7.5 mg |
| Greater than 25 kg up to 37.5 kg | 11.25 mg |
| Greater than 37.5 kg | 15 mg |
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LuproLoc Safety Device should be activated after product injection, refer to Step 9 (Figure 7).
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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. (Figure 6)
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For depot suspension: a white lyophilized powder supplied in a single-dose, prefilled dual-chamber syringe with a colorless diluent is available as:
LUPRON DEPOT-PED for depot suspension is supplied in a single dose, prefilled dual-chamber syringe containing a white lyophilized powder and a colorless diluent for reconstitution as follows (Table 8):
Table 8. LUPRON DEPOT-PED Product Presentations
| LUPRON DEPOT-PED 7.5 mg, 11.25 mg, or 15 mg for 1-Month Administration | ||
| Kit Type | Strength | NDC Number |
| 1-month kit | 7.5 mg | NDC 0074-2108-03 |
| 11.25 mg | NDC 0074-2282-03 | |
| 15 mg | NDC 0074-2440-03 | |
| LUPRON DEPOT-PED 11.25 mg or 30 mg for 3-Month Administration | ||
| 11.25 mg | NDC 0074-3779-03 | |
| LUPRON DEPOT-PED 7.5 mg, 11.25 mg, or 15 mg for 1-Month Administration | ||
| Kit Type | Strength | NDC Number |
| 3-month kit | 30 mg | NDC 0074-9694-03 |
| LUPRON DEPOT-PED 45 mg for 6-Month Administration | ||
| 6-month kit | 45 mg | NDC 0074-3575-01 |
Each kit contains:
Prior to reconstitution, store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [See USP Controlled Room Temperature].
After reconstitution, use immediately [see DOSAGE AND ADMINISTRATION].
Manufactured for: AbbVie Inc. North Chicago, IL 60064 By Takeda Pharmaceutical Company Limited Osaka, Japan 540-8645. Revised: May 2025
The following serious adverse reactions are described here and elsewhere in the label:
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.
LUPRON DEPOT-PED 1-month administration was evaluated in a pivotal, open label, multicenter study in which 55 (49 female and 6 male) pediatric patients with central precocious puberty were enrolled. The age ranged from 1 to 8 years of age at the beginning of treatment; the mean age for females was 6.8 years (range: 1 to 9 years) and the mean age for males was 7.5 years (range: 4 to 9 years); 61.8% were Caucasian; 20% Black; 1.8% Oriental; and 16.4% Hispanic.
Adverse reactions that occurred in ≥2% of patients are shown in Table 2.
Table 2. Adverse Reactions Occurring in ≥2% in Pediatric Patients with CPP Receiving LUPRON DEPOT-PED 1-month
| % of Patient (N = 421) |
|
| Injection Site Reactions Including Abscess* | 9 |
| Emotional Lability | 5 |
| Headache | 3 |
| General Pain | 3 |
| Acne/Seborrhea | 3 |
| Rash Including Erythema Multiforme | 3 |
| Vaginitis/Vaginal Bleeding/Vaginal Discharge | 3 |
| Vasodilation | 2 |
| * Most events were mild or moderate in severity. | |
The following adverse reactions were reported in less than 2% of the patients and are listed below by body system.
Body as a Whole – aggravation of preexisting tumor and decreased vision, allergic reaction, body odor, 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, feminization, goiter;
Hemic and Lymphatic System – purpura;
Metabolic and Nutritional Disorders – growth retarded, peripheral edema, weight gain;
Musculoskeletal System – arthralgia, joint disorder, myalgia, myopathy;
Nervous System – hyperkinesia, somnolence;
Psychiatric System – depression, nervousness;
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, dysmenorrhea, gynecomastia/breast disorders, menstrual disorder, urinary incontinence.
Laboratory: The following laboratory events were reported as adverse reactions: antinuclear antibody present and increased sedimentation rate.
LUPRON DEPOT-PED for 3-month administration was evaluated in a pivotal, open-label, multicenter, clinical study with 84 randomized pediatric patients with central precocious puberty; 76 (90.5%) were females and 8 (9.5%) were males. The age ranged from 1 to 11 years age at the beginning of treatment; 80/84 (95.2%) were 5 years or older, and female patients were younger than male; the mean age for 11.25 mg and 30 mg groups for females was 7.6 and 7.7 years, and for males 9.3 and 9.4 years, respectively; 58.3% were Caucasian; 22.6% were Black; 7.1% were Asian; 1.2% were Native Hawaiian or Other Pacific Islander; and 10.7% were Multi-race.
Adverse reactions that occurred in ≥2% of patients are shown in Table 3.
Table 3. Adverse Reactions Occurring in ≥2% in Pediatric Patients with CPP Receiving LUPRON DEPOT-PED for 3-month administration.
| % 11.25 mg every 3 Months N=42 |
% 30 mg every 3 Months N=42 |
% Overall N = 84 |
|
| Injection site pain | 19 | 21 | 20 |
| Weight increased | 7 | 7 | 7 |
| Headache | 2 | 7 | 5 |
| Mood altered | 5 | 5 | 5 |
| Injection site swelling | 2 | 2 | 2 |
The following 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 – dizziness;
Psychiatric Disorders – crying, tearfulness;
Respiratory, Thoracic and Mediastinal Disorders – cough;
Skin and Subcutaneous Tissue Disorders – hyperhidrosis;
Vascular Disorders – pallor.
LUPRON DEPOT-PED for 6-month administration was evaluated in an open-label, multicenter, clinical study with 45 pediatric patients with central precocious puberty; 41 (91%) were females and 4 (9%) were males. The baseline age ranged from 4 to 10 years. There were 30 (67%) Caucasian; 7 (16%) Black; and 1 (2%) Asian.
Adverse reactions that occurred in ≥4 % of all patients are shown in Table 4.
Table 4. Adverse Reactions Occurring in ≥4% in Pediatric Patients with CPP Receiving LUPRON DEPOT-PED for 6-month administration.
| Total (N = 45) n (%) |
|
| Injection Site Reactions a | 35 (78%) |
| Headache b | 15 (33%) |
| Psychiatric Events c | 10 (22%) |
| Abdominal Pain d | 8 (18%) |
| Diarrhea e | 7 (16%) |
| Hemorrhage f | 6 (13%) |
| Nausea and Vomiting | 6 (13%) |
| Pyrexia | 6 (13%) |
| Pruritus g | 5 (11%) |
| Pain in extremity | 4 (9%) |
| Rash | 3 (7%) |
| Back Pain | 3 (7%) |
| Ligament sprain | 3 (7%) |
| Weight increased | 3 (7%) |
| Fracture h | 2 (4%) |
| Breast tenderness i | 2 (4%) |
| Insomnia j | 2 (4%) |
| Chest pain | 2 (4%) |
| Hyperhidrosis | 2 (4%) |
| a Injection site reactions includes the preferred terms injection site pain, injection site erythema, injection site reaction, injection site warmth, injection site bruising, injection site discomfort, and injection site swelling b-Headache includes the preferred terms headache and cluster headache c Psychiatric events includes the preferred terms affect lability, affective disorder, aggression, crying, depressed mood, disruptive mood dysregulation disorder, hallucination auditory, mood altered, mood swings, and trichotillomania d Abdominal pain includes the preferred terms abdominal pain, abdominal pain upper, and abdominal discomfort e Diarrhea includes the preferred terms gastroenteritis and diarrhea f Hemorrhage includes the preferred terms contusion, epistaxis, hematochezia, and injection site bruising g Pruritus includes the preferred terms pruritus, vulvovaginal pruritus, nasal pruritus h Fracture includes the preferred terms ankle fracture and tibia fracture i Breast tenderness includes the preferred terms breast pain and breast tenderness j Insomnia includes the preferred terms initial insomnia and insomnia |
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The following adverse reactions have been identified during post-approval use of leuprolide acetate or LUPRON DEPOT-PED in pediatric patients. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Allergic reactions: anaphylactic, rash, urticaria, and photosensitivity reactions.
General: chest pain, weight increase, decreased appetite, fatigue.
Laboratory Abnormalities: decreased WBC.
Metabolic: diabetes mellitus.
Musculoskeletal and Connective Tissue: tenosynovitis-like symptoms, severe muscle pain, arthralgia, epiphysiolysis, muscle spasms, myalgia.
Published literature and postmarketing reports indicate that bone mineral density may decrease during GnRH therapy in pediatric patients with central precocious puberty. Published studies indicate that after discontinuation of therapy, subsequent bone mass accrual is preserved and peak bone mass in late adolescence does not seem to be affected.
Neurologic: neuropathy peripheral, convulsion, insomnia, pseudotumor cerebri (idiopathic intracranial hypertension).
Psychiatric Disorders: emotional lability, such as crying, irritability, impatience, anger, and aggression. Depression, including rare reports of suicidal ideation and attempt. Many, but not all, of these patients had a history of psychiatric illness or other comorbidities with an increased risk of depression.
Reproductive System: vaginal bleeding, breast enlargement.
Respiratory: dyspnea.
Skin and Subcutaneous Tissue: injection site reactions including induration and abscess, flushing, hyperhidrosis.
Vascular Disorders: hypertension, hypotension.
No pharmacokinetic-based drug-drug interaction studies have been conducted with LUPRON DEPOT-PED [see CLINICAL PHARMACOLOGY] .
Administration of LUPRON DEPOT-PED 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 may be affected. Normal pituitary-gonadal function is usually restored within six months after treatment with LUPRON DEPOT-PED is discontinued.
Included as part of the "PRECAUTIONS" Section
During the early phase of therapy or after subsequent doses, gonadotropins and sex steroids may rise above baseline because of a transient stimulatory effect of the drug [see CLINICAL PHARMACOLOGY]. Therefore, an increase in clinical signs and symptoms of puberty, including vaginal bleeding, may be observed during the first weeks of therapy or after subsequent doses [see ADVERSE REACTIONS].
Psychiatric events have been reported in patients taking GnRH agonists, including LUPRON DEPOT-PED. Postmarking reports with this class of drugs include symptoms of emotional lability, such as crying, irritability, impatience, anger and aggression. Monitor for development or worsening of psychiatric symptoms during treatment with LUPRON DEPOT-PED [see ADVERSE REACTIONS].
Postmarketing reports of convulsions have been observed in patients receiving GnRH agonists, including LUPRON DEPOT-PED. 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 [see ADVERSE REACTIONS].
Pseudotumor cerebri (idiopathic intracranial hypertension) have been reported in pediatric patients receiving GnRH agonists, including LUPRON DEPOT-PED. Monitor patients for signs and symptoms of pseudotumor cerebri, including headache, papilledema, blurred vision, diplopia, loss of vision, pain behind the eye or pain with eye movement, tinnitus, dizziness, and nausea.
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Inform patients and caregivers that during the early phase of therapy with LUPRON DEPOTPED, 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. Instruct patients and caregivers to notify the physician if these symptoms continue beyond the second month after LUPRON DEPOT-PED administration [see WARNINGS AND PRECAUTIONS].
Inform patients and caregivers that psychiatric events have been reported in patients taking GnRH agonists, including leuprolide acetate. Events include emotional lability, such as crying, irritability, impatience, anger, and aggression. Instruct patients and caregivers to monitor for development or worsening of psychiatric symptoms including depression during treatment with LUPRON DEPOT-PED [see WARNINGS AND PRECAUTIONS].
Inform patients and caregivers that reports of convulsions have been observed in patients receiving GnRH agonists, including leuprolide acetate. 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 may be at increased risk [see WARNINGS AND PRECAUTIONS].
Inform patients and caregivers that reports of pseudotumor cerebri (idiopathic intracranial hypertension) have been observed in pediatric patients receiving GnRH agonists, including LUPRON DEPOT-PED. Advise patients and caregivers to monitor for headache and vision issues such as blurred vision, double vision, loss of vision, pain behind the eye or pain with eye movement, ringing in the ears, dizziness, and nausea. Advise patients and caregivers to contact their healthcare provider if the patient develops any of these symptoms [see WARNINGS AND PRECAUTIONS].
Inform patients and caregivers that injection site related adverse reactions may occur such as transient burning/stinging, pain, bruising, and redness. Advise patients to contact their healthcare provider if they experience rash or severe injection site reactions [see ADVERSE REACTIONS].
LUPRON DEPOT-PED is contraindicated in pregnancy. If the patient becomes pregnant while taking the drug, the patient should be informed of the potential risk to the fetus [see Use In Specific Populations].
Inform caregivers about the importance of adherence to the LUPRON DEPOT-PED dosing schedule [see DOSAGE AND ADMINISTRATION].
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.
Mutagenicity studies have been performed with leuprolide acetate using bacterial and mammalian systems. These studies provided no evidence of a mutagenic potential.
LUPRON DEPOT-PED is contraindicated in pregnancy [see CONTRAINDICATIONS].
LUPRON DEPOT-PED may cause fetal harm, when administered to a pregnant woman, based on findings from animal studies and the drug’s mechanism of action [see CLINICAL PHARMACOLOGY]. The available data from published clinical studies and case reports and from the pharmacovigilance database on exposure to LUPRON DEPOT-PED during pregnancy are insufficient to assess the risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Based on animal reproduction studies, LUPRON DEPOT-PED may be associated with an increased risk of pregnancy complications, including early pregnancy loss and fetal harm. In animal reproduction studies, subcutaneous administration of leuprolide acetate to rabbits during the period of organogenesis caused embryo-fetal toxicity, decreased fetal weights and a dose-dependent increase in major fetal abnormalities in animals at doses less than the recommended human dose based on body surface area using an estimated daily dose. A similar rat study also showed increased fetal mortality and decreased fetal weights but no major fetal abnormalities at doses less than the recommended human dose based on body surface area using an estimated daily dose (see Data).
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% -4% and 15% -20%, respectively.
Animal Data
When administered on day 6 of pregnancy at test dosages of 0.00024 mg/kg, 0.0024 mg/kg, and 0.024 mg/kg (doses less than the recommended human dose) to rabbits, leuprolide acetate produced a dose-related increase in malformations comprised primarily of segmental and fusion defects of the skeleton and skull. 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 leuprolide acetate in rabbits and with the highest dose (0.024 mg/kg) in rats.
There are no data on the presence of leuprolide acetate in either animal or human milk, the effects on the breastfed infants, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for LUPRON DEPOT-PED and any potential adverse effects on the breastfed infant from LUPRON DEPOT-PED or from the underlying maternal condition.
Exclude pregnancy in women of reproductive potential prior to initiating LUPRON DEPOTPED if clinically indicated [see Pregnancy].
Females
LUPRON DEPOT-PED may cause embryo-fetal harm when administered during pregnancy. LUPRON DEPOT-PED is not a contraceptive. If contraception is indicated, advise females of reproductive potential to use a non-hormonal method of contraception during treatment with LUPRON DEPOT-PED [see Pregnancy].
Based on its pharmacodynamic effects of decreasing secretion of gonadal steroids, fertility is expected to be decreased while on treatment with LUPRON DEPOT-PED. Clinical and pharmacologic studies in adults (>18 years) with leuprolide acetate and similar analogs have shown reversibility of fertility suppression when the drug is discontinued after continuous administration for periods of up to 24 weeks [see CLINICAL PHARMACOLOGY].
There is no evidence that pregnancy rates are affected following discontinuation of LUPRON DEPOT-PED.
Animal studies (prepubertal and adult rats and monkeys) with leuprolide acetate and other GnRH analogs have shown functional recovery of fertility suppression.
The safety and effectiveness of LUPRON DEPOT-PED for the treatment of CPP has been established in pediatric patients 1 years of age and older. Use of LUPRON DEPOT-PED for this indication is supported by evidence from two pivotal, open label clinical studies of 139 pediatric patients with central precocious puberty with an age range of 1 to 11 years [see Clinical Studies]. The safety and effectiveness of LUPRON DEPOT-PED have not been established in pediatric patients less than 1 year old.
No specific antidotes for LUPRON DEPOT-PED are known. Contact Poison Control (1-800222-1222) for latest recommendations.
In cases of overdosage, standard of care monitoring and management principles should be followed.
Leuprolide acetate, a GnRH agonist, acts as a potent inhibitor of gonadotropin secretion (LH and follicle stimulating hormone (FSH)) when given continuously in therapeutic doses.
Following an initial stimulation of GnRH receptors, chronic administration of leuprolide acetate results in downregulation of GnRH receptors, reduction in release of LH and FSH, and consequent suppression of ovarian and testicular production of estradiol and testosterone, respectively. This inhibitory effect is reversible upon discontinuation of drug therapy.
LUPRON DEPOT-PED for 1-month Administration
Following a single LUPRON DEPOT-PED 7.5 mg for 1-month administration to adult patients, mean peak leuprolide plasma concentration was almost 20 ng/mL at 4 hours and then declined to 0.36 ng/mL at 4 weeks. However, intact leuprolide and an inactive major metabolite could not be distinguished by the assay which was employed in the study. Nondetectable leuprolide plasma concentrations have been observed during chronic LUPRON DEPOT-PED 7.5 mg administration, but testosterone levels appear to be maintained at castrate levels.
In a study of pediatric patients with CPP, doses of 7.5 mg, 11.25 mg and 15.0 mg of LUPRON DEPOT-PED were given every 4 weeks. In 22 pediatric patients, trough leuprolide plasma levels were determined according to weight categories as summarized below:
| Patient Weight Range (kg) | Group Weight Average (kg) | Dose (mg) | Trough Plasma Leuprolide Level Mean ±SD (ng/mL)* |
| 20.2 -27.0 | 22.7 | 7.5 | 0.77±0.033 |
| 28.4 -36.8 | 32.5 | 11.25 | 1.25±1.06 |
| 39.3 -57.5 | 44.2 | 15.0 | 1.59±0.65 |
| * Group average values determined at Week 4 immediately prior to leuprolide injection. Drug levels at 12 and 24 weeks were similar to respective 4 week levels. | |||
LUPRON DEPOT-PED for 3-month Administration
Following a single LUPRON DEPOT-PED 11.25 mg or 30 mg for 3-month administration to pediatric patients 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.
LUPRON DEPOT-PED for 6-month Administration
Following a single injection of LUPRON DEPOT-PED 45 mg for 6-month administration in 20 pediatric patients with CPP, mean peak plasma concentration increased rapidly to 15.7 ng/mL 1 hour post-dose. Following the initial rise, mean leuprolide plasma concentration declined to 0.03 ng/mL by Week 24. The mean leuprolide concentrations 6 months after the first and second injections were comparable indicating no accumulation of leuprolide from repeated administration.
The mean steady-state volume of distribution of leuprolide following intravenous bolus administration to healthy male subjects was 27 L. In vitro binding to human plasma proteins ranged from 43% to 49%.
Metabolism
In healthy male subjects given an intravenous 1 mg bolus of leuprolide 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.
Excretion
Following administration of LUPRON DEPOT 3.75 mg to 3 patients, less than 5% of the dose was recovered as parent and M-I metabolite in the urine.
The pharmacokinetics of LUPRON DEPOT-PED has not been determined in patients with hepatic or renal impairment.
No pharmacokinetic-based drug-drug interaction studies have been conducted with LUPRON DEPOT-PED. Leuprolide acetate is a peptide that is not degraded by cytochrome P-450 enzymes; hence, drug interactions associated with cytochrome P-450 enzymes would not be expected to occur.
The efficacy of LUPRON DEPOT-PED was evaluated in a pivotal open-label, multicenter clinical trial (NCT00660010) in which 55 pediatric patients with central precocious puberty (49 females and 6 males, naïve to previous GnRHa treatment) were treated with LUPRON DEPOTPED 1-month formulations until age was appropriate for entry into puberty (see treatment period data below)and a subset of 40 patients were then followed post-treatment (see follow-up period data below). The mean ± SD age at the start of treatment was 7 ± 2 years and the duration of treatment was 4 ± 2 years. Study drug was administered intramuscularly (IM) every 28 days, with incremental adjustments of 3.75mg at each clinic visit, if necessary based on clinical and laboratory results. During the follow-up period, GnRHa stimulation test was performed every 6 months until a pubertal response was observed.
During the treatment period, LUPRON DEPOT-PED suppressed gonadotropins and sex steroids to prepubertal levels. Suppression of peak stimulated LH concentrations to < 1.75 mIU/mL was achieved in 96% of patients by month 1. Five patients required increased doses of study drug to achieve or retain LH suppression. The number and percentage of patients with suppression of peak stimulated LH < 1.75 mIU/mL and mean ± SD peak stimulated LH over time is shown in Table 5. Six months after the treatment period was finished, the mean peak stimulated LH was 20.6 ± SD 13.7 mIU/mL (n=30).
The following effects have been noted with the chronic administration of leuprolide: cessation of menses (in girls), normalization and stabilization of linear growth and bone age advancement, stabilization of clinical signs and symptoms of puberty.
Table 5. The number and percentage of patients with peak stimulated LH < 1.75 mIU/mL and Mean (SD) peak LH at each clinic visit
| Weeks on Study | n with peak stimulated LH < 1.75 mIU/mL/ N with a LH measurement for that week | Mean (SD) peak LH | |
| n/N | % | ||
| Baseline | 0/55 | 0% | 35.0 (21.32) |
| Week 4 | 53/55 | 96.4% | 0.8 (0.57) |
| Week 12 | 48/54 | 88.9% | 1.1 (1.77) |
| Week 24 | 48/53 | 90.6% | 0.8 (0.79) |
| Week 36 | 51/54 | 94.4% | 0.6 (0.43) |
| Week 48 | 51/54 | 94.4% | 0.6 (0.47) |
| Week 72 | 52/52 | 100% | 0.5 (0.30) |
| Week 96 | 46/46 | 100% | 0.4 (0.33) |
| Week 120 | 40/40 | 100% | 0.4 (0.27) |
| Week 144 | 36/36 | 100% | 0.4 (0.24) |
| Week 168 | 27/28 | 96.4% | 1.2 (4.58) |
| Week 216 | 18/19 | 94.7% | 0.5 (0.90) |
| Week 240 | 16/17 | 94.1% | 0.4 (0.62) |
| Week 264 | 14/15 | 95.3% | 0.4 (0.41) |
| Week 288 | 11/11 | 100% | 0.3 (0.22) |
| Week 312 | 9/9 | 100% | 0.4 (0.20) |
| Week 336 | 6/6 | 100% | 0.3 (0.10) |
| Week 360 | 6/6 | 100% | 0.3 (0.13) |
| Week 384 | 5/5 | 100% | 0.2 (0.10) |
| Week 408 | 3/3 | 100% | 0.2 (0.09) |
| Week 432 | 2/2 | 100% | 0.3 (0.04) |
| Week 456 | 2/2 | 100% | 0.2 (0.04) |
| Week 480 | 1/1 | 100% | 0.2 (NA) |
| Week 504 | 1/1 | 100% | 0.2 (NA) |
Suppression (defined as regression or no change) of the clinical/physical signs of puberty was achieved in most patients. In females, suppression of breast development ranged from 66.7 to 90.6% of patients during the first 5 years of treatment. The mean stimulated estradiol was 15.1 pg/mL at baseline, decreased to the lower level of detection (5.0 pg/mL) by Week 4 and was maintained there during the first 5 years of treatment. In males, suppression of genitalia development ranged from 60% to 100% of patients during the first 5 years of treatment. The mean stimulated testosterone was 347.7 ng/dL at baseline and was maintained at levels no greater than 25.3 ng/dL during the first 5 years of treatment.
A “flare effect” of transient bleeding or spotting during the first 4 weeks of treatment was observed in 19.4% (7/36) females who had not reached menarche at baseline. After the first 4 weeks and for the remainder of the treatment period, no patients reported menstrual-like bleeding, and only rare spotting was noted.
The mean ratio of bone age to chronological age decreased from 1.5 at baseline to 1.1 by end of treatment. The mean height standard deviation z-score changed from 1.6 at baseline to 0.7 at the end of the treatment phase.
Thirty five (35) females and 5 males participated in a post-treatment follow-up period to assess reproductive function (in females) and final height. At 6 months post-treatment, most patients reverted to pubertal levels of LH (87.9%) and clinical signs of resumption of pubertal progression were evident with increase in breast development in girls (66.7%) and increase in genitalia development in boys (80%).
After stopping treatment, regular menses were reported for all female patients who reached 12 years of age during follow-up; mean time to menses was approximately 1.5 years; mean age of onset of menstruation after stopping treatment was 12.9 years.
Of the 40 patients evaluated in the follow-up, 33 were observed until they reached final or near-final adult height. These patients had a mean increase in final adult height compared to baseline predicted adult height. The mean final adult height standard deviation score was -0.2.
The efficacy was evaluated in a 6-month, randomized, open-label clinical study of LUPRON DEPOT-PED 3-Month formulations (NCT00667446). 84 patients (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 patients 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 6.
Table 6. 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 | |||||
| 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 LCP07-167. | ||||||
The mean peak stimulated LH levels for all visits are shown by dose and subgroup (naïve vs. previously treated patients) in Figures 8 and 9.
Figure 8. Mean Peak Stimulated LH for LUPRON DEPOT-PED 11.25 mg for 3-month administration
 |
Figure 9. Mean Peak Stimulated LH for LUPRON DEPOT-PED 30 mg for 3-month administration
 |
For the LUPRON DEPOT-PED 11.25 mg dose for 3-month administration, 93% (39/42) of patients and for LUPRON DEPOT-PED 30 mg dose for 3-month administration, 100% (42/42) of patients 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%) and 2 of 5 (40%) patients in the 11.25 mg and 30 mg groups, respectively, at month 6. In patients with complete data for bone age, 29 of 33 (88%) in the 11.25 mg group and 30 of 40 in the 30 mg group (75%) had a decrease in the ratio of bone age to chronological age at month 6 compared to screening.
The safety and efficacy of LUPRON DEPOT-PED 6-Month formulation was evaluated in an open-label, single-arm, multicenter, clinical trial (NCT03695237).
In the clinical trial, 27 pediatric patients with central precocious puberty (24 females and 3 males) naïve to previous GnRH agonist treatment and 18 pediatric patients with central precocious puberty (17 females and 1 males) previously treated with GnRH agonist therapy (including 1-,3-, 6-and 12-month) received LUPRON DEPOT-PED 45 mg. LUPRON DEPOTPED 45 mg was administered as an intramuscular injection at two intervals 24 weeks apart.
The primary efficacy endpoint of percentage of patients with suppression of peak-stimulated LH to < 4.0 mIU/mL at Week 24 was achieved in 39/45 (86.7 %) patients (Table 7). Of the patients previously treated with other GnRHa formulations 94.4% remained suppressed at Week 24.
Table 7. Suppression of Peak-Stimulated GnRHa-Stimulated LH at Week 24
| Parameter | LUPRON DEPOT-PED 45 mg | ||
| Naïve N = 27 |
Prev Trta N = 18 |
Total N =45 |
|
| Percent with Suppression, n (%) | 22 (81.5) | 17 (94.4) | 39 (86.7) |
| 95% CI | 61.9, 93.7 | 72.7, 99.9 | 73.2, 95.0 |
| a. Previously treated with GnRHa for at least 6 months prior to enrollment in pivotal Study M16-904 | |||
The mean peak stimulated LH levels decreased from 17.4 mIU/mL in treatment-naïve patients and from 2.1 mIU/ML in previously treated patients at baseline to 1.6 mIU/mL and 1.5 mIU/mL respectively at Week 4. The levels remained suppressed for all visits up to Week 48.
The proportion of female patients with suppression of basal estradiol to <20 pg/mL was 97.4% at Week 24 and 100% at Week 48. The proportion of male patients with suppression of testosterone to <30 ng/dL was 100% at Weeks 24 and 48. Suppression (defined as regression or no change) of the physical signs of puberty was achieved in most patients.
In patients with complete data for bone age, 40 of 45(88.9%) and 42 of 45 (93.3%) had a decrease in the ratio of bone age to chronological age at Weeks 24 and 48, respectively, compared to baseline.
In the extension part of the study (Weeks 49 to 144), 4 of 45 enrolled patients discontinued due to lack of efficacy. Twenty-three patients had complete data available through Week 144; LH suppression was maintained in all 23 patients.
LUPRON DEPOT-PED®
(loo-pron depo peed)
(leuprolide acetate for depot suspension)
What is the most important information I should know about LUPRON DEPOT-PED?
Call your child’s doctor right away if your child has any new or worsening mental symptoms or problems while taking LUPRON DEPOT-PED.
Seizures have also happened in people who have not had any of these problems. Call your child’s doctor right away if your child has a seizure while taking LUPRON DEPOT-PED.
What is LUPRON DEPOT-PED?
LUPRON DEPOT-PED should not be taken if your child is:
Before your child receives LUPRON DEPOT-PED, tell their doctor about all of your child’s medical conditions including if they:
Tell your doctor about all the medicines your child takes, including prescription and over-the-counter medicines, vitamins, and herbal supplements.
How will your child receive LUPRON DEPOT-PED?
What are the possible side effects of LUPRON DEPOT-PED?
LUPRON DEPOT-PED may cause serious side effects. See “What is the most important information I should know about LUPRON DEPOT-PED?”
The most common side effects of LUPRON DEPOT-PED received 1 time each month include:
The most common side effects of LUPRON DEPOT-PED received every 3 months include:
The most common side effects of LUPRON DEPOT-PED received every 6 months include:
These are not all the possible side effects of LUPRON DEPOT-PED. Call your doctor for medicaladvice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store LUPRON DEPOT-PED INJECTION?
General information about the safe and effective use of LUPRON DEPOT-PED.
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use LUPRON DEPOT-PED for a condition for which it was not prescribed.
This Medication Guide summarizes the most important information about LUPRON DEPOT-PED. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about LUPRON DEPOT-PED that is written for doctors or trained nurses.
What are the ingredients in LUPRON DEPOT-PED?
LUPRON DEPOT-PED 7.5 mg, 11.25 mg or 15 mg for 1-month administration:
Active Ingredients: leuprolide acetate for depot suspension
Inactive Ingredients: purified gelatin, DL-lactic and glycolic acids copolymer, D-mannitol, carboxymethylcellulose sodium, polysorbate 80, water for injection, USP, and glacial acetic acid, USP to control pH.
LUPRON DEPOT-PED 11.25 mg or 30 mg for 3-month administration:
Active Ingredients: leuprolide acetate for depot suspension
Inactive Ingredients: polylactic acid, D-mannitol, carboxymethylcellulose sodium, polysorbate 80, water for injection, USP, and glacial acetic acid, USP to control pH.
LUPRON DEPOT-PED 45 mg for 6-month administration:
Active Ingredients: leuprolide acetate for depot suspension
Inactive Ingredients: polylactic acid, D-mannitol, and stearic acid, carboxymethylcellulose sodium, Dmannitol, polysorbate 80, water for injection, USP, and glacial acetic acid, USP to control pH.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
