Lupron Depot-Ped

Description for Lupron Depot-Ped

Leuprolide acetate is a synthetic nonapeptide analog of naturally occurring gonadotropinreleasing 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 7.5 mg, 11.25 mg, Or 15 mg For 1-Month Administration

LUPRON DEPOT-PED is available in a prefilled dual-chamber syringe containing sterile lyophilized microspheres which, when mixed with diluent, become a suspension intended as a single intramuscular injection.

The front chamber of LUPRON DEPOT-PED 7.5 mg, 11.25 mg, and 15 mg prefilled dual-chamber syringe contains leuprolide acetate (7.5/11.25/15 mg), purified gelatin (1.3/1.95/2.6 mg), DL-lactic and glycolic acids copolymer (66.2/99.3/132.4 mg), and D-mannitol (13.2/19.8/26.4 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-PED 11.25 mg Or 30 mg For 3-Month Administration

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 Dmannitol (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 (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.

Uses for Lupron Depot-Ped

LUPRON DEPOT-PED is indicated for the treatment of pediatric patients with central precocious puberty (CPP).

Dosage for Lupron Depot-Ped

Important Dosing Information

• LUPRON DEPOT-PED must be administered by a healthcare professional.
• Individualize the dose of LUPRON DEPOT-PED for each patient.
• Select the appropriate LUPRON-DEPOT PED syringe for the intended dosing frequency and administer intramuscularly.
• Each LUPRON DEPOT-PED strength and formulation has different release characteristics. Do not use partial syringes or a combination of syringes to achieve a particular dose.
• In the case of inadequate suppression of pituitary gonadotropins and peripheral sex steroids with a maximal dosage, consider other available gonadotropin releasing hormone (GnRH) agonists indicated for the treatment of central precocious puberty.
• Discontinue LUPRON DEPOT-PED at the appropriate age of onset of puberty.

Dosage And Recommended Monitoring For 1-Month Administration

• Administer LUPRON DEPOT-PED 7.5 mg, 11.25 mg, or 15 mg for 1-month administration as a single-dose intramuscular injection once every month.
• The starting dose is based on the patient's weight (see Table 1).

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

• The dosage may need to be adjusted with changes in body weight.
• If adequate hormonal and clinical suppression is not achieved with the starting dose, increase the dosage to the next available higher dose (e.g., 11.25 mg or 15 mg at the next monthly injection).
• Monitor response with a GnRH stimulation test, basal luteinizing hormone (LH) or serum concentration of sex steroid levels beginning 1 to 2 months following initiation of therapy, with changing doses, or further as judged clinically appropriate in order to confirm maintenance of efficacy.
• Assess height (for calculation of growth rate) and bone age every 6 to 12 months.

Dosage And Recommended Monitoring For 3-Month Administration

• Use LUPRON DEPOT-PED 11.25 mg or 30 mg for 3-month administration once every three months (12 weeks) as a single-dose intramuscular injection.
• Monitor response with a GnRH stimulation test, basal LH or serum concentration of sex steroid levels at months 2 to 3, month 6 and further as judged clinically appropriate, to confirm maintenance of efficacy.
• Assess height (for calculation of growth rate) and bone age every 6 to 12 months.

Dosage And Recommended Monitoring For 6-Month Administration

• Use LUPRON DEPOT-PED 45 mg for 6-month administration once every six months (24 weeks) as a single-dose intramuscular injection.
• Monitor response with a GnRH stimulation test, basal LH or serum concentration of sex steroid levels at months 5 to 6 and further as judged clinically appropriate, to confirm maintenance of efficacy.
• Assess height (for calculation of growth rate) and bone age every 6 to 12 months.

Important Administration Instructions

• Administer LUPRON DEPOT-PED as a single-dose intramuscular injection into the gluteal area, anterior thigh, or shoulder.
• Rotate injection sites within the same region from one injection to the next.
• Inject immediately after reconstitution. Discard if not used within 2 hours.

Reconstitution Instructions

Figure 1

LuproLoc Safety Device should be activated after product injection, refer to Step 9 (Figure 7).

Figure 2

Figure 3

Figure 4

Figure 5

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. (Figure 6)

Figure 6

Figure 7

1. Visually inspect the LUPRON DEPOT-PED powder and diluent. Do not use the syringe if clumping or caking is evident. A thin layer of powder on the wall of the syringe is considered normal prior to mixing with the diluent. The diluent should appear clear and free from particulate matter. Do not use the diluent if it is not clear or there is particulate matter.
2. To prepare for injection, screw the white plunger into the end stopper until the stopper begins to turn. (see Figure 1 and Figure 2)
3. Hold the syringe upright. Release the diluent by slowly pushing the plunger for 6 to 8 seconds until the first stopper is at the blue line in the middle of the barrel. (Figure 3)
4. Keep the syringe upright. Mix the powder thoroughly by gently shaking the syringe until the powder forms a uniform suspension. The suspension will appear milky. If the powder adheres to the stopper or caking/clumping is present, tap the syringe with your finger to disperse. Do not use if any of the powder has not gone into suspension. (Figure 4)
5. Hold the syringe upright. With the opposite hand pull the needle cap upward without twisting.
6. Keep the syringe upright. Advance the plunger to expel the air from the syringe. Now the syringe is ready for injection.
7. After cleaning the injection site with an alcohol swab, administer the intramuscular injection by inserting the needle at a 90 degree angle into the deltoid, gluteal area, or anterior thigh. (Figure 5)
8. Inject the entire contents of the syringe intramuscularly immediately after reconstitution. The suspension settles very quickly following reconstitution.
9. Withdraw the needle. Once the syringe has been withdrawn, activate immediately the LuproLoc^® safety device by pushing the arrow on the lock upward towards the needle tip with the thumb or finger, as illustrated, until the needle cover of the safety device is fully extended over the needle and a click is heard or felt. (Figure 7)

HOW SUPPLIED

Dosage Forms And Strengths

For depot suspension: a white lyophilized powder supplied in a single-dose, prefilled dual-chamber syringe with a colorless diluent is available as:

• For 1-month administration: 7.5 mg, 11.25 mg, or 15 mg of leuprolide acetate
• For 3-month administration: 11.25 mg or 30 mg of leuprolide acetate
• For 6-month administraton: 45 mg of leuprolide acetate

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 7):

Table 7. 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:

• one single-dose, prefilled dual-chamber syringe containing 23 gauge 1½ inch needle with LuproLoc^® safety device
• one plunger
• two alcohol swabs
• population, dose and frequency confirmation insert
• a complete prescribing information enclosure

Storage And Handling

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: Apr 2023

Side Effects for Lupron Depot-Ped

The following serious adverse reactions are described here and elsewhere in the label:

• Initial rise in gonadotropin and sex steroid levels [see WARNINGS AND PRECAUTIONS].
• Psychiatric Events [see WARNINGS AND PRECAUTIONS].
• Convulsions [see WARNINGS AND PRECAUTIONS].
• Pseudotumor Cerebri (Idiopathic Intracranial Hypertension) [see WARNINGS AND PRECAUTIONS]

Clinical Trials Experience

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 For 1-Month Administration

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.

Less Common Adverse Reactions

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

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

Less Common Adverse Reactions

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

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

Postmarketing Experience

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.

Drug Interactions for Lupron Depot-Ped

Drug Interactions

No pharmacokinetic-based drug-drug interaction studies have been conducted with LUPRON DEPOT-PED [see CLINICAL PHARMACOLOGY] .

Drug-Laboratory Test Interactions

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.

Warnings for Lupron Depot-Ped

Included as part of the PRECAUTIONS section.

Precautions for Lupron Depot-Ped

Initial Rise Of Gonadotropins And Sex Steroid Levels

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].

Psychiatric Events

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].

Convulsions

Postmarketing reports of convulsions have been observed in patients receiving GnRH agonists, including leuprolide acetate. 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.

Monitoring And Laboratory Tests

Response to LUPRON DEPOT-PED 7.5 mg, 11.25 mg, or 15 mg for 1-month administration should be monitored with a GnRHa stimulation test, basal LH or serum concentration of sex steroid levels beginning 1-2 months following initiation of therapy, with changing doses, or potentially during therapy in order to confirm maintenance of efficacy. Measurement of bone age for advancement should be done every 6-12 months.

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 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 and ADVERSE REACTIONS].

Patient Counseling Information

Information For Caregivers

Prior to starting therapy with LUPRON DEPOT-PED, patients should be informed that:

• All formulations are contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking the drug, the patient should be informed of the potential risk to the fetus.
• Continuous therapy is important and that adherence to the recommended drug administration schedule (monthly for LUPRON DEPOT-PED for 1-month administration and every three months for LUPRON DEPOT-PED for 3-month administration) must be accepted if therapy is to be successful. If the injection schedule is not followed, pubertal development may begin again.
• During the first weeks of treatment, signs of puberty, e.g., vaginal bleeding, may occur. This is a common initial effect of the drug. If these symptoms continue beyond the second month of treatment, the physician should be notified.
• Inform caregivers that symptoms of emotional lability, such as crying, irritability, impatience, anger, and aggression, have been observed in patients receiving GnRH agonists, including LUPRON DEPOT-PED. Alert caregivers to the possibility of development or worsening of psychiatric symptoms, including depression, during treatment with LUPRON DEPOT-PED [see WARNINGS AND PRECAUTIONS, ADVERSE REACTIONS].
• Inform 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].
• The most common side effects related to treatment with LUPRON DEPOT-PED for 1-month or 3-month administration in clinical studies are: pain, acne/seborrhea, injection site reactions including pain, swelling and abscess, rash including erythema multiforme, vaginitis/bleeding/discharge, increased weight, headache, and altered mood.
• After injection, some pain and irritation is expected; however if more severe symptoms occur, the physician should be contacted. Any unusual signs or symptoms should be reported to the physician.
• The caregivers should notify the physician if new or worsened symptoms develop after beginning treatment.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

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.

Use In Specific Populations

Pregnancy

Pregnancy Category X

LUPRON DEPOT-PED is contraindicated in women who are or may become pregnant while receiving the drug [see CONTRAINDICATIONS].

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.

Nursing Mothers

It is not known whether leuprolide acetate is excreted in human milk. LUPRON DEPOT-PED should not be used by nursing mothers.

Pediatric Use

Safety and effectiveness in pediatric patients below the age of 2 years have not been established. The use of LUPRON DEPOT-PED in children under 2 years is not recommended.

Geriatric Use

LUPRON DEPOT 1-month 7.5 mg and 4-month 30 mg are indicated for the palliative treatment of advanced prostate cancer. For LUPRON DEPOT-PED 11.25 mg or 15 mg for 1-month administration and LUPRON DEPOT-PED 11.25 mg or 30 mg for 3-month administration, no clinical information is available for persons aged 65 and over.

Overdose Information for Lupron Depot-Ped

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.

Contraindications for Lupron Depot-Ped

• Hypersensitivity to GnRH, GnRH agonists or any of the excipients in LUPRON DEPOTPED. Anaphylactic reactions to synthetic GnRH or GnRH agonists have been reported [see ADVERSE REACTIONS].
• Pregnancy: LUPRON DEPOT-PED may cause fetal harm [see Use In Specific Populations].

Clinical Pharmacology for Lupron Depot-Ped

Mechanism Of Action

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.

Pharmacodynamics

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.

Pharmacokinetics

Absorption

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.

Distribution

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%.

Elimination

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.

Specific Populations

The pharmacokinetics of LUPRON DEPOT-PED has not been determined in patients with hepatic or renal impairment.

Drug-Drug Interactions

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.

Clinical Studies

LUPRON DEPOT-PED For 1-Month Administration

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 4. 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 4. 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.

LUPRON DEPOT-PED For 3-Month Administration

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 5.

Table 5. 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.

LUPRON DEPOT-PED For 6-Month Administration

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 6). Of the patients previously treated with other GnRHa formulations 94.4% remained suppressed at Week 24.

Table 6. 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.

Patient Information for Lupron Depot-Ped

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.

• During the first 2 to 4 weeks of treatment, LUPRON DEPOT-PED can cause an increase in some hormones. During this time you may notice more signs of puberty in your child, including vaginal bleeding. Call your doctor if these signs continue after the second month of treatment with LUPRON DEPOT-PED.
• Some people taking gonadotropin releasing hormone (GnRH) agonists like LUPRON DEPOTPED have had new or worsened mental (psychiatric) problems. Mental (psychiatric) problems may include emotional symptoms such as:
  • crying
  • irritability
  • restlessness (impatience)
  • anger
  • acting aggressive
• Some people taking GnRH agonists like LUPRON DEPOT-PED have had seizures. The risk ofseizures may be higher in people who:
  • have a history of seizures
  • have a history of epilepsy
  • have a history of brain or brain vessel (cerebrovascular) problems or tumors
  • are taking a medicine that has been connected to seizures such as bupropion or selective serotonin reuptake inhibitors (SSRIs)
• increased pressure in the fluid around the brain can happen in children taking gonadotropin releasing hormone (GnRH) agonist medicines including LUPRON DEPOT-PED. Call your child’s doctor right away if your child has any of the following symptoms during treatment with LUPRON DEPOT-PED:
  • headache
  • eye problems, including blurred vision, double vision and decreased eyesight
  • eye pain
  • ringing in the ears
  • dizziness
  • nausea

What is LUPRON DEPOT-PED?

• LUPRON DEPOT-PED is an injectable prescription gonadotropin releasing hormone (GnRH) medicine used for the treatment of children with central precocious puberty (CPP).
• It is not known if LUPRON DEPOT-PED is safe and effective in children less than 1 year old.

LUPRON DEPOT-PED should not be taken if your child is:

• allergic to GnRH, GnRH agonist medicines, or any ingredients in LUPRON DEPOT-PED. See the end of this Medication Guide for a complete list of ingredients in LUPRON DEPOT-PED.
• pregnant or becomes pregnant. LUPRON DEPOT-PED can cause birth defects or loss of the baby. If your child becomes pregnant call your doctor.

Before your child receives LUPRON DEPOT-PED, tell their doctor about all of your child’s medical conditions including if they:

• have a history of mental (psychiatric) problems.
• have a history of seizures.
• have a history of epilepsy.
• have a history of brain or brain vessel (cerebrovascular) problems or tumors.
• are taking a medicine that has been connected to seizures such as bupropion or selective serotonin reuptake inhibitors (SSRIs).
• are breastfeeding or plans to breastfeed. It is not known if LUPRON DEPOT-PED passes into the breast milk.

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?

• Your child’s doctor should do tests to make sure your child has CPP before treating them with LUPRON DEPOT-PED.
• LUPRON DEPOT-PED is given as a single-dose injection into your child’s muscle each month, every 3 months, or every 6 months by a doctor or trained nurse. Your doctor will decide how often your child will receive the injection.
• Keep all scheduled visits to the doctor. If a scheduled dose is missed, your child may start having signs of puberty again. The doctor will do regular exams and blood tests to check for signs of puberty.

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:

• injection site reactions such as pain, swelling, and abscess
• weight gain
• pain throughout body
• headache
• acne or red, itchy, rash, and white scales (seborrhea)
• serious skin rash (erythema multiforme)
• mood changes
• swelling of vagina (vaginitis), vaginal bleeding, and vaginal discharge

The most common side effects of LUPRON DEPOT-PED received every 3 months include:

• injection site reactions such as pain and swelling
• weight gain
• headache
• mood changes

The most common side effects of LUPRON DEPOT-PED received every 6 months include:

• injection site reactions such as pain, swelling, and abscess
• headache
• mood changes
• upper stomach pain
• diarrhea
• bleeding
• nausea and vomiting
• fever
• itching
• pain in extremity
• rash
• back pain
• ligament sprain
• weight gain
• fracture
• breast tenderness
• difficulty sleeping
• chest pain
• excessive sweating

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?

• Store LUPRON DEPOT-PED INJECTION at room temperature between 68°F to 77°F (20°C to 25°C).
• Keep LUPRON DEPOT-PED INJECTION and all medicines out of the reach of children.

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.