Lupron Depot-PED

1 INDICATIONS AND USAGE LUPRON DEPOT-PED is indicated for the treatment of pediatric patients with central precocious puberty (CPP). LUPRON DEPOT-PED is a gonadotropin releasing hormone (GnRH) agonist indicated for the treatment of pediatric patients with central precocious puberty. ( 1 )

2 DOSAGE AND ADMINISTRATION Must be administered by a healthcare professional. ( 2.1 ) Select appropriate LUPRON DEPOT-PED syringe for the intended dosing frequency and administer intramuscularly. ( 2.1 ) For 1-month administration: Starting dose is 7.5, 11.25, or 15 mg based on the patient’s weight. ( 2.2 ) For 3-month administration: Doses are either 11.25 or 30 mg. ( 2.3 ) For 6-month administration: Dose is 45 mg. ( 2.4 ) Monitor hormonal and clinical parameters during treatment to ensure adequate suppression. ( 2.2 , 2.3 , 2.4 ) Rotate injection site periodically. ( 2.5 ) See Full Prescribing Information for administration and reconstitution instructions. ( 2.5 , 2.6 ) Figure 1 Figure 2 blue line syringe shake Figure 5 lupro loc click one 2.1 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. 2.2 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. Dos age Recommendations Based on Body Weight for LUPRON DEPOT-PED for 1- M onth A dministration Body Weight Once Monthly Recommended Dos ag e 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. 2.3 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. 2.4 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. 2.5 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. 2.6 Reconstitution Instr…

5 WARNINGS AND PRECAUTIONS Initial Rise of Gonadotropins and Sex Steroid Levels: During the early phase of therapy, gonadotropins and sex steroids may rise above baseline because of the initial stimulatory effect of the drug. 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. ( 5.1 ) Psychiatric events : Have been reported in patients taking GnRH agonists. Events include emotional lability, such as crying, irritability, impatience, anger, and aggression. Monitor for development or worsening of psychiatric symptoms. ( 5.2 ) Convulsions : Have been observed in patients with or without a history of seizures, epilepsy, cerebrovascular disorders, central nervous system anomalies or tumors, and in patients on concomitant medications that have been associated with convulsions. ( 5.3 ) Severe Cutaneous Adverse Reactions (SCARs) : Have been reported in patients receiving GnRH agonists, including leuprolide products. Interrupt LUPRON DEPOT-PED if signs or symptoms of SCARs develop. Permanently discontinue LUPRON DEPOT-PED if a SCAR is confirmed. ( 5.4 ) Pseudotumor C erebri (I diopathic I ntracranial H ypertension ): Have been reported in pediatric patients receiving GnRH agonists, including LUPRON DEPOT-PED. Monitor patients for headache, papilledema, and blurred vision. ( 5.5 ) 5.1 Initial Rise of Gonadotropins and Sex Steroid Levels 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 ( 12.2 )] . 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 ( 6 )] . 5.2 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 ( 6.2 ) ] . 5.3 Convulsions 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 ( 6.2 ) ] . 5.4 Severe Cutaneous Adverse Reactions Severe cutaneous adverse reactions (SCARs) have been reported in patients receiving GnRH agonists, including leuprolide products [see Adverse Reactions ( 6.2 )] . These reactions include Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP), including cases with visceral involvement and/or requiring skin grafts. Monitor patients for signs and symptoms of SCARs such as fever, flu-like symptoms, mucosal lesions, progressive skin rash or lymphadenopathy. Advise patients and caregivers of the signs and symptoms of SCARs. If a SCAR is suspected, interrupt LUPRON DEPOT-PED. Consult a healthcare provider with expertise in the diagnosis and management of SCARs. If a diagnosis of SCAR is confirmed permanently discontinue LUPRON DEPOT-PED. 5.5 Pseudotumor Cerebri (Idiopathic Intracranial Hypertension) 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, includin…

4 CONTRAINDICATIONS Hypersensitivity to GnRH, GnRH agonists or any of the excipients in LUPRON DEPOT-PED. Anaphylactic reactions to synthetic GnRH or GnRH agonists have been reported [see Adverse Reactions ( 6.2 )] . Pregnancy: LUPRON DEPOT-PED may cause fetal harm [see Use in Specific Populations ( 8.1 )] . Hypersensitivity reactions to GnRH, GnRH agonists or any of the excipients in LUPRON DEPOT-PED ( 4 ) Pregnancy ( 4 , 8.1 )

7 DRUG INTERACTIONS 7.1 Drug Interactions No pharmacokinetic-based drug-drug interaction studies have been conducted with LUPRON DEPOT-PED [see C linical P harmacology ( 12.3 ) ] . 7.2 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. 7.1 Drug Interactions No pharmacokinetic-based drug-drug interaction studies have been conducted with LUPRON DEPOT-PED [see C linical P harmacology ( 12.3 ) ] .

8.1 Pregnancy Risk Summary LUPRON DEPOT-PED is contraindicated in pregnancy [see Contraindications ( 4 ) ]. 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 ( 12.1 ) ]. 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. Data 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.

6 ADVERSE REACTIONS 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 ( 5.1 ) ] . Psychiatric Events [see Warnings and Precautions ( 5.2 ) ] . Convulsions [see Warnings and Precautions ( 5.3 ) ] . Severe Cutaneous Adverse Reactions (SCARs) [see Warnings and Precautions ( 5.4 )] Pseudotumor Cerebri (Idiopathic Intracranial Hypertension) [see Warnings and Precautions ( 5.5 ) ] Adverse events related to suppression of endogenous sex steroid secretion and injection site reactions including abscess may occur with LUPRON DEPOT-PED 7.5 mg, 11.25 mg, or 15 mg for 1-month administration. ( 6.1 , 6.2 ) In the clinical studies for LUPRON DEPOT-PED 7.5 mg, 11.25 mg, or 15mg for 1-month administration the most common (≥2%) adverse reactions were: emotional lability, headache, general pain, acne/seborrhea, rash including erythema multiforme and vaginitis/vaginal bleeding/vaginal discharge. ( 6.1 ) In the clinical studies for LUPRON DEPOT-PED 11.25 mg or 30 mg for 3-month administration the most common ( > 2%) adverse reactions were: injection site pain, weight increased, headache, mood altered, and injection site swelling. ( 6.1 ) In the clinical study for LUPRON DEPOT-PED 45 mg for 6-month administration the most common (≥4%) adverse reactions were: injection site reactions, headache, psychiatric events, abdominal pain, diarrhea, hemorrhage, nausea and vomiting, pyrexia, pruritus, pain in extremity, rash, back pain, ligament sprain, weight increased, fracture, breast tenderness, insomnia, chest pain, and hyperhidrosis. ( 6.1 ) 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 6.1 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 Patients (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 an…