Lupron Depot-PED

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, including headache, papilledema, blurred vision, diplopia, loss of vision, pain behind the eye or pain with eye movement, tinnitus, dizziness, and nausea.

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 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 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of LUPRON DEPOT-PED or GnRH agonists 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 disorders and administration site conditions : chest pain, weight increase, decreased appetite, fatigue, injection site reactions including induration, abscess, and necrosis. Laboratory Abnormalities : decreased WBC. Metaboli c : 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 : flushing, hyperhidrosis, erythema multiforme, bullous dermatitis, dermatitis exfoliative, drug reaction with eosinophilia and systemic symptoms, Stevens-Johnson syndrome and toxic epidermal necrolysis, and acute generalized exanthematous pustulosis. Vascular Disorders : hypertension, hypotension.

<table><col width="480"/><col width="146"/><tbody><tr><td styleCode="Toprule Lrule Rrule " colspan="2" valign="bottom" align="center"><content styleCode="bold">Table 2. Adverse Reactions Occurring in &#x2265;2% </content><content styleCode="bold">in </content><content styleCode="bold">Pediatric Patients </content><content styleCode="bold">with CPP </content><content styleCode="bold">Receiving</content> <content styleCode="bold">LUPRON DEPOT-PED 1-month</content></td></tr><tr><td styleCode="Toprule Lrule Rrule "> </td><td styleCode="Toprule Lrule Rrule " align="center"><content styleCode="bold">% </content><content styleCode="bold">of Patients</content><content styleCode="bold"> (N = 421)</content></td></tr><tr><td styleCode="Toprule Lrule Rrule "> Injection Site Reactions Including Abscess*</td><td styleCode="Toprule Lrule Rrule " align="center">9</td></tr><tr><td styleCode="Toprule Lrule Rrule "> Emotional Lability </td><td styleCode="Toprule Lrule Rrule " align="center">5 </td></tr><tr><td styleCode="Toprule Lrule Rrule "> Headache</td><td styleCode="Toprule Lrule Rrule " align="center">3</td></tr><tr><td styleCode="Toprule Lrule Rrule "> General Pain</td><td styleCode="Toprule Lrule Rrule " align="center">3</td></tr><tr><td styleCode="Toprule Lrule Rrule "> Acne/Seborrhea</td><td styleCode="Toprule Lrule Rrule " align="center">3</td></tr><tr><td styleCode="Toprule Lrule Rrule "> Rash Including Erythema Multiforme</td><td styleCode="Toprule Lrule Rrule " align="center">3</td></tr><tr><td styleCode="Toprule Lrule Rrule "> Vaginitis/Vaginal Bleeding/Vaginal Discharge</td><td styleCode="Toprule Lrule Rrule " align="center">3</td></tr><tr><td styleCode="Toprule Lrule Rrule "> Vasodilation</td><td styleCode="Toprule Lrule Rrule " align="center">2</td></tr><tr><td styleCode="Toprule Lrule Rrule " colspan="2">* Most events were mild or moderate in severity.</td></tr></tbody></table>

<table><col width="241"/><col width="156"/><col width="114"/><col width="115"/><tbody><tr><td styleCode="Toprule Lrule Rrule " colspan="4" valign="bottom" align="center"><content styleCode="bold">Table 3. Adverse Reactions Occurring in &#x2265;2</content><content styleCode="bold">% in</content><content styleCode="bold"> Pediatric Patients </content><content styleCode="bold">with CPP</content><content styleCode="bold"> Receiving LUPRON DEPOT-PED for 3-month administration.</content></td></tr><tr><td styleCode="Toprule Lrule Rrule "> </td><td styleCode="Toprule Lrule Rrule " valign="bottom" align="center"><content styleCode="bold">% </content> <content styleCode="bold">11.25 mg </content> <content styleCode="bold">every 3 Months</content><content styleCode="bold"> N=42</content></td><td styleCode="Toprule Lrule Rrule " valign="bottom" align="center"><content styleCode="bold">% </content> <content styleCode="bold">30 mg </content> <content styleCode="bold">every 3 Months</content><content styleCode="bold"> N=42</content></td><td styleCode="Toprule Lrule Rrule " valign="bottom" align="center"><content styleCode="bold">%</content> <content styleCode="bold"> </content><content styleCode="bold">Overall </content><content styleCode="bold"> N = 84</content></td></tr><tr><td styleCode="Toprule Lrule Rrule ">Injection site pain</td><td styleCode="Toprule Lrule Rrule " align="center">19</td><td styleCode="Toprule Lrule Rrule " align="center">21</td><td styleCode="Toprule Lrule Rrule " align="center">20</td></tr><tr><td styleCode="Toprule Lrule Rrule ">Weight increased</td><td styleCode="Toprule Lrule Rrule " align="center">7</td><td styleCode="Toprule Lrule Rrule " align="center">7</td><td styleCode="Toprule Lrule Rrule " align="center">7</td></tr><tr><td styleCode="Toprule Lrule Rrule ">Headache</td><td styleCode="Toprule Lrule Rrule " align="center">2</td><td styleCode="Toprule Lrule Rrule " align="center">7</td><td styleCode="Toprule Lrule Rrule " align="center">5</td></tr><tr><td styleCode="Toprule Lrule Rrule ">Mood altered</td><td styleCode="Toprule Lrule Rrule " align="center">5</td><td styleCode="Toprule Lrule Rrule " align="center">5</td><td styleCode="Toprule Lrule Rrule " align="center">5</td></tr><tr><td styleCode="Toprule Lrule Rrule ">Injection site swelling</td><td styleCode="Toprule Lrule Rrule " align="center">2</td><td styleCode="Toprule Lrule Rrule " align="center">2</td><td styleCode="Toprule Lrule Rrule " align="center">2</td></tr></tbody></table>

<table><col width="267"/><col width="279"/><tbody><tr><td styleCode="Toprule Lrule Rrule " colspan="2" valign="bottom" align="center"><content styleCode="bold">Table 4. Adverse Reactions Occurring in &#x2265;4% in Pediatric Patients with CPP</content><content styleCode="bold"> Receiving LUPRON DEPOT-PED for 6-month administration.</content></td></tr><tr><td styleCode="Toprule Lrule Rrule "/><td styleCode="Toprule Lrule Rrule " align="center"><content styleCode="bold">Total</content> <content styleCode="bold">(N = 45)</content> <content styleCode="bold">n (%)</content></td></tr><tr><td styleCode="Toprule Lrule Rrule ">Injection Site Reactions ^a </td><td styleCode="Toprule Lrule Rrule " valign="bottom" align="center">35 (78%)</td></tr><tr><td styleCode="Toprule Lrule Rrule " valign="bottom">Headache ^b</td><td styleCode="Toprule Lrule Rrule " valign="bottom" align="center">15 (33%)</td></tr><tr><td styleCode="Toprule Lrule Rrule " valign="bottom">Psychiatric Events ^c</td><td styleCode="Toprule Lrule Rrule " valign="bottom" align="center">10 (22%)</td></tr><tr><td styleCode="Toprule Lrule Rrule " valign="bottom">Abdominal Pain ^d</td><td styleCode="Toprule Lrule Rrule " valign="bottom" align="center">8 (18%)</td></tr><tr><td styleCode="Toprule Lrule Rrule " valign="bottom">Diarrhea ^e </td><td styleCode="Toprule Lrule Rrule " valign="bottom" align="center">7 (16%)</td></tr><tr><td styleCode="Toprule Lrule Rrule " valign="bottom">Hemorrhage ^f</td><td styleCode="Toprule Lrule Rrule " valign="bottom" align="center">6 (13%)</td></tr><tr><td styleCode="Toprule Lrule Rrule " valign="bottom">Nausea and Vomiting </td><td styleCode="Toprule Lrule Rrule " valign="bottom" align="center">6 (13%)</td></tr><tr><td styleCode="Toprule Lrule Rrule " valign="bottom">Pyrexia </td><td styleCode="Toprule Lrule Rrule " valign="bottom" align="center">6 (13%)</td></tr><tr><td styleCode="Toprule Lrule Rrule " valign="bottom">Pruritus ^g</td><td styleCode="Toprule Lrule Rrule " valign="bottom" align="center">5 (11%)</td></tr><tr><td styleCode="Toprule Lrule Rrule ">Pain in extremity</td><td styleCode="Toprule Lrule Rrule " valign="bottom" align="center">4 (9%)</td></tr><tr><td styleCode="Toprule Lrule Rrule " valign="bottom">Rash</td><td styleCode="Toprule Lrule Rrule " valign="bottom" align="center">3 (7%)</td></tr><tr><td styleCode="Toprule Lrule Rrule " valign="bottom">Back Pain </td><td styleCode="Toprule Lrule Rrule " valign="bottom" align="center">3 (7%)</td></tr><tr><td styleCode="Toprule Lrule Rrule ">Ligament sprain</td><td styleCode="Toprule Lrule Rrule " valign="bottom" align="center">3 (7%)</td></tr><tr><td styleCode="Toprule Lrule Rrule ">Weight increased</td><td styleCode="Toprule Lrule Rrule " valign="bottom" align="center">3 (7%)</td></tr><tr><td styleCode="Toprule Lrule Rrule " valign="bottom">Fracture ^h</td><td styleCode="Toprule Lrule Rrule " valign="bottom" align="center">2 (4%)</td></tr><tr><td styleCode="Toprule Lrule Rrule " valign="bottom">Breast tenderness ⁱ</td><td styleCode="Toprule Lrule Rrule " valign="bottom" align="center">2 (4%)</td></tr><tr><td styleCode="Toprule Lrule Rrule " valign="bottom">Insomnia ^j</td><td styleCode="Toprule Lrule Rrule " valign="bottom" align="center">2 (4%)</td></tr><tr><td styleCode="Toprule Lrule Rrule ">Chest pain</td><td styleCode="Toprule Lrule Rrule " valign="bottom" align="center">2 (4%)</td></tr><tr><td styleCode="Toprule Lrule Rrule ">Hyperhidrosis</td><td styleCode="Toprule Lrule Rrule " valign="bottom" align="center">2 (4%)</td></tr><tr><td styleCode="Toprule " colspan="2">^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 ⁱBreast tenderness includes the preferred terms breast pain and breast tenderness ^j Insomnia includes the preferred terms initial insomnia and insomnia </td></tr></tbody></table>