Skytrofa

5 WARNINGS AND PRECAUTIONS Severe Hypersensitivity: Hypersensitivity reactions, including anaphylaxis and angioedema have occurred. In the event of an allergic reaction, seek prompt medical attention ( 5.2 ). Increased Risk of Neoplasms: Monitor patients with preexisting tumors for progressions or recurrence. Increased risk of a second neoplasm in childhood cancer survivors treated with somatropin – in particular meningiomas in patients treated with radiation to the head for their first neoplasm ( 5.3 ). Glucose Intolerance and Diabetes Mellitus: May be unmasked. Periodically monitor glucose levels in all patients. Doses of concurrent antihyperglycemic drugs in diabetics may require adjustment ( 5.4 ). Intracranial Hypertension: Exclude preexisting papilledema. May develop and is usually reversible after discontinuation or dose reduction ( 5.5 ). Fluid Retention (i.e., edema, arthralgia, carpal tunnel syndrome): May occur. Reduce dose as necessary ( 5.6 ). Hypoadrenalism: Monitor patients for reduced serum cortisol levels and/or need for glucocorticoid dose increases in those with known hypoadrenalism ( 5.7 ). Hypothyroidism: May first become evident or worsen ( 5.8 ). Slipped Capital Femoral Epiphysis in Pediatric Patients: May develop. Evaluate children with the onset of a limp or persistent hip/knee pain ( 5.9 ). Progression of Preexisting Scoliosis: May develop ( 5.10 ). Pancreatitis: Consider pancreatitis in patients with persistent severe abdominal pain ( 5.11 ). 5.1 Increased Mortality in Patients With Acute Critical Illness Increased mortality in patients with acute critical illness due to complications following open heart surgery, abdominal surgery or multiple accidental trauma, or those with acute respiratory failure has been reported after treatment with pharmacologic doses of somatropin [see Contraindications (4) ]. The safety of continuing SKYTROFA treatment in patients receiving replacement doses for the approved indication who concurrently develop these illnesses has not been established. 5.2 Severe Hypersensitivity Severe systemic hypersensitivity reactions, including anaphylactic reactions and angioedema have been reported with postmarketing use of somatropin products, including SKYTROFA. Inform patients and/or caregivers that such reactions are possible, and that prompt medical attention should be sought if an allergic reaction occurs. SKYTROFA is contraindicated in patients with known hypersensitivity to somatropin or any of the excipients in SKYTROFA. 5.3 Increased Risk of Neoplasms Active Malignancy There is an increased risk of malignancy progression with somatropin treatment in patients with active malignancy [see Contraindications (4) ]. Any preexisting malignancy should be inactive, and its treatment should be completed prior to instituting therapy with SKYTROFA. Discontinue SKYTROFA if there is evidence of recurrent malignancy. Risk of Second Neoplasm in Pediatric Patients In childhood cancer survivors who were treated with radiation to the brain/head for their first neoplasm and who developed subsequent growth hormone deficiency (GHD) and were treated with somatropin, an increased risk of a second neoplasm has been reported. Intracranial tumors, in particular meningiomas, were the most common of these second neoplasms. Monitor all patients with a history of GHD secondary to an intracranial neoplasm while on somatropin therapy for progression or recurrence of the tumor. New Malignancy During Treatment Because children with certain rare genetic causes of short stature have an increased risk of developing malignancies, thoroughly consider the risks and benefits of starting somatropin in these patients. If treatment with somatropin is initiated, carefully monitor these patients for development of neoplasms. Monitor patients on SKYTROFA therapy carefully for increased growth or potential malignant changes of preexisting nevi. Advise patients/caregivers to report marked changes in behavior, onset of headaches, vision disturbances and/or changes in skin pigmentation or changes in the appearance of preexisting nevi. 5.4 Glucose Intolerance and Diabetes Mellitus Treatment with somatropin may decrease insulin sensitivity, particularly at higher doses. Previously undiagnosed impaired glucose tolerance and overt type 2 diabetes mellitus may be unmasked. Monitor glucose levels in all patients receiving SKYTROFA, especially in those with risk factors for type 2 diabetes mellitus, such as obesity or a family history of type 2 diabetes mellitus. When initiating SKYTROFA, monitor closely patients with preexisting type 1 or type 2 diabetes mellitus or impaired glucose tolerance and adjust the doses of antihyperglycemic drugs as needed. 5.5 Intracranial Hypertension Intracranial hypertension (IH) with papilledema, visual changes, headache, nausea, and/or vomiting has been reported in a small number of patients treated with somatropin. Symptoms usually occurred within 8 weeks after the initiation of somatropin. In all reported cases, IH-associated signs and symptoms resolved rapidly after cessation of therapy or a reduction of the somatropin dose. To exclude preexisting papilledema, perform fundoscopic examination before initiating treatment with SKYTROFA, and reassess periodically thereafter. If papilledema is observed by fundoscopy, stop somatropin treatment. If somatropin-induced IH is confirmed, restart treatment with SKYTROFA at a lower dose after IH-associated signs and symptoms have resolved. 5.6 Fluid Retention Fluid retention during somatropin therapy may occur. Clinical manifestations of fluid retention (e.g., edema, arthralgia, myalgia, nerve compression syndromes, including carpal tunnel syndrome/paresthesia) are usually transient and dose dependent. 5.7 Hypoadrenalism Patients receiving somatropin therapy who have or are at risk for pituitary hormone deficiency(s) may be at risk for reduced serum cortisol levels and/or unmasking of central (secondary) hypoadrenalism. In addition, patients treated with glucocorticoid replacement for previously diagnosed hypoadrenalism may require an increase in their maintenance or stress doses following initiation of SKYTROFA therapy. Monitor patients for reduced serum cortisol levels and/or need for glucocorticoid dose increases in patients with known hypoadrenalism [see Drug Interactions (7) ] . 5.8 Hypothyroidism Undiagnosed or untreated hypothyroidism may prevent optimal response to SKYTROFA. In patients with GHD, central (secondary) hypothyroidism may first become evident or worsen during SKYTROFA treatment. Therefore, perform periodic thyroid function tests in patients and initiate or appropriately adjust thyroid hormone replacement therapy when indicated. 5.9 Slipped Capital Femoral Epiphysis in Pediatric Patients Slipped capital femoral epiphysis may occur more frequently in patients undergoing rapid growth. Slipped capital femoral epiphysis may lead to osteonecrosis. Cases of slipped capital femoral epiphysis with or without osteonecrosis have been reported in pediatric patients with short stature receiving somatropin. Evaluate pediatric patients receiving SKYTROFA with the onset of a limp or complaints of persistent hip or knee pain for slipped capital femoral epiphysis and osteonecrosis and manage accordingly. 5.10 Progression of Preexisting Scoliosis in Pediatric Patients Somatropin increases growth rate in pediatric patients, and progression of existing scoliosis can occur in patients who experience rapid growth. Somatropin has not been shown to increase the occurrence of scoliosis. Monitor patients with a history of scoliosis for disease progression. 5.11 Pancreatitis Pancreatitis has been reported in pediatric patients receiving somatropin. The risk may be greater in pediatric patients than adults. Consider pancreatitis in patients who develop persistent severe abdominal pain. 5.12 Lipoatrophy When SKYTROFA is administered subcutaneously at the same site over a long period of time, lipoatrophy may result. Rotate injection sites when administering SKYTROFA to reduce this risk [see Dosage and Administration (2.7) ] . 5.13 Sudden Death in Pediatric Patients With Prader-Willi Syndrome There have been reports of fatalities after initiating therapy with somatropin in pediatric patients with Prader-Willi syndrome who had one or more of the following risk factors: severe obesity, history of upper airway obstruction or sleep apnea, or unidentified respiratory infection. Male patients with one or more of these factors may be at greater risk than females. SKYTROFA is not indicated for the treatment of pediatric patients who have growth failure due to genetically confirmed Prader-Willi syndrome. 5.14 Laboratory Tests Serum levels of alkaline phosphatase and phosphate may increase after SKYTROFA therapy. Serum levels of parathyroid hormone may increase after somatropin treatment. If a patient is found to have abnormal laboratory tests, monitor as appropriate.

6 ADVERSE REACTIONS The following important adverse reactions are described elsewhere in the labeling: Increased mortality in patients with acute critical illness [see Warnings and Precautions (5.1) ] Severe hypersensitivity [see Warnings and Precautions (5.2) ] Increased risk of neoplasms [see Warnings and Precautions (5.3) ] Glucose intolerance and diabetes mellitus [see Warnings and Precautions (5.4) ] Intracranial hypertension [see Warnings and Precautions (5.5) ] Fluid retention [see Warnings and Precautions (5.6) ] Hypoadrenalism [see Warnings and Precautions (5.7) ] Hypothyroidism [see Warnings and Precautions (5.8) ] Slipped capital femoral epiphysis in pediatric patients [see Warnings and Precautions (5.9) ] Progression of preexisting scoliosis in pediatric patients [see Warnings and Precautions (5.10) ] Pancreatitis [see Warnings and Precautions (5.11) ] Lipoatrophy [see Warnings and Precautions (5.12) ] Sudden death in pediatric patients with Prader-Willi syndrome [see Warnings and Precautions (5.13) ] Pediatric Patients: Most common adverse reactions (≥ 5%): viral infection, pyrexia, cough, nausea and vomiting, hemorrhage, diarrhea, abdominal pain, and arthralgia and arthritis ( 6.1 ). Adults: Most common adverse reaction (≥ 5%): edema peripheral ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Ascendis Pharma Endocrinology, Inc., at 1-844-442-7236 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in clinical practice. Pediatric Patients with Growth Hormone Deficiency SKYTROFA was studied in a 52-week, open-label, active-controlled trial in 161 treatment-naïve, prepubertal pediatric patients with growth hormone deficiency (GHD) [see Clinical Studies (14.1) ] . The subjects ranged in age from 3.2 to 13.1 years with a mean of 8.5 years. One hundred thirty-two (82%) of the subjects were male and 29 (18%) were female. One subject was Asian, 3 were Black or African American, 152 were Caucasian, and 5 were categorized as "other." Table 2 shows common adverse reactions that occurred in ≥ 5% of patients treated with SKYTROFA in this trial. Table 2: Adverse Reactions Occurring in ≥ 5% SKYTROFA-Treated Pediatric Patients and More Frequently Than in Daily Somatropin-Treated Pediatric Patients (52 Weeks of Treatment) Adverse reactions Daily Somatropin (N = 56) n (%) SKYTROFA (N = 105) n (%) Adverse reactions that are medically related were grouped to a single preferred term. Infection, viral 6 (11%) 16 (15%) Pyrexia 5 (9%) 16 (15%) Cough 4 (7%) 11 (11%) Nausea and vomiting 4 (7%) 11 (11%) Hemorrhage Hemorrhage in the SKYTROFA treatment group included epistaxis (3), contusion (2), petechiae (1) and eye hemorrhage (1). 1 (2%) 7 (7%) Diarrhea 3 (5%) 6 (6%) Abdominal pain 2 (4%) 6 (6%) Arthralgia and arthritis Arthralgia and arthritis in the SKYTROFA treatment group included arthralgia (5) and reactive arthritis (1). 1 (2%) 6 (6%) Laboratory Tests More SKYTROFA-treated patients shifted from normal baseline levels to elevated phosphate and alkaline phosphatase levels at the end of the trial compared to the daily somatropin group (44.2% vs. 30.2% and 19.2% vs. 9.4%, respectively); these laboratory changes occurred intermittently [see Warnings and Precautions (5.14) ] . Adults with Growth Hormone Deficiency SKYTROFA was studied in a 38-week parallel-arm, placebo-controlled (double-blind) and active-controlled (open label) trial in 259 adults with growth hormone deficiency (GHD) [see Clinical Studies (14.2) ] . The mean (range) age at enrollment was 43 (23 to 81) years old, with 119 (46%) females (55 on oral estrogen) and 140 (54%) males. One subject was American Indian or Alaska Native, one was Black or African American, 28 were Asian, and 218 were Caucasian. Table 3 shows adverse reactions that occurred in ≥ 5% of adults treated with SKYTROFA and more frequently than in placebo-treated adults in this trial. Table 3: Adverse Reactions Occurring in ≥ 5% of SKYTROFA-Treated Adults and More Frequently Than in Placebo-treated Adults (38 Weeks of Treatment) Adverse reactions Placebo (N = 84) n (%) SKYTROFA (N = 89) n (%) Adverse reactions that are medically related were grouped to a single preferred term. Edema Edema in the SKYTROFA treatment group included edema peripheral (6) and peripheral swelling (1). 1 (1%) 7 (8%) Central (secondary) hypothyroidism Central (secondary) hypothyroidism in the SKYTROFA treatment group included thyroxine free decreased (3), central hypothyroidism (2), thyroxine decreased (1), blood thyroid stimulating hormone decreased (1), tri-iodothyronine free decreased (1). Preexisting central hypothyroidism in 5 of 6 SKYTROFA-treated patients. 1 (1%) 6 (7%) Laboratory Tests More SKYTROFA-treated patients shifted from normal or low baseline levels to elevated alkaline phosphatase levels at the end of the trial compared to the placebo group (14% vs. 6%); these laboratory changes were noted with increased frequency as the trial progressed [see Warnings and Precautions (5.14) ] . 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of somatropin products or SKYTROFA. 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. Severe systemic hypersensitivity reactions, including anaphylactic reactions and angioedema Musculoskeletal and connective tissue disorders – osteonecrosis in pediatric patients

<table width="85%"><caption>Table 2: Adverse Reactions Occurring in &#x2265; 5% SKYTROFA-Treated Pediatric Patients and More Frequently Than in Daily Somatropin-Treated Pediatric Patients (52 Weeks of Treatment)</caption><col width="40%" align="left" valign="top"/><col width="30%" align="center" valign="top"/><col width="30%" align="center" valign="top"/><thead><tr><th styleCode="Lrule Rrule" valign="bottom">Adverse reactions</th><th styleCode="Rrule" valign="bottom">Daily Somatropin (N = 56) n (%)</th><th styleCode="Rrule">SKYTROFA (N = 105) n (%)</th></tr></thead><tfoot><tr><td align="left" colspan="3">Adverse reactions that are medically related were grouped to a single preferred term.</td></tr></tfoot><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Infection, viral</td><td styleCode="Rrule">6 (11%)</td><td styleCode="Rrule">16 (15%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Pyrexia</td><td styleCode="Rrule">5 (9%)</td><td styleCode="Rrule">16 (15%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Cough</td><td styleCode="Rrule">4 (7%)</td><td styleCode="Rrule">11 (11%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Nausea and vomiting</td><td styleCode="Rrule">4 (7%)</td><td styleCode="Rrule">11 (11%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Hemorrhage<footnote>Hemorrhage in the SKYTROFA treatment group included epistaxis (3), contusion (2), petechiae (1) and eye hemorrhage (1).</footnote></td><td styleCode="Rrule">1 (2%)</td><td styleCode="Rrule">7 (7%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Diarrhea</td><td styleCode="Rrule">3 (5%)</td><td styleCode="Rrule">6 (6%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Abdominal pain</td><td styleCode="Rrule">2 (4%)</td><td styleCode="Rrule">6 (6%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Arthralgia and arthritis<footnote>Arthralgia and arthritis in the SKYTROFA treatment group included arthralgia (5) and reactive arthritis (1).</footnote></td><td styleCode="Rrule">1 (2%)</td><td styleCode="Rrule">6 (6%)</td></tr></tbody></table>

<table width="70%" ID="table3"><caption>Table 3: Adverse Reactions Occurring in &#x2265; 5% of SKYTROFA-Treated Adults and More Frequently Than in Placebo-treated Adults (38 Weeks of Treatment) </caption><col width="40%" align="left" valign="middle"/><col width="30%" align="center" valign="middle"/><col width="30%" align="center" valign="middle"/><thead><tr><th styleCode="Lrule Rrule" align="center">Adverse reactions</th><th styleCode="Rrule">Placebo (N = 84) n (%)</th><th styleCode="Rrule">SKYTROFA (N = 89) n (%)</th></tr></thead><tfoot><tr><td align="left" valign="top" colspan="3">Adverse reactions that are medically related were grouped to a single preferred term. </td></tr></tfoot><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Edema<footnote>Edema in the SKYTROFA treatment group included edema peripheral (6) and peripheral swelling (1).</footnote></td><td styleCode="Rrule">1 (1%)</td><td styleCode="Rrule">7 (8%)</td></tr><tr><td styleCode="Lrule Rrule">Central (secondary) hypothyroidism<footnote>Central (secondary) hypothyroidism in the SKYTROFA treatment group included thyroxine free decreased (3), central hypothyroidism (2), thyroxine decreased (1), blood thyroid stimulating hormone decreased (1), tri-iodothyronine free decreased (1). Preexisting central hypothyroidism in 5 of 6 SKYTROFA-treated patients.</footnote></td><td styleCode="Rrule">1 (1%)</td><td styleCode="Rrule">6 (7%)</td></tr></tbody></table>