Lonapegsomatropin

SKYTROFA (lonapegsomatropin-tcgd) is a human growth hormone indicated for the: Treatment of pediatric patients 1 year and older who weigh at least 11.5 kg and have growth failure due to inadequate secretion of endogenous growth hormone (GH). Replacement of endogenous growth hormone in adults with growth hormone deficiency (GHD). SKYTROFA is a human growth hormone indicated for: Pediatric Patients: Treatment of pediatric patients 1 year and older who weigh at least 11.5 kg and have growth failure due to inadequate secretion of endogenous growth hormone (GH) ( 1 ). Adults: Replacement of endogenous growth hormone in adults with growth hormone deficiency (GHD) ( 1 ).

SKYTROFA is a white to off-white lyophilized powder available in a single-dose, dual-chamber, prefilled cartridge containing lonapegsomatropin-tcgd in one chamber and diluent, Water for Injection, in the other chamber and is available in the following strengths: For injection: 0.7 mg, 1.4 mg, 1.8 mg, 2.1 mg, 2.5 mg, 3 mg, 3.6 mg, 4.3 mg, 5.2 mg, 6.3 mg, 7.6 mg, 9.1 mg, 11 mg, and 13.3 mg. SKYTROFA is a lyophilized powder available in single-dose, dual-chamber, prefilled cartridges containing lonapegsomatropin-tcgd and diluent, Water for Injection, as follows: For injection: 0.7 mg, 1.4 mg, 1.8 mg, 2.1 mg, 2.5 mg, 3 mg, 3.6 mg, 4.3 mg, 5.2 mg, 6.3 mg, 7.6 mg, 9.1 mg, 11 mg, and 13.3 mg ( 3 )

SKYTROFA is contraindicated in patients with: Acute critical illness after open heart surgery, abdominal surgery or multiple accidental trauma, or those with acute respiratory failure due to the risk of increased mortality with use of pharmacologic doses of somatropin [see Warnings and Precautions (5.1) ] . Hypersensitivity to somatropin or any of the excipients in SKYTROFA. Severe systemic hypersensitivity reactions, including anaphylactic reactions and angioedema, have been reported [see Warnings and Precautions (5.2) ]. Pediatric patients with closed epiphyses. Active malignancy due to the risk of malignancy progression [see Warnings and Precautions (5.3) ]. Active proliferative or severe non-proliferative diabetic retinopathy because treatment with somatropin may worsen this condition. Pediatric patients with Prader-Willi syndrome who are severely obese, have a history of upper airway obstruction or sleep apnea or have severe respiratory impairment due to the risk of sudden death [see Warnings and Precautions (5.13) ]. Acute critical illness ( 4 ) Hypersensitivity to somatropin or any of the excipients in SKYTROFA ( 4 ) Children with closed epiphyses ( 4 ) Active malignancy ( 4 ) Active proliferative or severe non-proliferative diabetic retinopathy ( 4 ) Children with Prader-Willi syndrome who are severely obese or have severe respiratory impairment due to risk of sudden death ( 4 )

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. […]

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 4 includes a list of drugs with clinically important drug interactions when administered concomitantly with SKYTROFA and instructions for preventing or managing them. Table 4: Clinically Important Drug Interactions with SKYTROFA Replacement Glucocorticoid Treatment Clinical Impact: Microsomal enzyme 11β-hydroxysteroid dehydrogenase type 1 (11βHSD-1) is required for conversion of cortisone to its active metabolite, cortisol, in hepatic and adipose tissue. Somatropin inhibits 11βHSD-1. Consequently, individuals with untreated growth hormone deficiency (GHD) have relative increases in 11βHSD-1 and serum cortisol. Initiation of SKYTROFA may result in inhibition of 11βHSD-1 and reduced serum cortisol concentrations. Intervention: Patients treated with glucocorticoid replacement for hypoadrenalism may require an increase in their maintenance or stress doses following initiation of SKYTROFA [see Warnings and Precautions (5.7) ] Examples Cortisone acetate and prednisone may be affected more than others because conversion of these drugs to their biologically active metabolites is dependent on the activity of 11βHSD-1. Pharmacologic Glucocorticoid Therapy and Supraphysiologic Glucocorticoid Treatment Clinical Impact: Pharmacologic glucocorticoid therapy and supraphysiologic glucocorticoid treatment may attenuate the growth-promoting effects of SKYTROFA in pediatric patients. Intervention: Carefully adjust glucocorticoid replacement dosing in pediatric patients receiving glucocorticoid treatments to avoid both hypoadrenalism and an inhibitory effect on growth. Cytochrome P450-Metabolized Drugs Clinical Impact: Limited published data indicate that somatropin treatment increases cytochrome P450 (CYP450)-mediated antipyrine clearance. SKYTROFA may alter the clearance of compounds known to be metabolized by CYP450 liver enzymes. Intervention: Careful monitoring is advisable when SKYTROFA is administered in combination with drugs metabolized by CYP450 liver enzymes. Oral Estrogen Clinical Impact: Oral estrogens may reduce the serum insulin-like growth factor-1 (IGF-1) response to SKYTROFA. Intervention: Patients receiving oral estrogen replacement may require higher SKYTROFA dosages. Insulin and/or Other Antihyperglycemic Agents Clinical Impact: Treatment with SKYTROFA may decrease insulin sensitivity, particularly at higher doses. Intervention: Patients with diabetes mellitus may require adjustment of their doses of insulin and/or other antihyperglycemic agents [see Warnings and Precautions (5.4) ] . Replacement Glucocorticoid Treatment: Patients treated with glucocorticoid for hypoadrenalism may require an increase in their maintenance or stress doses following initiation of SKYTROFA ( 7 ). Pharmacologic Glucocorticoid Therapy and Supraphysiologic Glucocorticoid Treatment: Adjust glucocorticoid dosing in pediatric patients to avoid both hypoadrenalism and an inhibitory effect on growth ( 7 ). Cytochrome P450-Metabolized Drugs: SKYTROFA may alter the clearance. Monitor carefully if used with SKYTROFA ( 7 ). Oral Estrogen: Larger doses of SKYTROFA may be required ( 7 ). Insulin and/or Other Antihyperglycemic Agents: Dose adjustment of insulin or antihyperglycemic agent may be required ( 7 ).

8.1 Pregnancy Risk Summary There are no available data on lonapegsomatropin-tcgd use in pregnant patients to evaluate a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Available published data over several decades for somatropin, the active component of lonapegsomatropin-tcgd, have not identified a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. In animal reproduction studies, there was no evidence of embryo-fetal or neonatal harm when pregnant rats were administered subcutaneous lonapegsomatropin-tcgd at doses up to 13-fold the clinical pediatric dose of 0.24 mg/kg/week and approximately 30-fold the maximum clinical therapeutic dose for adult GHD of 6.3 mg hGH/week (see Data ) . The estimated background risk of birth defects and miscarriages for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriages in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data No embryonic or fetal development toxicities occurred in rats administered subcutaneous lonapegsomatropin-tcgd at doses up to 13-fold the clinical pediatric dose of 0.24 mg/kg/week and approximately 30-fold the maximum clinical therapeutic dose for adult GHD of 6.3 mg hGH/week. In a peri- and post-natal developmental study in rats, there were no adverse effects on the pregnant/lactating female or on development of the conceptus and the offspring following exposure of the female from implantation through weaning to doses of a structurally related pegylated somatropin prodrug up to 13-fold the clinical pediatric dose of 0.24 mg/kg/week and approximately 30-fold the maximum clinical therapeutic dose for adult GHD of 6.3 mg hGH/week.

8.2 Lactation Risk Summary There are no data on the presence of lonapegsomatropin-tcgd in human milk, effects on the breastfed infant, or effects on milk production. High molecular weight therapeutic proteins, including lonapegsomatropin-tcgd, are expected to have low passage into human milk and limited systemic exposure in the breastfed infant. Additionally, published data indicate that exogenous somatropin does not increase normal human milk concentrations of growth hormone. No adverse effects on the breastfed infant have been reported with somatropin. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for SKYTROFA and any potential adverse effects on the breastfed infant from SKYTROFA or from the underlying maternal condition.

8.4 Pediatric Use Safety and effectiveness of SKYTROFA have been established in pediatric patients 1 year and older and who weigh at least 11.5 kg. Pediatric use was established in a controlled study of 161 treatment-naïve pediatric patients ages 3 to 13 years and by supportive data in pediatric patients 1 year and older [see Adverse Reactions (6) and Clinical Studies (14) ] . The safety and effectiveness of SKYTROFA in children less than 1 year of age have not been established. Use of somatropin in pediatric patients with Prader-Willi syndrome has been associated with reports of sudden death. SKYTROFA is not indicated for the treatment of pediatric patients with growth failure due to genetically confirmed Prader-Willi syndrome [see Warnings and Precautions (5.13) ] .

8.5 Geriatric Use Of the 249 patients who received SKYTROFA in clinical studies, 24 (10%) patients were 65 years of age and older, and 4 (2%) patients were 75 years of age and older. Geriatric patients may be at an increased risk for adverse reactions. Initiate SKYTROFA at 0.7 mg once weekly in patients 60 years of age and older, not on estrogen therapy [see Dosage and Administration (2.3) ] .

SKYTROFA is a pegylated human growth hormone (somatropin) for once-weekly subcutaneous injection [see Clinical Pharmacology (12.3) ] . Somatropin binds to the growth hormone (GH) receptor in the cell membrane of target cells resulting in intracellular signal transduction and a host of pharmacodynamic effects. Somatropin has direct tissue and metabolic effects, and indirect effects mediated by insulin-like growth factor-1 (IGF-1), including stimulation of chondrocyte differentiation and proliferation, stimulation of hepatic glucose output, protein synthesis and lipolysis. Somatropin stimulates skeletal growth in pediatric patients with growth hormone deficiency (GHD) as a result of effects on the growth plates (epiphyses) of long bones.