Sogroya Drug Information

• The following clinically significant adverse drug 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 )]
• Lipohypertrophy/Lipoatrophy [see Warnings and Precautions ( 5.12 )]
• Sudden death in pediatric patients with Prader-Willi syndrome [see Warnings and Precautions ( 5.13 )]
• Common adverse reactions reported in pediatric patients treated with SOGROYA include: cough, diarrhea, ear infection, headache, injection site reaction, nasopharyngitis, pain in extremity, pyrexia, respiratory tract infection, and vomiting. ( 6.1 )
• Adult patients with GHD: Adverse reactions reported in >2% of patients treated with SOGROYA are: back pain, arthralgia, dyspepsia, sleep disorder, dizziness, tonsillitis, peripheral edema, vomiting, adrenal insufficiency, hypertension, blood creatine phosphokinase increase, weight increase, anemia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Novo Nordisk Inc. at 1-800-727-6500 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 trials of another drug and may not reflect the rates observed in practice. Pediatric Patients with GHD SOGROYA 0.16 mg/kg/week was studied in a 52-week randomized, open-label, active-controlled, parallel-group clinical study in 200 treatment-naïve, prepubertal pediatric patients with growth hormone deficiency [see Clinical Studies ( 14.1 )] . Table 2 shows common adverse reactions that occurred in ≥ 5% of patients treated with either SOGROYA or somatropin in this trial. Table 2. Adverse Reactions Occurring ≥5% in SOGROYA or Somatropin-treated Pediatric Patients (52 Weeks of Treatment) Somatropin (N=68) SOGROYA (N=132) Adverse Reactions % % Nasopharyngitis a 16.2 16.7 Headache 8.8 12.1 Pyrexia b 11.8 9.1 Pain in extremity c 2.9 9.8 Injection site reaction d 5.9 6.1 Diarrhea e 5.9 4.5 Nausea/vomiting f 5.9 4.5 Bronchitis 7.4 3 a Nasopharyngitis in the SOGROYA treatment group included nasopharyngitis (11.4%), rhinitis (3.8%), pharyngitis streptococcal (0.8%), acute sinusitis (0.8%), nasal congestion (0.8%), pharyngitis (0.8%), and sinusitis (0.8%). b Pyrexia in the SOGROYA treatment group included pyrexia (8.3%) and hyperthermia (0.8%). c Pain in extremity in the SOGROYA treatment group included pain in extremity (9.1%) and growing pains (0.8%). d Injection site reaction in the SOGROYA treatment group included injection site bruising (1.5%), injection site pain (1.5%), injection site hematoma (1.5%), injection site reaction (0.8%), and injection site swelling (0.8%) e Diarrhea in the SOGROYA treatment group included diarrhea (2.3%), gastroenteritis viral (1.5%), and gastrointestinal viral infection (0.8%) f Nausea/vomiting in the SOGROYA treatment group included vomiting (4.5%) and nausea (1.5%) Pediatric Patients Born Small for Gestational Age and with no Catch-up Growth by 2 Years of Age SOGROYA 0.24 mg/kg/week was studied in a 52-week randomized, open-label, active-comparator, basket clinical study in GH treatment-naïve, pre-pubertal patients with short stature born small for gestational age (SGA), Noonan syndrome (NS) or idiopathic short stature (ISS) compared to somatropin [see Clinical Studies ( 14.2 )] . Table 3 shows the adverse reactions occurring at ≥10% in the SGA cohort with 141 pediatric patients. Table 3. Adverse Reactions Occurring ≥10% in SOGROYA or Somatropin-Treated Pediatric Patients with SGA at Week 52 Somatropin 0.035 mg/kg/day (N=37) Somatropin 0.067 mg/kg/day (N=35) SOGROYA 0.24 mg/kg/week (N=69) Adverse Reactions % % % Nasopharyngitis a 38 29 26 Respiratory Tract Infection b 30 20 26 Pyrexia 16 17 19 Cough c 16 9 16 Ear Infection d 16 17 13 Diarrhea e 8 6 10 Vomiting f 11 11 10 Bronchitis 11 11 7 a Nasopharyngitis in the SOGROYA treatment group included nasopharyngitis (15.9%), pharyngitis (2.9%), rhinitis (2.9%), pharyngitis streptococcal (1.4%), sinusitis (1.4%), and viral rhinitis (1.4%). b Respiratory tract infections in the SOGROYA treatment group included upper respiratory tract infection (20.3%), influenza (10.1%), metapneuomovirus infection (1.4%), mycoplasma infection (1.4%), pneumonia (1.4%), pneumonia bacterial (1.4%), pneumonia mycoplasmal (1.4%), respiratory syncytial virus infection (1.4%), and respiratory tract infection (1.4%). c Cough in the SOGROYA treatment group included cough (15.9%). d Ear infection in the SOGROYA treatment group included otitis media (7.2%), ear infection (2.9%), otitis externa (1.4%), and otitis media acute (1.4%). e Diarrhea in the SOGROYA treatment group included diarrhea (4.3%), gastroenteritis (4.3%), and gastrointestinal viral infection (1.4%) f Vomiting in the SOGROYA treatment group included vomiting (10.1%) Description of Select Adverse Reactions Adenoidal and tonsillar hypertrophy was reported in 1 (1%) subject with SGA in the first year of treatment with SOGROYA who received tonsillectomy and adenoidectomy. The adenoidal and tonsillar hypertrophy resolved after the procedure. Pediatric Patients with Growth Failure Associated with Noonan Syndrome SOGROYA 0.24 mg/kg/week was studied in a 52-week randomized, open-label, active-comparator, basket clinical study in GH treatment-naïve, pre-pubertal patients with NS compared to somatropin 0.05 mg/kg/day [see Clinical Studies (14.3)] . Table 4 shows the adverse reactions occurring at ≥10% in the NS cohort with 77 pediatric patients. Table 4. Adverse Reactions Occurring ≥10% in SOGROYA or Somatropin-Treated Pediatric Patients with NS at Week 52 Somatropin 0.05 mg/kg/day (N=28) SOGROYA 0.24 mg/kg/week (N=49) Adverse Reactions % % Respiratory Tract Infection a 29 43 Nasopharyngitis b 25 29 Diarrhea c 14 22 Ear Infection d 14 16 Cough e 14 14 Vomiting f 11 12 Pyrexia 25 10 Headache 7 10 Injection site reaction g 14 8 Abdominal Pain h 11 2 Wound 11 0 a Respiratory tract infection in the SOGROYA treatment group included upper respiratory tract infection (20.4%), influenza (10.2%), pneumonia (6.1%), influenza like illness (2%), respiratory syncytial virus infection (2%), respiratory tract infection (2%), respiratory tract infection viral (2%), upper respiratory tract infection bacterial (2%), and viral upper respiratory tract infection (2%). b Nasopharyngitis in the SOGROYA treatment group included nasopharyngitis (24.5%), pharyngitis (4.1%), bacterial infection (2%), herpes pharyngitis (2%), pharyngitis streptococcal (2%), pharyngotonsillitis (2%), and rhinitis (2%). c Diarrhea in the SOGROYA treatment group included gastroenteritis (14.3%), diarrhea (6.1%), gastroenteritis viral (2%), and parasitic gastroenteritis (2%). d Ear infection in the SOGROYA treatment group included otitis media (8.2%), otitis externa (4.1%), ear infection (2%), otitis media acute (2%), and otitis media chronic (2%). e Cough in the SOGROYA treatment group included cough (12.2%) and bacterial infection (2%). f Vomiting in the SOGROYA treatment group included vomiting (8.2%) and gastritis (4.1%). g Injection site reaction in the SOGROYA treatment group included injection site bruising (6.1%) and injection site hemorrhage (2%) h Abdominal pain in the SOGROYA treatment group included abdominal distension (2%) Pediatric Patients with Growth Failure Associated with Idiopathic Short Stature SOGROYA 0.24 mg/kg/week was studied in a 52-week randomized, open-label, active-comparator, basket clinical study in GH treatment-naïve, pre-pubertal patients with ISS compared to somatropin 0.05 mg/kg/day [see Clinical Studies (14.4)] . Table 5 shows the adverse reactions occurring at ≥10% in the ISS cohort with 87 pediatric patients. Table 5. Adverse Reactions Occurring ≥10% in SOGROYA or Somatropin-Treated Pediatric Patients with ISS at Week 52 Somatropin 0.05 mg/kg/day (N=28) SOGROYA 0.24 mg/kg/week (N=59) Adverse Reactions % % Respiratory Tract Infection a 29 31 Nasopharyngitis b 21 22 Ear Infection c 7 12 Diarrhea d 25 10 Headache 11 10 Injection site reaction e 7 10 Cough f 11 5 Vomiting g 11 5 a Respiratory tract infection in the SOGROYA treatment group included influenza (16.9%), upper respiratory tract infection (6.8%), respiratory tract infection (3.4%), pneumonia (1.7%), pneumonia bacterial (1.7%), respiratory tract infection viral (1.7%), and viral upper respiratory tract infection (1.7%). b Nasopharyngitis in the SOGROYA treatment group included nasopharyngitis (15.3%), pharyngitis streptococcal (5.1%), pharyngitis (1.7%), rhinitis (1.7%), sinusitis (1.7%), and tracheitis (1.7%). c Ear infection in the SOGROYA treatment group included otitis media (6.8%), ear infection (3.4%), and otitis media acute (1.7%). d Diarrhea in the SOGROYA treatment group included gastroenteritis (3.4%), gastroenteritis viral (3.4%), diarrhea (1.7%), enterobiasis (1.7%), and parasitic gastroenteritis (1.7%). e Injection site reaction in the SOGROYA treatment group included application site reaction (1.7%), injection site bruising (1.7%), injection site hematoma (1.7%), injection site hemorrhage (1.7%), injection site pruritis (1.7%), and injection site urticaria (1.7%). f Cough in the SOGROYA treatment group included cough (5.1%). g Vomiting in the SOGROYA treatment group included vomiting (5.1%). Description of Select Adverse Reactions Adenoidal and tonsillar hypertrophy was reported in 1 (2%) subject with ISS in the first year of treatment with SOGROYA who received tonsillectomy and adenoidectomy. The adenoidal and tonsillar hypertrophy resolved after the procedure. Adult Patients with GHD SOGROYA was studied in adult patients with GHD in a 35-week, placebo-controlled, double-blind trial with an active-control arm [see Clinical Studies ( 14.5 )] . Adverse reactions occurring >2% with SOGROYA are presented in Table 6 . Table 6. Adverse Reactions Occurring >2% in Adults with GHD Treated with SOGROYA and More Frequently # than in Placebo-Treated Patients for 34 Weeks Placebo (N=61) SOGROYA (N=120) Adverse Reactions % % Back pain 3.3 10 Arthralgia 1.6 6.7 Dyspepsia 3.3 5 Sleep disorder 1.6 4.2 Dizziness 1.6 4.2 Tonsillitis 1.6 3.3 Peripheral edema 1.6 3.3 Vomiting 1.6 3.3 Adrenal insufficiency 1.6 3.3 Hypertension 1.6 3.3 Blood creatine phosphokinase increase 0 3.3 Weight increased 0 3.3 Anemia 0 2.5 # Included adverse reactions reported with at least 1% greater incidence in SOGROYA group compared to the placebo group More SOGROYA treated patients shifted from normal baseline levels to elevated phosphate and creatine phosphokinase levels at the end of the trial compared to the placebo group (17.5% vs 4.9% and 9.2% vs. 6.6%, respectively); these laboratory changes occurred intermittently, and were non-progressive. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of somatropins. 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. Musculoskeletal and connective tissue disorders – osteonecrosis in pediatric patients.

• Table 7 includes a list of drugs with clinically important drug interactions when administered concomitantly with SOGROYA and instructions for preventing or managing them. Table 7. Clinically Important Drug Interactions with SOGROYA 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. GH inhibits 11βHSD-1. Consequently, individuals with untreated GH deficiency have relative increases in 11βHSD-1 and serum cortisol. Initiation of SOGROYA 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 SOGROYA [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. Cytochrome P450-Metabolized Drugs Clinical Impact: Limited published data indicate that GH treatment increases cytochrome P450 (CP450)-mediated antipyrine clearance. SOGROYA may alter the clearance of compounds known to be metabolized by CP450 liver enzymes. Intervention: Careful monitoring is advisable when SOGROYA is administered in combination with drugs metabolized by CP450 liver enzymes. Oral Estrogen Clinical Impact: Oral estrogens may reduce the serum IGF-1 response to SOGROYA. Intervention: Patients receiving oral estrogen replacement may require higher SOGROYA dosages [see Dosage and Administration (2.5 )] . Insulin and/or Other Hypoglycemic Agents Clinical Impact: Treatment with SOGROYA may decrease insulin sensitivity, particularly at higher doses. Intervention: Patients with diabetes mellitus may require adjustment of their doses of insulin and/or other hypoglycemic 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 SOGROYA. ( 7 )
• Cytochrome P450-Metabolized Drugs : SOGROYA may alter the clearance. Monitor carefully if used with SOGROYA. ( 7 )
• Oral Estrogen : Larger doses of SOGROYA may be required. ( 7 )
• Insulin and/or Other Antihyperglycemic Agents : Dose adjustment of insulin or antihyperglycemic agent may be required. ( 5.4 , 7 )

Pregnancy Risk Summary There are no available data on the use of SOGROYA during pregnancy; however, published studies describing the use of short-acting recombinant growth hormone (rhGH) during pregnancy over several decades have not identified any drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies, subcutaneously administered somapacitan-beco was not teratogenic in rats or rabbits during organogenesis at doses approximately 12 times the clinical exposure at the maximum recommended human dose (MRHD) of 8 mg/week. No adverse developmental outcomes were observed in a pre- and post-natal development study with administration of somapacitan-beco to pregnant rats from organogenesis through lactation at approximately 275 times the clinical exposure at the MRHD (see Data). The background risk of birth defects and miscarriage for the indicated population is unknown.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal Data In an embryo-fetal development study in rats, somapacitan-beco was administered by subcutaneous injection at doses of 2, 6, and 18 mg/kg/day during the period of organogenesis from gestation day 6 to 17. Fetal viability and development were not affected at doses up to 6 mg/kg/day (31 times the MRHD, based on AUC). Transient, fetal skeletal variations (short/bent/thickened long bones) were observed at 18 mg/kg/day (261 times the MRHD, based on AUC). In an embryo-fetal development study in rabbits, somapacitan-beco was administered by subcutaneous injection at doses of 1, 3, and 9 mg/kg every two days during the period of organogenesis from gestation day 6 to 18. Fetal viability and development were not adversely affected at somapacitan-beco dose of 1 mg/kg/every two days (12 times the MRHD, based on AUC). Reduced fetal growth was observed at doses ≥3 mg/kg/every two days (≥130 times the MRHD, based on C 12h ). In a pre- and post-natal development study in pregnant rats, somapacitan-beco was administered by subcutaneous injection at doses of 4, 9, and 18 mg/kg twice a week from gestation day 6 through lactation day 18. No adverse developmental effects were observed in the offspring at doses up to 9 mg/kg (275 times the MRHD, based on AUC). Increased incidence of renal pelvic dilatation was observed on post-natal day 21 at 18 mg/kg (630 times the MRHD, based on AUC), but was not observed in the adult F1 generation.

• Pediatric Use The safety and effectiveness of SOGROYA have been established in pediatric patients 2.5 years of age and older for the treatment of:
• Growth failure due to inadequate secretion of endogenous GH. The use of SOGROYA for this indication is supported by evidence from a 52-week randomized, multi-center, open-label, active-controlled, parallel-group phase 3 trial in 200 treatment-naïve, pediatric patients aged 2.5 to 11 years with GHD [see Clinical Studies (14.1)] . The safety profile from the pediatric trial was similar to that reported in adults [see Adverse Reactions (6.1)] .
• Short stature born SGA with no catch-up growth by 2 years of age. The use of SOGROYA for this indication is supported by evidence from a multi-center, randomized open-label, active-comparator, phase 3 basket study in 142 pediatric patients aged 2.6 to 10.7 years with short stature born SGA with no catch-up growth by 2 years of age [see Clinical Studies (14.2)] .
• Growth failure associated with NS. The use of SOGROYA for this indication is supported by evidence from a multi-center, randomized open-label, active-comparator, phase 3 basket study in 77 pediatric patients aged 2 to 11.1 years with growth failure associated with NS [see Clinical Studies (14.3)].
• ISS. The use of SOGROYA for this indication is supported by evidence from a multi-center, randomized open-label, active-comparator, phase 3 basket study in 88 pediatric patients aged 2.8 to 10.8 years with ISS [see Clinical Studies (14.4)]. The safety and effectiveness of SOGROYA have not been established in pediatric patients less than 2.5 years of age for the treatment of growth failure due to inadequate secretion of endogenous GH, short stature born SGA with no catch-up growth, growth failure associated with NS, or with ISS. Risks in pediatric patients associated with growth hormone use include:
• Sudden death in pediatric patients with Prader-Willi Syndrome. SOGROYA is not indicated for the treatment of pediatric patients with growth failure secondary to genetically confirmed Prader-Willi syndrome. [see Warnings and Precautions (5.13)]
• Increased risk of second neoplasm in pediatric cancer survivors treated with radiation to the brain and/or head [see Warnings and Precautions (5.3)]
• 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)]

• is contraindicated in patients with:
• Acute critical illness after open-heart surgery, abdominal surgery or multiple accidental trauma, or those with acute respiratory failure because of the risk of increased mortality with use of pharmacologic doses of SOGROYA [see Warnings and Precautions ( 5.1 )] .
• Hypersensitivity to SOGROYA or any of its excipients. Systemic hypersensitivity reactions have been reported postmarketing with somatropin [see Warnings and Precautions ( 5.2 )] .
• Pediatric patients with closed epiphyses.
• Active malignancy [see Warnings and Precautions ( 5.3 )].
• Active proliferative or severe non-proliferative diabetic retinopathy.
• 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 risk of sudden death [see Warnings and Precautions ( 5.13 )] .
• Acute critical illness ( 4 )
• Active malignancy ( 4 )
• Hypersensitivity to somapacitan-beco or excipients ( 4 )
• Active proliferative or severe non-proliferative diabetic retinopathy ( 4 )
• Closed epiphyses in children used for longitudinal growth promotion ( 4 )
• Children with Prader-Willi syndrome who are severely obese or have severe respiratory impairment due to risk of sudden death ( 4 )

Acute overdosage could lead initially to hypoglycemia and subsequently to hyperglycemia. Overdose with SOGROYA is likely to cause fluid retention. Long-term overdosage could result in signs and symptoms of gigantism and/or acromegaly consistent with the known effects of excess endogenous growth hormone.