Sogroya Drug Information

• SOGROYA is indicated for the treatment of pediatric patients aged 2.5 years and older with:
• Growth failure due to inadequate secretion of endogenous growth hormone (GH).
• Short stature born small for gestational age (SGA) and with no catch-up growth by 2 years of age.
• Growth failure associated with Noonan syndrome (NS).
• Idiopathic Short Stature (ISS). SOGROYA is indicated for the replacement of endogenous GH in adults with growth hormone deficiency (GHD). SOGROYA is a human growth hormone analog indicated for: Pediatric Patients: Treatment of pediatric patients aged 2.5 years and older with:
• Idiopathic Short Stature (ISS). Adults: Replacement of endogenous growth hormone in adults with growth hormone deficiency (GHD).

Important Dosing and Administration Information •

SOGROYA treatment should be supervised by a healthcare provider who is experienced in the diagnosis and management of pediatric patients with growth failure due to GHD, pediatric patients born SGA, pediatric patients with NS, pediatric patients with ISS and/or adults with GHD. • SOGROYA should be administered by subcutaneous injection, once weekly, any time of the day, in the upper arms, thigh, abdomen or buttocks with weekly rotation of injection site. • Inspect visually for particulate matter and discoloration. SOGROYA should be a clear to slightly opalescent and colorless to slightly yellow solution. If the solution is cloudy or contains particulate matter do not use. • Advise patients to read the PATIENT INFORMATION and INSTRUCTIONS FOR USE leaflets enclosed with the SOGROYA prefilled pen. • SOGROYA is available in 3 single-patient-use prefilled pens with 3 different dosing ranges ( Table 1 ).

Table 1. Strength and Dosing Range of SOGROYA Prefilled Pens

Perform Fundoscopic Examination Prior to Initiation of SOGROYA • Perform fundoscopic examination before initiating treatment with SOGROYA to exclude preexisting papilledema. If papilledema is identified, evaluate the etiology and treat the underlying cause before initiating treatment with SOGROYA.

• Recommended Dosage and Monitoring for Pediatric Patients • GH Deficiency: Recommended dosage of SOGROYA is 0.16 mg/kg based on actual body weight once weekly for treatment-naïve patients and patients switching from daily growth hormone (somatropin). • Small for Gestational Age (SGA), Noonan Syndrome (NS), and Idiopathic Short Stature (ISS): Recommended dosage of SOGROYA is 0.24 mg/kg based on actual body weight once weekly for treatment-naïve patients and patients switching from daily growth hormone (somatropin). • Individualize dosage for each patient based on the growth response. • When switching from daily human growth hormone to once-weekly SOGROYA, choose the preferred day for the weekly dose. Take the final dose of daily treatment on the day before (or at least 8 hours before) the first dose of SOGROYA. • When switching from a weekly human growth hormone to once-weekly SOGROYA, continue once weekly dosing schedule. • Assess compliance and evaluate other causes of poor growth such as hypothyroidism, undernutrition, advanced bone age, and antibodies to recombinant human growth hormone if patients experience failure to increase height velocity, particularly during the first year of treatment. • Patients who were treated with SOGROYA for GH deficiency in childhood and whose epiphyses are closed should be reevaluated before continuing SOGROYA.

Recommended Dosage, Titration, and Monitoring for Adults with GHD • Initiate SOGROYA with a dosage of 1.5 mg once weekly for treatment naïve patients and patients switching from daily growth hormone (somatropin). • Increase the weekly dosage every 2 to 4 weeks by approximately 0.5 mg to 1.5 mg until the desired response is achieved. • Titrate the dosage based on clinical response and serum insulin-like growth factor-1 (IGF-1) concentrations. Draw IGF-1 samples 3 to 4 days after the prior dose. • Decrease the dosage as necessary on the basis of adverse reactions and/or serum IGF-1 concentrations above the age- and sex-specific normal range. • The maximum recommended dosage is 8 mg once weekly.

Recommended Dosage and Titration for Specific Populations Patients Aged 65 Years and Older Initiate SOGROYA with a dosage of 1 mg once weekly and use smaller dose increment increases when titrating the dosage. See above for monitoring recommendations and the maximum recommended dosage of SOGROYA. Patients with Hepatic Impairment • SOGROYA is not recommended in adult and pediatric patients with severe hepatic impairment. • For adult patients with moderate hepatic impairment, initiate SOGROYA with a dosage of 1 mg once weekly and use smaller dose increment increases when titrating the dosage.

See above for monitoring recommendations. The maximum recommended dosage is 4 mg once weekly. • For pediatric patients with moderate hepatic impairment, SOGROYA is not recommended. • No dosage adjustment is recommended for adult and pediatric patients with mild hepatic impairment. Women Receiving Oral Estrogen Initiate SOGROYA with a dosage of 2 mg once weekly.

Missed Doses • If the dose is missed, SOGROYA can be taken within 3 days after the scheduled dosing day. Once-weekly dosing for the next dose could be resumed at the regularly scheduled dosing day. • If more than 3 days have passed since the missed dose, skip the dose and administer the next dose on the regularly scheduled dosing day.

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. Table 2 shows common adverse reactions that occurred in ≥ 5% of patients treated with either SOGROYA or somatropin in this trial.

Table 2. Table 3 shows the adverse reactions occurring at ≥10% in the SGA cohort with 141 pediatric patients. Table 3.

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. Table 4 shows the adverse reactions occurring at ≥10% in the NS cohort with 77 pediatric patients.

Table 4. Table 5 shows the adverse reactions occurring at ≥10% in the ISS cohort with 87 pediatric patients. Table 5.

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. 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. 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 # 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 respectively; these laboratory changes occurred intermittently, and were non-progressive.

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. Intervention: Patients treated with glucocorticoid replacement for hypoadrenalism may require an increase in their maintenance or stress doses following initiation of SOGROYA. Patients receiving oral estrogen replacement may require higher SOGROYA dosages. 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.
• Replacement Glucocorticoid Treatment: Patients treated with glucocorticoid for hypoadrenalism may require an increase in their maintenance or stress doses following initiation of SOGROYA.
• Cytochrome P450-Metabolized Drugs: SOGROYA may alter the clearance. Monitor carefully if used with SOGROYA.
• Oral Estrogen: Larger doses of SOGROYA may be required.
• Insulin and/or Other Antihyperglycemic Agents: Dose adjustment of insulin or antihyperglycemic agent may be required.

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 respectively. 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). 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 ).

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. The safety profile from the pediatric trial was similar to that reported in adults.
• 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.
• 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.
• ISS. 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.
• Increased risk of second neoplasm in pediatric cancer survivors treated with radiation to the brain and/or head
• Slipped capital femoral epiphysis in pediatric patients
• Progression of preexisting scoliosis in pediatric patients
• Pancreatitis

• SOGROYA 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.
• Hypersensitivity to SOGROYA or any of its excipients. Systemic hypersensitivity reactions have been reported postmarketing with somatropin.
• Pediatric patients with closed epiphyses.
• Active malignancy.
• 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.
• Acute critical illness
• Active malignancy
• Hypersensitivity to somapacitan-beco or excipients
• Closed epiphyses in children used for longitudinal growth promotion
• Children with Prader-Willi syndrome who are severely obese or have severe respiratory impairment due to risk of sudden death

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.