Somapacitan

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 )

8.1 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.