Somatrogon-Ghla

NGENLA is indicated for the treatment of pediatric patients aged 3 years and older who have growth failure due to an inadequate secretion of endogenous growth hormone. NGENLA is a human growth hormone analog indicated for treatment of pediatric patients aged 3 years and older who have growth failure due to inadequate secretion of endogenous growth hormone ( 1 ).

• NGENLA treatment should be supervised by a healthcare provider who is experienced in the diagnosis and management of pediatric patients with growth hormone deficiency ( 2.1 ).
• Administer NGENLA by subcutaneous injection once weekly, on the same day each week, at any time of the day in the abdomen, thighs, buttocks, or upper arms with weekly rotation of injection site ( 2.1 ).
• The recommended dosage is 0.66 mg/kg based on actual body weight administered once weekly ( 2.3 ).
• Individualize dosage for each patient based on the growth response ( 2.3 ).
• Patients switching from daily growth hormone may initiate treatment with once-weekly NGENLA on the day following their last daily injection ( 2.3 ).
• If more than one injection is required to deliver a complete dose, each injection should be administered at a different injection site ( 2.3 ).

2.1 Important Dosing and Administration Information

• NGENLA treatment should be supervised by a healthcare provider who is experienced in the diagnosis and management of pediatric patients aged 3 years and older with growth failure due to growth hormone deficiency (GHD) [see Indications and Usage (1) ] .
• Refer patient to the Instructions for Use for complete administration instructions.
• Administer NGENLA by subcutaneous injection, once weekly, on the same day each week, at any time of the day in the abdomen, thighs, buttocks, or upper arms. Rotate the injection site weekly.
• Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. If flakes, particles or discoloration are observed, do not use the pen. Do not shake; shaking can damage the product.
• Prefilled pens deliver somatrogon-ghla in 0.2 mg or 0.5 mg increments.

2.2 Perform Fundoscopic Examination Prior to Initiation of NGENLA

• Perform fundoscopic examination before initiating treatment with NGENLA to exclude preexisting papilledema. If papilledema is identified, evaluate the etiology and treat the underlying cause before initiating treatment with NGENLA [see Warnings and Precautions (5.5) ] .

2.3 Recommended Dosage and Monitoring for Pediatric Patients with GHD

• Recommended dosage of NGENLA is 0.66 mg/kg based on actual body weight administered once weekly by subcutaneous (SC) injection.
• Individualize dosage for each patient based on the growth response.
• The day of weekly administration can be changed if necessary as long as the time between 2 doses is at least 3 days. After selecting a new dosing day, the once weekly dosing should be continued.
• When switching from daily growth hormone, the once-weekly NGENLA may be initiated on the day following their last daily injection.
• If more than one injection is required to deliver a complete dose, each injection should be administered at a different injection site.

2.4 Missed Dose

• If a dose is missed, administer NGENLA as soon as possible within 3 days after the missed dose.
• If more than 3 days have passed, skip the missed dose and administer the next dose on the regularly scheduled day.

NGENLA (somatrogon-ghla) is a clear and colorless to slightly light yellow solution available as:

• Injection: 24 mg/1.2 mL (20 mg/mL) in a single-patient-use, disposable prefilled pen that delivers a dose in 0.2 mg increments.
• Injection: 60 mg/1.2 mL (50 mg/mL) in a single-patient-use, disposable prefilled pen that delivers a dose in 0.5 mg increments. Injection:
• 24 mg/1.2 mL (20 mg/mL) single-patient-use prefilled pen that delivers a dose in 0.2 mg increments ( 3 ).
• 60 mg/1.2 mL (50 mg/mL) single-patient-use prefilled pen that delivers a dose in 0.5 mg increments ( 3 ).

• 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 somatropin [see Warnings and Precautions (5.1) ] .
• Hypersensitivity to somatrogon-ghla or any of the excipients in NGENLA [see Warnings and Precautions (5.2) ].
• 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 [see Warnings and Precautions (5.4) ] .
• 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 somatrogon-ghla or excipients ( 4 ).
• Closed epiphyses ( 4 ).
• Active malignancy ( 4 ).
• Active proliferative or severe non-proliferative diabetic retinopathy ( 4 ).
• Prader-Willi syndrome who are severely obese or have severe respiratory impairment ( 4 ).

Table 2 includes a list of drugs with clinically significant drug interactions when administered concomitantly with NGENLA and instructions for preventing or managing them. Table 2 Clinically Significant Drug Interactions with NGENLA 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. Growth hormone inhibits 11βHSD-1. Consequently, individuals with untreated GH deficiency have relative increases in 11βHSD-1 and serum cortisol. Initiation of NGENLA 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 NGENLA [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. Supraphysiologic Glucocorticoid Treatment Clinical Impact: Supraphysiologic glucocorticoid treatment may attenuate the growth-promoting effects of NGENLA in pediatric patients. Intervention: Carefully adjust glucocorticoid replacement dosing in pediatric patients receiving glucocorticoid treatments to avoid hypoadrenalism and an inhibitory effect on growth. Cytochrome P450-Metabolized Drugs Clinical Impact: Limited published data indicate that growth hormone treatment increases cytochrome P450 (CYP450)-mediated antipyrine clearance. NGENLA may alter the clearance of compounds known to be metabolized by CYP450 liver enzymes. Intervention: Careful monitoring is advisable when NGENLA is administered in combination with drugs metabolized by CYP450 liver enzymes. Oral Estrogen Clinical Impact: Oral estrogens may reduce the serum IGF-1 response to NGENLA. Intervention: Patients receiving oral estrogen replacement may require higher NGENLA dosages. Insulin and/or Other Antihyperglycemic Agents Clinical Impact: Treatment with NGENLA 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 dose following initiation of NGENLA ( 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: NGENLA may alter the clearance. Monitor carefully if used with NGENLA ( 7 ).
• Oral Estrogen: Larger doses of NGENLA may be required ( 7 ).
• Insulin and/or Other Antihyperglycemic Agents: Dose adjustment of insulin or antihyperglycemic agent may be required ( 5.4 , 7 ).

The following clinically significant 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 neoplasm [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 [see Warnings and Precautions (5.9) ]
• Progression of preexisting scoliosis [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) ] Adverse reactions reported in ≥5% of patients treated with NGENLA are: injection site reactions, nasopharyngitis, headache, pyrexia, anemia, cough, vomiting, hypothyroidism, abdominal pain, rash, and oropharyngeal pain ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at 1-800-438-1985 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. Safety data are derived from a safety and efficacy study in pediatric patients with GHD [see Clinical Studies (14.1) ]. The data from the 12-month main study period reflect exposure of 109 patients to NGENLA administered once weekly (0.66 mg/kg/wk) and 115 patients to somatropin administered once daily (0.034 mg/kg/day). The mean age across the treatment groups, was 7.7 years (min 3.01, max 11.96); 40.2% of patients were >3 years to ≤7 years, 59.8% were >7 years, 71.9% of patients were male, and 28.1% were female. In this study, 74.6% of patients were White, 20.1% were Asian, 0.9% were Black or African American, 0.5% were American Indian or Alaska Native, 0.5% were Native Hawaiian or Other Pacific Islander, and for 3.6% race information was missing; 10.7% of patients identified as Hispanic or Latino. Baseline disease characteristics were balanced across treatment groups. Table 1 shows the adverse reactions that occurred in ≥5% of patients treated with NGENLA or daily somatropin during the 12-month main study period. Reporting of injection site reactions was solicited through the use of a patient diary after each weekly injection for patients administered NGENLA and once weekly for patients administered daily injections of somatropin. Table 1 Adverse Reactions Occurring in ≥5% of NGENLA- or Somatropin-Treated Pediatric Patients (52 Weeks of Treatment) Adverse reactions that are medically related were grouped to a single preferred term. Adverse Drug Reactions Daily Somatropin (N=115) n (%) NGENLA (N=109) n (%) Injection site reactions Injection site reactions included: injection site pain (39% somatrogon-ghla vs 25% daily somatropin), injection site swelling/induration/hypertrophy/inflammation (10% somatrogon-ghla vs 1% daily somatropin), injection site erythema (8% somatrogon-ghla vs none daily somatropin), injection site pruritus (5% somatrogon-ghla vs none daily somatropin), injection site hemorrhage (5% somatrogon-ghla vs none daily somatropin). 29 (25.2) 46 (42.2) Nasopharyngitis Nasopharyngitis included: rhinitis, pharyngitis, rhinitis allergic, pharyngitis streptococcal, viral pharyngitis, nasopharyngitis. 33 (28.7) 36 (33) Headache 25 (21.7) 18 (16.5) Pyrexia 17 (14.8) 18 (16.5) Anemia 10 (8.7) 10 (9.2) Cough 9 (7.8) 9 (8.3) Vomiting 9 (7.8) 8 (7.3) Hypothyroidism 3 (2.6) 7 (6.4) Abdominal pain 8 (7.0) 7 (6.4) Rash 7 (6.1) 6 (5.5) Oropharyngeal pain 4 (3.5) 6 (5.5) Arthralgia 8 (7.0) 5 (4.6) Otitis media 10 (8.7) 5 (4.6) Tonsillitis 6 (5.2) 5 (4.6) Bronchitis 9 (7.8) 3 (2.8) Laboratory Tests More NGENLA-treated patients shifted from normal eosinophil levels at baseline to elevated eosinophil levels at the end of the 12-month study compared to the daily somatropin group (29% vs 12%).

6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of somatropin products or NGENLA. 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. Skin and subcutaneous tissue disorders – lipoatrophy Musculoskeletal and connective tissue disorders – osteonecrosis in pediatric patients, slipped capital femoral epiphysis

Acute overdosage may lead initially to hypoglycemia and subsequently to hyperglycemia. Overdose with growth hormone may cause fluid retention. Long-term overdosage could result in signs and symptoms of gigantism consistent with the effects of excess growth hormone.

8.1 Pregnancy Risk Summary There are no available data on NGENLA use in pregnant women to evaluate for a drug associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. In reproduction studies with pregnant rats, there was no evidence of embryo-fetal toxicity following administration of somatrogon-ghla subcutaneously during organogenesis at doses up to 45 times the maximum recommended human dose based on exposure (see Data ) . The background risk of major birth defects and miscarriage in 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 toxicity study in rats, no adverse maternal or embryo-fetal effects were observed when somatrogon-ghla was administered via subcutaneous injection every 2 days from gestation day (GD) 6 to 18 at doses up to 30 mg/kg (45 times the maximum recommended human dose based on C av exposure). In a pre- and postnatal development study in rats, somatrogon-ghla was administered via subcutaneous injection to pregnant rats every 2 days from GD 6 to lactation day 20 at doses up to 30 mg/kg. There was no evidence of maternal toxicity and no adverse effects on the first generation (F1) offspring. Somatrogon-ghla elicited an increase in F1 mean body weights in both sexes and increased the mean copulatory interval in F1 females at the highest dose (30 mg/kg), consistent with a longer estrous cycle length. However, there were no effects on mating indices in F1 females.

8.2 Lactation Risk Summary There are no data on the presence of somatrogon-ghla in human or animal milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for NGENLA and any potential adverse effects on the breastfed infant from NGENLA or from the underlying maternal condition.

8.3 Females and Males of Reproductive Potential Pregnancy Testing Although somatrogon-ghla did not interfere with hCG pregnancy testing in a limited number of commercial tests, interference with hCG blood and urine pregnancy testing in patients receiving somatrogon-ghla may be possible, leading to either false positive or false negative results. Alternative methods (i.e., not reliant on hCG) are recommended to determine pregnancy.

8.4 Pediatric Use The safety and effectiveness of NGENLA have been established for the treatment of growth failure due to inadequate secretion of endogenous growth hormone (GH) in pediatric patients aged 3 years and older [see Clinical Studies (14.1) ]. The use of NGENLA for this indication is supported by evidence from a 52‑week, multi-center, randomized, open-label, active-controlled, parallel-group phase 3 study in 224 treatment-naïve, prepubertal pediatric subjects with growth hormone deficiency. Risks in pediatric patients associated with growth hormone use include:

• 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 [see Warnings and Precautions (5.9) ]
• Progression of preexisting scoliosis [see Warnings and Precautions (5.10) ]
• Pancreatitis [see Warnings and Precautions (5.11) ]
• Sudden death in pediatric patients with Prader-Willi Syndrome. NGENLA 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) ]

Risk Summary There are no available data on NGENLA use in pregnant women to evaluate for a drug associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. In reproduction studies with pregnant rats, there was no evidence of embryo-fetal toxicity following administration of somatrogon-ghla subcutaneously during organogenesis at doses up to 45 times the maximum recommended human dose based on exposure (see Data ) . The background risk of major birth defects and miscarriage in 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 toxicity study in rats, no adverse maternal or embryo-fetal effects were observed when somatrogon-ghla was administered via subcutaneous injection every 2 days from gestation day (GD) 6 to 18 at doses up to 30 mg/kg (45 times the maximum recommended human dose based on C av exposure). In a pre- and postnatal development study in rats, somatrogon-ghla was administered via subcutaneous injection to pregnant rats every 2 days from GD 6 to lactation day 20 at doses up to 30 mg/kg. There was no evidence of maternal toxicity and no adverse effects on the first generation (F1) offspring. Somatrogon-ghla elicited an increase in F1 mean body weights in both sexes and increased the mean copulatory interval in F1 females at the highest dose (30 mg/kg), consistent with a longer estrous cycle length. However, there were no effects on mating indices in F1 females.

The safety and effectiveness of NGENLA have been established for the treatment of growth failure due to inadequate secretion of endogenous growth hormone (GH) in pediatric patients aged 3 years and older [see Clinical Studies (14.1) ]. The use of NGENLA for this indication is supported by evidence from a 52‑week, multi-center, randomized, open-label, active-controlled, parallel-group phase 3 study in 224 treatment-naïve, prepubertal pediatric subjects with growth hormone deficiency. Risks in pediatric patients associated with growth hormone use include:

• 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 [see Warnings and Precautions (5.9) ]
• Progression of preexisting scoliosis [see Warnings and Precautions (5.10) ]
• Pancreatitis [see Warnings and Precautions (5.11) ]
• Sudden death in pediatric patients with Prader-Willi Syndrome. NGENLA 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) ]

Somatrogon-ghla, a human growth hormone analog, is a fusion protein produced in Chinese Hamster Ovary (CHO) cells by recombinant DNA technology. It is comprised of the amino acid sequence of human growth hormone (hGH) with one copy of the C-terminal peptide (CTP) from the beta chain of human chorionic gonadotropin (hCG) at the N-terminus and 2 copies of CTP (in tandem) at the C-terminus. Somatrogon-ghla has an approximate molecular weight of 40 KDa. NGENLA (somatrogon-ghla) injection is a sterile, clear and colorless to slightly light yellow solution for subcutaneous use supplied in a 24 mg/1.2 mL (20 mg/mL) or 60 mg/1.2 mL (50 mg/mL) single-patient-use prefilled pen. Each 1.2 mL of solution contains either 24 mg or 60 mg of somatrogon-ghla, and the inactive ingredients citric acid monohydrate (0.3 mg), histidine (1.9 mg), metacresol (4 mg, as a preservative), poloxamer 188 (2 mg), sodium chloride (10 mg) and sodium citrate (2.8 mg) in water for injection. NGENLA has a pH of approximately 6.6.

12.1 Mechanism of Action Somatrogon-ghla binds to the GH receptor and initiates a signal transduction cascade culminating in changes in growth and metabolism. Somatrogon-ghla binding leads to activation of the STAT5b signaling pathway and increases the serum concentration of Insulin-like Growth Factor (IGF-1). GH and IGF-1 stimulate metabolic changes, linear growth, and enhance growth velocity in pediatric patients with GHD.

12.2 Pharmacodynamics Following single dose administration of somatrogon, dose-dependent increases in IGF-1 response were observed. Following multiple dosing, IGF-1 SDS levels were in the normal range for pediatric patients with GHD, similar to daily somatropin. IGF-1 levels peak approximately 2 days (48 hours) post-dose, with the average weekly IGF-1 occurring approximately 4 days post-dose.

12.3 Pharmacokinetics Somatrogon-ghla pharmacokinetics (PK) was assessed using a population PK approach for NGENLA in 151 pediatric patients (aged 3 to 15.5 years) with GHD. Absorption Following subcutaneous injection, serum concentrations increased slowly, peaking 6 to 25 hours with a median of 11 hours after dosing. In pediatric patients with GHD, somatrogon-ghla exposure increases in a dose-proportional manner for doses of 0.25 mg/kg/wk, 0.48 mg/kg/wk, and 0.66 mg/kg/wk. There is no accumulation of somatrogon-ghla after once weekly administration. In pediatric patients with GHD, the mean population PK estimated steady-state peak concentrations (mean ± SD) following 0.66 mg/kg/wk was 495 ± 90 ng/mL. Distribution In pediatric patients with GHD, the mean population PK estimated apparent central volume of distribution was 0.342 L/kg and apparent peripheral volume of distribution was 0.671 L/kg. Elimination In pediatric patients with GHD, the mean population PK estimated apparent clearance was 0.0398 L/h/kg. The mean population PK estimated effective half-life was 37.7 hours, which allows for weekly dosing. Somatrogon-ghla will be present in the circulation for about 8 days after the last dose. Metabolism The metabolism of somatrogon-ghla is believed to be classical protein catabolism, with subsequent recovery of the amino acids and return to the systemic circulation. Excretion Excretion was not evaluated in clinical studies. Specific Populations Based on population PK analyses, age, sex, race, and ethnicity do not have a clinically meaningful effect on the pharmacokinetics of somatrogon-ghla in pediatric patients with GHD. The exposure of somatrogon-ghla decreases with an increase in body weight. However, the somatrogon-ghla dosing regimen of 0.66 mg/kg/wk provides adequate systemic exposure over the body weight range of 10 to 54 kg evaluated in the clinical studies. Renal or Hepatic Impairment NGENLA has not been studied in patients with hepatic or renal impairment.

12.6 Immunogenicity The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of somatrogon or other growth hormone products. During the 12-month main period of study NCT 02968004, 84/109 (77.1%) of somatrogon-ghla‑treated patients tested positive for anti-drug antibodies, with most showing specificity to human growth hormone. The anti-drug antibodies persisted in most of the subjects during the study. Neutralizing antibodies developed in 8/217 (3.7%) of somatrogon-ghla-treated patients during the study for up to 42 months of exposure to somatrogon-ghla. The neutralizing antibodies were transient in all subjects. Anti-drug antibodies, including neutralizing-antibodies, did not appear to have a clinically significant impact on the safety or effectiveness of NGENLA during the 12‑month randomized treatment period. Additionally, no apparent effect of anti-drug antibodies on growth was observed for additional 30 months of exposure to somatrogon-ghla in the uncontrolled extension period of study NCT 02968004. Anti-Drug Antibody Effects on Pharmacokinetics The population pharmacokinetic analysis of data from study NCT 02968004 showed that patients who tested positive for anti-drug antibodies had an approximately 26% decrease in apparent clearance. These anti-drug antibody-associated pharmacokinetic changes are not considered to be clinically significant.

Somatrogon-ghla binds to the GH receptor and initiates a signal transduction cascade culminating in changes in growth and metabolism. Somatrogon-ghla binding leads to activation of the STAT5b signaling pathway and increases the serum concentration of Insulin-like Growth Factor (IGF-1). GH and IGF-1 stimulate metabolic changes, linear growth, and enhance growth velocity in pediatric patients with GHD.

Following single dose administration of somatrogon, dose-dependent increases in IGF-1 response were observed. Following multiple dosing, IGF-1 SDS levels were in the normal range for pediatric patients with GHD, similar to daily somatropin. IGF-1 levels peak approximately 2 days (48 hours) post-dose, with the average weekly IGF-1 occurring approximately 4 days post-dose.

Somatrogon-ghla pharmacokinetics (PK) was assessed using a population PK approach for NGENLA in 151 pediatric patients (aged 3 to 15.5 years) with GHD. Absorption Following subcutaneous injection, serum concentrations increased slowly, peaking 6 to 25 hours with a median of 11 hours after dosing. In pediatric patients with GHD, somatrogon-ghla exposure increases in a dose-proportional manner for doses of 0.25 mg/kg/wk, 0.48 mg/kg/wk, and 0.66 mg/kg/wk. There is no accumulation of somatrogon-ghla after once weekly administration. In pediatric patients with GHD, the mean population PK estimated steady-state peak concentrations (mean ± SD) following 0.66 mg/kg/wk was 495 ± 90 ng/mL. Distribution In pediatric patients with GHD, the mean population PK estimated apparent central volume of distribution was 0.342 L/kg and apparent peripheral volume of distribution was 0.671 L/kg. Elimination In pediatric patients with GHD, the mean population PK estimated apparent clearance was 0.0398 L/h/kg. The mean population PK estimated effective half-life was 37.7 hours, which allows for weekly dosing. Somatrogon-ghla will be present in the circulation for about 8 days after the last dose. Metabolism The metabolism of somatrogon-ghla is believed to be classical protein catabolism, with subsequent recovery of the amino acids and return to the systemic circulation. Excretion Excretion was not evaluated in clinical studies. Specific Populations Based on population PK analyses, age, sex, race, and ethnicity do not have a clinically meaningful effect on the pharmacokinetics of somatrogon-ghla in pediatric patients with GHD. The exposure of somatrogon-ghla decreases with an increase in body weight. However, the somatrogon-ghla dosing regimen of 0.66 mg/kg/wk provides adequate systemic exposure over the body weight range of 10 to 54 kg evaluated in the clinical studies. Renal or Hepatic Impairment NGENLA has not been studied in patients with hepatic or renal impairment.

, Mutagenesis, Impairment of Fertility Carcinogenesis No long term carcinogenicity studies have been performed with somatrogon-ghla. Mutagenesis Genotoxicity studies have not been performed. Impairment of Fertility The potential for somatrogon-ghla to affect fertility and early embryonic development was evaluated in male and female rats administered subcutaneously before cohabitation, through mating to implantation. Somatrogon‑ghla elicited an increase in estrous cycle length, copulatory interval, and number of corpora lutea at exposures ≥22-fold the MRHD, but there was no impact on female fertility, mating indices, number of viable embryos or early embryonic development, or on male fertility up to 30 mg/kg every two days (45-fold the MRHD based on exposure).

17 PATIENT COUNSELING INFORMATION Advise the patient and/or caregiver to read the FDA-approved patient labeling (Patient Information and Instructions for Use).

• Hypersensitivity Reactions Advise patients and caregivers that serious systemic hypersensitivity reactions (anaphylaxis and angioedema) are possible and that prompt medical attention should be sought if an allergic reaction occurs [see Warnings and Precautions (5.2) ] .
• Neoplasm Advise childhood cancer survivors and caregivers that individuals treated with radiation to the head are at increased risk of secondary neoplasms and, as a precaution, need to be monitored for recurrence. Advise patients to report marked changes in skin pigmentation or changes in the appearance of preexisting nevi [see Warnings and Precautions (5.3) ] .
• Glucose Intolerance/Diabetes Mellitus Advise patients and caregivers that new onset of insulin resistance and hyperglycemia may occur and monitoring of blood glucose during treatment with NGENLA in patients with glucose intolerance or who have risk factors for diabetes, may be needed [see Warnings and Precautions (5.4) ] .
• Intracranial Hypertension Advise patients and caregivers to report to their healthcare provider any visual changes, headache, and nausea and/or vomiting [see Warnings and Precautions (5.5) ] .
• Fluid Retention Advise patients and caregivers that fluid retention during NGENLA therapy may occur. Inform patients of the clinical manifestations of fluid retention (e.g. edema, arthralgia, myalgia, nerve compression syndromes including carpal tunnel syndrome/paresthesia) and to report to their healthcare provider if any of these signs or symptoms occur during treatment with NGENLA.
• Hypoadrenalism Advise patients and caregivers who have or who are at risk for corticotropin deficiency that hypoadrenalism may develop and to report to their healthcare provider if extreme fatigue, dizziness, weakness, vomiting, dehydration or weight loss is experienced during treatment with NGENLA [see Warnings and Precautions (5.7) ] .
• Hypothyroidism Advise patients and caregivers that undiagnosed/untreated hypothyroidism may prevent an optimal response to NGENLA. Advise patients and caregivers they may require periodic thyroid function tests during treatment with NGENLA [see Warnings and Precautions (5.8) ] .
• Pancreatitis Advise patients and caregivers that pancreatitis may develop and to report to their healthcare provider any new onset persistent severe abdominal pain.
• Lipoatrophy Advise patients and caregivers that lipoatrophy may occur if NGENLA is administered subcutaneously at the same site over a long period of time. Advise patients to rotate injection sites when administering NGENLA to reduce this risk.

Before first use: Store refrigerated at 36°F to 46°F (2°C to 8°C) in the original carton to protect from light. After first use: Store the pen refrigerated at 36°F to 46°F (2°C to 8°C) between each use, for up to 28 days. Do not freeze or shake. Do not expose to heat. Do not use if it has been frozen. Store away from direct sunlight. Always remove and safely discard the needle after each injection and store the NGENLA prefilled pen without an injection needle attached. Always use a new needle for each injection. Replace the cap on your prefilled pen when it is not in use. Write the date of first use in the space provided on the pen label. The prefilled pen should not be used more than 28 days after first use.