Somatrogon

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 (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 ).

• Severe Hypersensitivity : Severe hypersensitivity reactions may occur. In the event of an allergic reaction, seek prompt medical attention ( 5.2 ).
• Increased Risk of Neoplasms : Monitor patients with preexisting tumors for progression 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 : NGENLA may decrease insulin sensitivity, particularly at higher doses. Monitor glucose levels periodically in all patients receiving NGENLA, especially in patients with existing diabetes mellitus or at risk for its development ( 5.4 ).
• Intracranial Hypertension : Perform fundoscopic examinations prior to initiation of treatment with NGENLA and periodically thereafter. If preexisting papilledema is identified, evaluate the etiology and treat the underlying cause before initiating. If papilledema occurs with NGENLA, stop treatment ( 5.5 ).
• Fluid Retention: May occur and may be dose dependent. 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 : Monitor thyroid function periodically as hypothyroidism may become evident or worsen after initiation with NGENLA ( 5.8 ).
• Slipped Capital Femoral Epiphysis : May develop. Evaluate patients with the onset of a limp or persistent hip or knee pain ( 5.9 ).
• Progression of Preexisting Scoliosis : Monitor for development or progression of scoliosis ( 5.10 ).
• Pancreatitis : Consider pancreatitis in patients with persistent severe abdominal pain ( 5.11 ).
• Lipoatrophy: May occur if NGENLA is administered in the same location over a long period of time. Rotate injection sites ( 5.12 ).

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 with somatropin [see Contraindications (4) ] . The safety of continuing NGENLA treatment for the approved indication in patients who concurrently develop these illnesses has not been established.

5.2 Severe Hypersensitivity Severe systemic hypersensitivity reactions including anaphylaxis and angioedema have been reported with somatropin. Inform patients and/or caregivers that such reactions are possible and that prompt medical attention should be sought if an allergic reaction occurs. NGENLA is contraindicated in patients with known hypersensitivity to somatrogon-ghla or any excipients in NGENLA [see Contraindications (4) ] .

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 NGENLA. Discontinue NGENLA 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 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 NGENLA 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 NGENLA in these patients. If treatment with NGENLA is initiated, carefully monitor these patients for development of neoplasms. Monitor patients on NGENLA therapy carefully for increased growth or potential malignant changes of preexisting nevi. Advise patients and/or 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 growth hormone may decrease insulin sensitivity, particularly at higher doses. New onset type 2 diabetes mellitus has been reported in patients receiving growth hormone. Patients with undiagnosed pre-diabetes and diabetes mellitus may experience worsened glycemic control and become symptomatic. Monitor glucose levels periodically in all patients receiving NGENLA, especially in those with risk factors for diabetes mellitus, such as obesity, Turner syndrome, or a family history of diabetes mellitus. Patients with preexisting type 1 or type 2 diabetes mellitus or pre-diabetes should be monitored closely. The doses of antidiabetic agents may require adjustment when NGENLA is initiated.

5.5 Intracranial Hypertension Intracranial hypertension (IH) with papilledema, visual changes, headache, nausea, and/or vomiting has been reported in patients treated with somatropin. Symptoms usually occurred within the first eight (8) weeks after the initiation of somatropin therapy. In all reported cases, IH-associated signs and symptoms rapidly resolved after cessation of therapy or a reduction of somatropin dose. Perform fundoscopic examination before initiating treatment with NGENLA to exclude preexisting papilledema and periodically thereafter. If papilledema is identified prior to initiation, evaluate the etiology and treat the underlying cause before initiating NGENLA. NGENLA should be temporarily discontinued in patients with clinical or fundoscopic evidence of IH. If IH is confirmed, restart treatment with NGENLA at a lower dose after IH-associated signs and symptoms have resolved.

5.6 Fluid Retention Fluid retention during NGENLA therapy may occur. Clinical manifestations of fluid retention (e.g. edema and nerve compression syndromes including carpal tunnel syndrome/paresthesia) are usually transient and dose dependent.

5.7 Hypoadrenalism Patients receiving growth hormone 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 NGENLA treatment. Monitor patients for reduced serum cortisol levels and/or need for glucocorticoid dose increases in those with known hypoadrenalism [see Drug Interactions (7) ] .

5.8 Hypothyroidism Undiagnosed/untreated hypothyroidism may prevent an optimal response to NGENLA therapy. In patients with GH deficiency, central (secondary) hypothyroidism may first become evident or worsen during treatment with growth hormone therapy. Therefore, patients should have periodic thyroid function tests and thyroid hormone replacement therapy should be initiated or appropriately adjusted when indicated.

5.9 Slipped Capital Femoral Epiphysis 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 products or NGENLA. Evaluate pediatric patients receiving NGENLA with the onset of a limp or complaints of persistent hip or knee pain for slipped capital femoral epiphysis and osteonecrosis and manage accordingly. […]

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

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 ).

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) ]

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.