NGENLA- somatrogon-ghla_injection, solution

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. 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. 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.

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.

DOSAGE AND ADMINISTRATION
3 [see Indications and Usage (1) [see Warnings and Precautions (5. 4) .
Instructions for Use
NGENLA registered (somatrogon-ghla) 24 mg Important information about your NGENLA pen: Do not Do not Do not not recommended Supplies you will need each time you inject Included in the carton: Not included in the carton: (See How should I dispose of the pen needles and pens? 24 mg NGENLA pen: Needles to use Pen needles are not included o o o o o Sterile needle (example) not supplied: Sterile needle with safety shield (example) not supplied: Note: Caution: Do not Preparing for your injection Step 1 - Getting ready Do not Do not o o o o Do not Step 2 - Choose and clean your injection site Do not Do not Step 3 - Check medicine Do not Do not Note: Step 4 - Attach needle Do not Note: Caution: Step 5 - Pull off outer needle cover Note: Note: Step 6 - Pull off inner needle cap Note: Is this pen new? Yes: Go to new pen set up (arrow directing to “New pen set up (priming) - for the first use of a new pen only”) No (arrow directing to “Setting your prescribed dose”) New pen set up (priming) en dash for the first use of a new pen only You must set up each new pen (priming) before using it for the first time Important: Note: A - Set priming dose 0. 4 o Note: B - Tap cartridge holder Tap Important: C - Press button and check for liquid Press the injection button "0" Check o Do not Setting your prescribed dose Step 7 - Set your dose Example A: 3. 8 mg shown in the dose window Example B: 12. 0 mg shown in the dose window o o o o Examples A B Always check the dose window to make sure you have set the correct dose. Important: Do not What should I do if I cannot set the dose I need? o (See Step 4: Attach needle o What should I do if I do not have enough medicine left in my pen? o o Only split your dose if you have been trained or told by your healthcare provider on how to do this. Injecting your dose Step 8 - Insert the needle Note: Step 9 - Inject your medicine Press the injection button "0" Step 10 - Count to 10 Continue to press the injection button while counting to 10 straight out. Note: Step 11 - Attach outer needle cover Caution: Note: Step 12 - Remove the needle Note: (See How should I dispose of the pen needles and pens? ). Important: Do not Step 13 - Replace the pen cap Do not (See How should I store my pen? Step 14 - After your injection Do not more than 28 days Storage and disposal Storage and disposal: How should I store my pen? Do not Do not Do not Keep NGENLA and all medicines out of the reach of children. Before first use (unused pens): After first use (up to 28 days of use): Do not more than 28 days Date of first use How should I dispose of the pen needles and pens? o o o o https://www. gov/safesharpsdisposal Do not Manufactured by: US License No: 2060 This Instructions for Use has been approved by the U. Food and Drug Administration. Revised: 7/2024 Image Image Image Step 2 Step 3 Step 4 Step 5 Step 6 Image Image Image Image Step 7 Example A Example B Step 8 Step 9 Step 10 Step 11 Step 12 Step 13 Logo.

The following clinically significant adverse reactions are described elsewhere in the labeling: [see Warnings and Precautions (5. 1) [see Warnings and Precautions (5. 2) [see Warnings and Precautions (5. 3) [see Warnings and Precautions (5. 4) [see Warnings and Precautions (5. 5) [see Warnings and Precautions (5. 6) [see Warnings and Precautions (5. 7) [see Warnings and Precautions (5. 8) [see Warnings and Precautions (5. 9) [see Warnings and Precautions (5. 10) [see Warnings and Precautions (5. 11) [see Warnings and Precautions (5. 12) [ 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. gov/medwatch 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 mean age across the treatment groups, was 7. 7 years (min 3. 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). 2) Nasopharyngitis Nasopharyngitis included: rhinitis, pharyngitis, rhinitis allergic, pharyngitis streptococcal, viral pharyngitis, nasopharyngitis. 7) 36 (33) Headache 25 (21. 5) Pyrexia 17 (14. 5) Anemia 10 (8. 2) Cough 9 (7. 3) Vomiting 9 (7. 3) Hypothyroidism 3 (2. 4) Abdominal pain 8 (7. 4) Rash 7 (6. 5) Oropharyngeal pain 4 (3. 5) Arthralgia 8 (7. 6) Otitis media 10 (8. 6) Tonsillitis 6 (5. 6) Bronchitis 9 (7. 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%).

[see Warnings and Precautions (5. 1) [see Warnings and Precautions (5. 2) [see Warnings and Precautions (5. 3) [see Warnings and Precautions (5. 4) [see Warnings and Precautions (5. 13) 4 4 4 4 4 4.

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. 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 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. 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. 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. , not reliant on hCG) are recommended to determine pregnancy. 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) Risks in pediatric patients associated with growth hormone use include: [see Warnings and Precautions (5. 3) [see Warnings and Precautions (5. 9) [see Warnings and Precautions (5. 10) [see Warnings and Precautions (5. 11) [see Warnings and Precautions (5.

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 11beta-hydroxysteroid dehydrogenase type 1 (11betaHSD-1) is required for conversion of cortisone to its active metabolite, cortisol, in hepatic and adipose tissue. Growth hormone inhibits 11betaHSD-1. Consequently, individuals with untreated GH deficiency have relative increases in 11betaHSD-1 and serum cortisol. Initiation of NGENLA may result in inhibition of 11betaHSD-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 11betaHSD-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: 7 Pharmacologic Glucocorticoid Therapy and Supraphysiologic Glucocorticoid Treatment: 7 Cytochrome P450-Metabolized Drugs: 7 Oral Estrogen: 7 Insulin and/or Other Antihyperglycemic Agents: 5.

OVERDOSAGE
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.
NONCLINICAL TOXICOLOGY
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).
CLINICAL STUDIES
A multi-center, randomized, open-label, active-controlled, parallel-group phase 3 study (NCT 02968004) was conducted in 224 treatment-naïve, prepubertal pediatric subjects with growth hormone deficiency (GHD). The primary efficacy endpoint was annualized height velocity at Week 52. One hundred nine (109) subjects received 0.66 mg/kg/week NGENLA, and 115 subjects received 0.034 mg/kg/day daily somatropin. The subjects age ranged from 3 to 12 years, with a mean of 7.7 years. One hundred sixty-one (71.9%) subjects were male and 63 (28.1%) were female. One hundred sixty-seven (74.6%) subjects were White, 45 (20.1%) subjects were Asian, 2 (0.9%) subjects were Black or African-American, 1 (0.5%) subject was American Indian or Alaska Native, 1 (0.5%) subject was Native Hawaiian or Other Pacific Islander, and for 8 (3.6%) subjects race information was missing; 24 (10.7%) subjects identified as Hispanic or Latino. The subjects had a mean baseline height standard deviation score (SDS) of -2.9. Treatment with once-weekly NGENLA for 52 weeks resulted in an annualized height velocity of 10.1 cm/year. Patients treated with daily somatropin achieved an annualized height velocity of 9.8 cm/year after 52 weeks of treatment. Refer to Table 3 Table 3. Annualized Height Velocity at Week 52 in Pediatric Patients with GHD Abbreviations: CI=confidence interval; LSM=least square mean; N=number of patients randomized and treated The estimates of LSM are from analysis of covariance model with treatment, age group, gender, peak growth hormone levels, and region as fixed factors and baseline height SDS as a covariate. Missing data is imputed by multiple imputation using SAS PROC MI with MNAR/FCS Method. Treatment Parameter Treatment Group LSM Treatment Difference (95% CI) (NGENLA minus Daily Somatropin) NGENLA (N=109) Daily Somatropin (N=115) LSM Estimate LSM Estimate Annualized Height Velocity (cm/yr) 10.1 9.8 0.3 (-0.2, 0.9) The mean height SDS at Week 52 was -1.94 in NGENLA arm and -1.99 in the daily somatropin arm. The mean increase in height SDS from baseline at Week 52 was 0.92 in NGENLA arm and 0.87 in the daily somatropin arm, respectively.

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