STORAGE AND HANDLING SECTION.

Storage and HandlingBefore first use: Store refrigerated at 36F to 46F (2C to 8C) in the original carton to protect from light. After first use: Store the pen refrigerated at 36F to 46F (2C to 8C) 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 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.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Risk SummaryThere are no available data on NGENLA use in pregnant women to evaluate for 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 DataIn 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 days from gestation day (GD) to 18 at doses up to 30 mg/kg (45 times the maximum recommended human dose based on Cav exposure).In pre- and postnatal development study in rats, somatrogon-ghla was administered via subcutaneous injection to pregnant rats every days from GD 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 longer estrous cycle length. However, there were no effects on mating indices in F1 females.. 8.2 Lactation. Risk SummaryThere 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 mothers 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 TestingAlthough somatrogon-ghla did not interfere with hCG pregnancy testing in 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 years and older [see Clinical Studies (14.1)]. The use of NGENLA for this indication is supported by evidence from 52-week, multi-center, randomized, open-label, active-controlled, parallel-group phase study in 224 treatment-naive, prepubertal pediatric subjects with growth hormone deficiency.Risks in pediatric patients associated with growth hormone use include:oIncreased risk of second neoplasm in pediatric cancer survivors treated with radiation to the brain and/or head [see Warnings and Precautions (5.3)]oSlipped capital femoral epiphysis [see Warnings and Precautions (5.9)]oProgression of preexisting scoliosis [see Warnings and Precautions (5.10)]oPancreatitis [see Warnings and Precautions (5.11)]oSudden 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)] oIncreased risk of second neoplasm in pediatric cancer survivors treated with radiation to the brain and/or head [see Warnings and Precautions (5.3)]. oSlipped capital femoral epiphysis [see Warnings and Precautions (5.9)]. oProgression of preexisting scoliosis [see Warnings and Precautions (5.10)]. oPancreatitis [see Warnings and Precautions (5.11)]. oSudden 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)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. oSevere Hypersensitivity: Severe hypersensitivity reactions may occur. In the event of an allergic reaction, seek prompt medical attention (5.2).oIncreased Risk of Neoplasms: Monitor patients with preexisting tumors for progression or recurrence. Increased risk of 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).oGlucose 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).oIntracranial 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).oFluid Retention: May occur and may be dose dependent. Reduce dose as necessary (5.6).oHypoadrenalism: Monitor patients for reduced serum cortisol levels and/or need for glucocorticoid dose increases in those with known hypoadrenalism (5.7).oHypothyroidism: Monitor thyroid function periodically as hypothyroidism may become evident or worsen after initiation with NGENLA (5.8).oSlipped Capital Femoral Epiphysis: May develop. Evaluate patients with the onset of limp or persistent hip or knee pain (5.9).oProgression of Preexisting Scoliosis: Monitor for development or progression of scoliosis (5.10).oPancreatitis: Consider pancreatitis in patients with persistent severe abdominal pain (5.11).oLipoatrophy: May occur if NGENLA is administered in the same location over long period of time. Rotate injection sites (5.12).. oSevere Hypersensitivity: Severe hypersensitivity reactions may occur. In the event of an allergic reaction, seek prompt medical attention (5.2).. oIncreased Risk of Neoplasms: Monitor patients with preexisting tumors for progression or recurrence. Increased risk of 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).. oGlucose 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).. oIntracranial 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).. oFluid Retention: May occur and may be dose dependent. Reduce dose as necessary (5.6).. oHypoadrenalism: Monitor patients for reduced serum cortisol levels and/or need for glucocorticoid dose increases in those with known hypoadrenalism (5.7).. oHypothyroidism: Monitor thyroid function periodically as hypothyroidism may become evident or worsen after initiation with NGENLA (5.8).. oSlipped Capital Femoral Epiphysis: May develop. Evaluate patients with the onset of limp or persistent hip or knee pain (5.9).. oProgression of Preexisting Scoliosis: Monitor for development or progression of scoliosis (5.10).. oPancreatitis: Consider pancreatitis in patients with persistent severe abdominal pain (5.11).. oLipoatrophy: May occur if NGENLA is administered in the same location over long period of time. Rotate injection sites (5.12).. 5.1Increased 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.. 5.2Severe 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)].. 5.3Increased Risk of Neoplasms. Active MalignancyThere 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 PatientsIn 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 second neoplasm has been reported. Intracranial tumors, in particular meningiomas, were the most common of these second neoplasms. Monitor all patients with history of GHD secondary to an intracranial neoplasm while on NGENLA therapy for progression or recurrence of the tumor.New Malignancy During TreatmentBecause 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.. 5.4Glucose Intolerance and Diabetes Mellitus. Treatment with growth hormone may decrease insulin sensitivity, particularly at higher doses. New onset type 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 family history of diabetes mellitus. Patients with preexisting type or type diabetes mellitus or pre-diabetes should be monitored closely. The doses of antidiabetic agents may require adjustment when NGENLA is initiated.. 5.5Intracranial 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 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 lower dose after IH-associated signs and symptoms have resolved.. 5.6Fluid 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.. 5.7Hypoadrenalism. 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)].. 5.8Hypothyroidism. 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.. 5.9Slipped Capital Femoral Epiphysis. Slipped capital femoral epiphysis may occur more frequently in patients undergoing rapid growth. Evaluate pediatric patients with the onset of limp or complaints of persistent hip or knee pain.. 5.10Progression of Preexisting Scoliosis. NGENLA increases growth rate, and progression of preexisting scoliosis can occur in patients who experience rapid growth. Growth hormone treatment has not been shown to increase the occurrence of scoliosis. Monitor patients with history of scoliosis for disease progression.. 5.11Pancreatitis. Cases of pancreatitis have been reported in patients receiving somatropin. The risk may be greater in pediatric patients compared with adults. Consider pancreatitis in patients who develop persistent severe abdominal pain.. 5.12Lipoatrophy. When NGENLA is administered subcutaneously at the same site over long period of time, lipoatrophy may result. Rotate injection sites when administering NGENLA to reduce this risk [see Dosage and Administration (2.1)].. 5.13Sudden Death in Pediatric Patients with Prader-Willi Syndrome There have been reports of sudden death after initiating therapy with somatropin in pediatric patients with Prader-Willi syndrome who had one or more of the following risk factors: severe obesity, history of upper airway obstruction or sleep apnea, or unidentified respiratory infection. Male patients with one or more of these factors may be at greater risk than females. NGENLA is not indicated for the treatment of pediatric patients who have growth failure due to genetically confirmed Prader-Willi syndrome.. 5.14Laboratory Tests Serum levels of phosphorus, alkaline phosphatase, and parathyroid hormone may increase with NGENLA therapy. If patient is found to have abnormal laboratory tests, monitor as appropriate.

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following clinically significant adverse reactions are described elsewhere in the labeling:oIncreased mortality in patients with acute critical illness [see Warnings and Precautions (5.1)]oSevere hypersensitivity [see Warnings and Precautions (5.2)]oIncreased risk of neoplasm [see Warnings and Precautions (5.3)]oGlucose intolerance and diabetes mellitus [see Warnings and Precautions (5.4)]oIntracranial hypertension [see Warnings and Precautions (5.5)]oFluid retention [see Warnings and Precautions (5.6)]oHypoadrenalism [see Warnings and Precautions (5.7)]oHypothyroidism [see Warnings and Precautions (5.8)]oSlipped capital femoral epiphysis [see Warnings and Precautions (5.9)]oProgression of preexisting scoliosis [see Warnings and Precautions (5.10)]oPancreatitis [see Warnings and Precautions (5.11)]oLipoatrophy [see Warnings and Precautions (5.12)]oSudden death in pediatric patients with Prader-Willi syndrome [see Warnings and Precautions (5.13)]. oIncreased mortality in patients with acute critical illness [see Warnings and Precautions (5.1)]. oSevere hypersensitivity [see Warnings and Precautions (5.2)]. oIncreased risk of neoplasm [see Warnings and Precautions (5.3)]. oGlucose intolerance and diabetes mellitus [see Warnings and Precautions (5.4)]. oIntracranial hypertension [see Warnings and Precautions (5.5)]. oFluid retention [see Warnings and Precautions (5.6)]. oHypoadrenalism [see Warnings and Precautions (5.7)]. oHypothyroidism [see Warnings and Precautions (5.8)]. oSlipped capital femoral epiphysis [see Warnings and Precautions (5.9)]. oProgression of preexisting scoliosis [see Warnings and Precautions (5.10)]. oPancreatitis [see Warnings and Precautions (5.11)]. oLipoatrophy [see Warnings and Precautions (5.12)]. oSudden 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 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 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 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 patient diary after each weekly injection for patients administered NGENLA and once weekly for patients administered daily injections of somatropin. Table 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 single preferred term.Adverse Drug ReactionsDaily Somatropin(N=115)n (%)NGENLA(N=109)n (%)Injection site reactionsInjection 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)NasopharyngitisNasopharyngitis included: rhinitis, pharyngitis, rhinitis allergic, pharyngitis streptococcal, viral pharyngitis, nasopharyngitis. 33 (28.7)36 (33)Headache 25 (21.7)18 (16.5)Pyrexia17 (14.8)18 (16.5)Anemia10 (8.7)10 (9.2)Cough9 (7.8)9 (8.3)Vomiting9 (7.8)8 (7.3)Hypothyroidism3 (2.6)7 (6.4)Abdominal pain8 (7.0)7 (6.4)Rash7 (6.1)6 (5.5)Oropharyngeal pain4 (3.5)6 (5.5)Arthralgia8 (7.0)5 (4.6)Otitis media10 (8.7)5 (4.6)Tonsillitis6 (5.2)5 (4.6)Bronchitis9 (7.8)3 (2.8)Laboratory TestsMore 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%).

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenesisNo long term carcinogenicity studies have been performed with somatrogon-ghla.. MutagenesisGenotoxicity studies have not been performed.. Impairment of FertilityThe 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 PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Somatrogon-ghla binds to the GH receptor and initiates 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 days (48 hours) post-dose, with the average weekly IGF-1 occurring approximately days post-dose. 12.3 Pharmacokinetics. Somatrogon-ghla pharmacokinetics (PK) was assessed using population PK approach for NGENLA in 151 pediatric patients (aged to 15.5 years) with GHD.. AbsorptionFollowing subcutaneous injection, serum concentrations increased slowly, peaking to 25 hours with median of 11 hours after dosing.In pediatric patients with GHD, somatrogon-ghla exposure increases in 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.. DistributionIn 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.. EliminationIn 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 days after the last dose.. MetabolismThe metabolism of somatrogon-ghla is believed to be classical protein catabolism, with subsequent recovery of the amino acids and return to the systemic circulation.. ExcretionExcretion was not evaluated in clinical studies.. Specific PopulationsBased on population PK analyses, age, sex, race, and ethnicity do not have 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 ImpairmentNGENLA has not been studied in patients with hepatic or renal impairment.. 12.6Immunogenicity. 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 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 PharmacokineticsThe 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.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1Treatment-Naive Pediatric Patients with Growth Hormone Deficiency A multi-center, randomized, open-label, active-controlled, parallel-group phase study (NCT 02968004) was conducted in 224 treatment-naive, 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 to 12 years, with 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, (0.9%) subjects were Black or African-American, (0.5%) subject was American Indian or Alaska Native, (0.5%) subject was Native Hawaiian or Other Pacific Islander, and for (3.6%) subjects race information was missing; 24 (10.7%) subjects identified as Hispanic or Latino. The subjects had 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 covariate. Missing data is imputed by multiple imputation using SAS PROC MI with MNAR/FCS Method.Treatment ParameterTreatment GroupLSM Treatment Difference (95% CI) (NGENLA minus Daily Somatropin)NGENLA (N=109)Daily Somatropin(N=115)LSM EstimateLSM EstimateAnnualized Height Velocity (cm/yr)10.19.80.3 (-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.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. oAcute 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)].oHypersensitivity to somatrogon-ghla or any of the excipients in NGENLA [see Warnings and Precautions (5.2)].oClosed epiphyses.oActive malignancy due to the risk of malignancy progression [see Warnings and Precautions (5.3)].oActive proliferative or severe non-proliferative diabetic retinopathy [see Warnings and Precautions (5.4)].oPrader-Willi syndrome who are severely obese, have 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)].. oAcute 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)].. oHypersensitivity to somatrogon-ghla or any of the excipients in NGENLA [see Warnings and Precautions (5.2)].. oClosed epiphyses.. oActive malignancy due to the risk of malignancy progression [see Warnings and Precautions (5.3)].. oActive proliferative or severe non-proliferative diabetic retinopathy [see Warnings and Precautions (5.4)].. oPrader-Willi syndrome who are severely obese, have 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)].. oAcute critical illness (4).oHypersensitivity to somatrogon-ghla or excipients (4).oClosed epiphyses (4). oActive malignancy (4).oActive proliferative or severe non-proliferative diabetic retinopathy (4).oPrader-Willi syndrome who are severely obese or have severe respiratory impairment (4).. oAcute critical illness (4).. oHypersensitivity to somatrogon-ghla or excipients (4).. oClosed epiphyses (4). oActive malignancy (4).. oActive proliferative or severe non-proliferative diabetic retinopathy (4).. oPrader-Willi syndrome who are severely obese or have severe respiratory impairment (4).

DESCRIPTION SECTION.

11 DESCRIPTION. Somatrogon-ghla, human growth hormone analog, is 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 copies of CTP (in tandem) at the C-terminus. Somatrogon-ghla has an approximate molecular weight of 40 KDa.NGENLA (somatrogon-ghla) injection is sterile, clear and colorless to slightly light yellow solution for subcutaneous use supplied in 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 preservative), poloxamer 188 (2 mg), sodium chloride (10 mg) and sodium citrate (2.8 mg) in water for injection. NGENLA has pH of approximately 6.6.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. oNGENLA treatment should be supervised by healthcare provider who is experienced in the diagnosis and management of pediatric patients with growth hormone deficiency (2.1).oAdminister 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).oThe recommended dosage is 0.66 mg/kg based on actual body weight administered once weekly (2.3).oIndividualize dosage for each patient based on the growth response (2.3).oPatients switching from daily growth hormone may initiate treatment with once-weekly NGENLA on the day following their last daily injection (2.3).oIf more than one injection is required to deliver complete dose, each injection should be administered at different injection site (2.3).. oNGENLA treatment should be supervised by healthcare provider who is experienced in the diagnosis and management of pediatric patients with growth hormone deficiency (2.1).. oAdminister 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).. oThe recommended dosage is 0.66 mg/kg based on actual body weight administered once weekly (2.3).. oIndividualize dosage for each patient based on the growth response (2.3).. oPatients switching from daily growth hormone may initiate treatment with once-weekly NGENLA on the day following their last daily injection (2.3).. oIf more than one injection is required to deliver complete dose, each injection should be administered at different injection site (2.3).. 2.1Important Dosing and Administration Information. oNGENLA treatment should be supervised by healthcare provider who is experienced in the diagnosis and management of pediatric patients aged years and older with growth failure due to growth hormone deficiency (GHD) [see Indications and Usage (1)].oRefer patient to the Instructions for Use for complete administration instructions.oAdminister 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.oParenteral 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.oPrefilled pens deliver somatrogon-ghla in 0.2 mg or 0.5 mg increments.. oNGENLA treatment should be supervised by healthcare provider who is experienced in the diagnosis and management of pediatric patients aged years and older with growth failure due to growth hormone deficiency (GHD) [see Indications and Usage (1)].. oRefer patient to the Instructions for Use for complete administration instructions.. oAdminister 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.. oParenteral 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.. oPrefilled pens deliver somatrogon-ghla in 0.2 mg or 0.5 mg increments.. 2.2Perform Fundoscopic Examination Prior to Initiation of NGENLA. oPerform 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 (5.4)].. oPerform 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 (5.4)].. 2.3Recommended Dosage and Monitoring for Pediatric Patients with GHD. oRecommended dosage of NGENLA is 0.66 mg/kg based on actual body weight administered once weekly by subcutaneous (SC) injection.oIndividualize dosage for each patient based on the growth response.oThe day of weekly administration can be changed if necessary as long as the time between doses is at least days. After selecting new dosing day, the once weekly dosing should be continued.oWhen switching from daily growth hormone, the once-weekly NGENLA may be initiated on the day following their last daily injection.oIf more than one injection is required to deliver complete dose, each injection should be administered at different injection site.. oRecommended dosage of NGENLA is 0.66 mg/kg based on actual body weight administered once weekly by subcutaneous (SC) injection.. oIndividualize dosage for each patient based on the growth response.. oThe day of weekly administration can be changed if necessary as long as the time between doses is at least days. After selecting new dosing day, the once weekly dosing should be continued.. oWhen switching from daily growth hormone, the once-weekly NGENLA may be initiated on the day following their last daily injection.. oIf more than one injection is required to deliver complete dose, each injection should be administered at different injection site.. 2.4Missed Dose oIf dose is missed, administer NGENLA as soon as possible within days after the missed dose.oIf more than days have passed, skip the missed dose and administer the next dose on the regularly scheduled day.. oIf dose is missed, administer NGENLA as soon as possible within days after the missed dose.. oIf more than days have passed, skip the missed dose and administer the next dose on the regularly scheduled day.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. NGENLA (somatrogon-ghla) is clear and colorless to slightly light yellow solution available as:oInjection: 24 mg/1.2 mL (20 mg/mL) in single-patient-use, disposable prefilled pen that delivers dose in 0.2 mg increments.oInjection: 60 mg/1.2 mL (50 mg/mL) in single-patient-use, disposable prefilled pen that delivers dose in 0.5 mg increments.. oInjection: 24 mg/1.2 mL (20 mg/mL) in single-patient-use, disposable prefilled pen that delivers dose in 0.2 mg increments.. oInjection: 60 mg/1.2 mL (50 mg/mL) in single-patient-use, disposable prefilled pen that delivers dose in 0.5 mg increments.. Injection:o24 mg/1.2 mL (20 mg/mL) single-patient-use prefilled pen that delivers dose in 0.2 mg increments (3).o60 mg/1.2 mL (50 mg/mL) single-patient-use prefilled pen that delivers dose in 0.5 mg increments (3).. o24 mg/1.2 mL (20 mg/mL) single-patient-use prefilled pen that delivers dose in 0.2 mg increments (3).. o60 mg/1.2 mL (50 mg/mL) single-patient-use prefilled pen that delivers dose in 0.5 mg increments (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Table includes list of drugs with clinically significant drug interactions when administered concomitantly with NGENLA and instructions for preventing or managing them.Table Clinically Significant Drug Interactions with NGENLAReplacement Glucocorticoid TreatmentClinical Impact:Microsomal enzyme 11-hydroxysteroid dehydrogenase type (11HSD-1) is required for conversion of cortisone to its active metabolite, cortisol, in hepatic and adipose tissue. Growth hormone inhibits 11HSD-1. Consequently, individuals with untreated GH deficiency have relative increases in 11HSD-1 and serum cortisol. Initiation of NGENLA may result in inhibition of 11HSD-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 11HSD-1.Supraphysiologic Glucocorticoid TreatmentClinical 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 DrugsClinical 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 EstrogenClinical 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 AgentsClinical 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)].. oReplacement Glucocorticoid Treatment: Patients treated with glucocorticoid for hypoadrenalism may require an increase in their maintenance or stress dose following initiation of NGENLA (7). oPharmacologic Glucocorticoid Therapy and Supraphysiologic Glucocorticoid Treatment: Adjust glucocorticoid dosing in pediatric patients to avoid both hypoadrenalism and an inhibitory effect on growth (7).oCytochrome P450-Metabolized Drugs: NGENLA may alter the clearance. Monitor carefully if used with NGENLA (7).oOral Estrogen: Larger doses of NGENLA may be required (7).oInsulin and/or Other Antihyperglycemic Agents: Dose adjustment of insulin or hypoglycemic agent may be required (5.4, 7).. oReplacement Glucocorticoid Treatment: Patients treated with glucocorticoid for hypoadrenalism may require an increase in their maintenance or stress dose following initiation of NGENLA (7). oPharmacologic Glucocorticoid Therapy and Supraphysiologic Glucocorticoid Treatment: Adjust glucocorticoid dosing in pediatric patients to avoid both hypoadrenalism and an inhibitory effect on growth (7).. oCytochrome P450-Metabolized Drugs: NGENLA may alter the clearance. Monitor carefully if used with NGENLA (7).. oOral Estrogen: Larger doses of NGENLA may be required (7).. oInsulin and/or Other Antihyperglycemic Agents: Dose adjustment of insulin or hypoglycemic agent may be required (5.4, 7).

FEMALES & MALES OF REPRODUCTIVE POTENTIAL SECTION.

8.3 Females and Males of Reproductive Potential. Pregnancy TestingAlthough somatrogon-ghla did not interfere with hCG pregnancy testing in 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.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. How SuppliedNGENLA (somatrogon-ghla) injection is clear and colorless to slightly light yellow solution containing preservative and supplied as one single-patient-use disposable prefilled pen per carton available in the following packages:24 mg/1.2 mL Prefilled Pen NDC: 0069-0505-0260 mg/1.2 mL Prefilled Pen NDC: 0069-0520-02Somatrogon-ghla solution concentration20 mg/mL50 mg/mLColor schemeLilac pen cap, injection button and labelBlue pen cap, injection button and labelDose increments0.2 mg/0.01 mL0.5 mg/0.01 mLMaximum dose12 mg (0.6 mL)30 mg (0.6 mL)Not made with natural rubber latex. Sterile needles are required for administration but not included. Consult the Instructions for Use for needles that can be used.. Storage and HandlingBefore first use: Store refrigerated at 36F to 46F (2C to 8C) in the original carton to protect from light. After first use: Store the pen refrigerated at 36F to 46F (2C to 8C) 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 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.

IMMUNOGENICITY.

12.6Immunogenicity. 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 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 PharmacokineticsThe 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.

INDICATIONS & USAGE SECTION.

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

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient and/or caregiver to read the FDA-approved patient labeling (Patient Information and Instructions for Use).oHypersensitivity ReactionsAdvise 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)].oNeoplasmAdvise childhood cancer survivors and caregivers that individuals treated with radiation to the head are at increased risk of secondary neoplasms and, as 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)].oGlucose Intolerance/Diabetes MellitusAdvise 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)].oIntracranial HypertensionAdvise patients and caregivers to report to their healthcare provider any visual changes, headache, and nausea and/or vomiting [see Warnings and Precautions (5.5)].oFluid RetentionAdvise 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.oHypoadrenalismAdvise 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)].oHypothyroidismAdvise 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)].oPancreatitisAdvise patients and caregivers that pancreatitis may develop and to report to their healthcare provider any new onset persistent severe abdominal pain.oLipoatrophyAdvise patients and caregivers that lipoatrophy may occur if NGENLA is administered subcutaneously at the same site over long period of time. Advise patients to rotate injection sites when administering NGENLA to reduce this risk.. oHypersensitivity ReactionsAdvise 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)].. oNeoplasmAdvise childhood cancer survivors and caregivers that individuals treated with radiation to the head are at increased risk of secondary neoplasms and, as 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)].. oGlucose Intolerance/Diabetes MellitusAdvise 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)].. oIntracranial HypertensionAdvise patients and caregivers to report to their healthcare provider any visual changes, headache, and nausea and/or vomiting [see Warnings and Precautions (5.5)].. oFluid RetentionAdvise 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.. oHypoadrenalismAdvise 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)].. oHypothyroidismAdvise 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)].. oPancreatitisAdvise patients and caregivers that pancreatitis may develop and to report to their healthcare provider any new onset persistent severe abdominal pain.. oLipoatrophyAdvise patients and caregivers that lipoatrophy may occur if NGENLA is administered subcutaneously at the same site over long period of time. Advise patients to rotate injection sites when administering NGENLA to reduce this risk.

INSTRUCTIONS FOR USE SECTION.

Instructions for Use. NGENLA(R) (en JEN-lah)(somatrogon-ghla)24 mginjection, for subcutaneous useRead this Instructions for Use before you start using NGENLA and each time you get new refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment. Important information about your NGENLA pen:oThe NGENLA pen for injection is single-patient-use, disposable (throw away) prefilled pen containing 24 mg of medicine. You can give more than dose from the pen.oNGENLA can be given by patient, caregiver or healthcare provider. Do not try to inject NGENLA yourself until you are shown the right way to give the injections and read and understand the Instructions for Use. If your healthcare provider decides that you or caregiver may be able to give your injections of NGENLA at home, you should receive training on the right way to prepare and inject NGENLA. It is important that you read, understand, and follow these instructions so that you inject NGENLA the right way.oIt is important to talk to your healthcare provider to be sure you understand your NGENLA dosing instructions. To help you remember when to inject NGENLA, you can mark your calendar ahead of time. Call your healthcare provider if you or your caregiver have any questions about the right way to inject NGENLA, or call the helpline on 1-800-645-1280.oDo not share your pen with other people, even if the needle has been changed. You may give other people serious infection or get serious infection from them.oEach turn (click) of the dose knob dials 0.2 mg of medicine. You can give from 0.2 mg to 12 mg in single injection. If your dose is more than 12 mg, you will need to give more than injection.oA new pen may contain slightly more than 24 mg of medicine, this is normal.oAlways use new sterile needle for each injection. This will decrease the risk of contamination, infection, leakage of medicine, and blocked needles leading to the wrong dose.oDo not shake your pen. Shaking can damage the medicine.oThe pen is not recommended for use by the blind or visually impaired without the assistance of person trained in the proper use of the product.Supplies you will need each time you injectIncluded in the carton:o1 NGENLA prefilled penNot included in the carton:o1 new sterile needle for each injectionoAlcohol swabsoCotton balls or gauze padsoAdhesive bandageo1 FDA-cleared sharps disposal container for disposal of pen needles and pens (See How should dispose of the pen needles and pens)24 mg NGENLA pen:Needles to usePen needles are not included with your NGENLA pen. You will need prescription from your healthcare provider to get pen needles up to length of mm from your pharmacy.oNeedles to use with your NGENLA pen:o32G (Novo Nordisk(R), NovoFine(R) Plus)o31G (Novo Nordisk(R), NovoFine(R))o31G (Becton Dickinson and Company, BD Ultra-Fine(TM) or BD Micro-Fine(TM))oTalk with your healthcare provider about the right needle for you.Sterile needle (example) not supplied:Caution: Never use bent or damaged needle. Always handle pen needles with care to make sure you do not prick yourself (or anyone else) with the needle. Do not attach new needle to your pen until you are ready to take your injection.Preparing for your injectionStep - Getting readyoWash and dry your hands.oYou can use your pen straight from the refrigerator. For more comfortable injection, leave your pen at room temperature for up to 30 minutes.oCheck the name, strength, and label of your pen to make sure it is the medicine your healthcare provider has prescribed for you.oCheck the expiration date on the pen label. Do not use if the expiration date has passed.oDo not use your pen if:oit has been frozen or exposed to heatoit has been droppedoit looks broken or damagedoit has been more than 28 days after first use of the pen. oDo not remove the pen cap from your pen until you are ready to inject.Step - Choose and clean your injection siteoNGENLA can be given in the abdomen, thighs, buttocks, or upper arms.oChoose the best place to inject, as recommended by your healthcare provider.oIf more than injection is needed to complete your full dose, each injection should be given in different injection site.oDo not inject into bony areas, areas that are bruised, red, sore or hard, and areas that have scars or skin conditions.oClean the injection site with an alcohol swab.oAllow the injection site to dry.oDo not touch injection site after cleaning.Step - Check medicineoPull off the pen cap and keep it for after your injection.oCheck the medicine inside the cartridge holder.oMake sure the medicine is colorless to slightly light yellow. Do not inject the medicine if it is cloudy or dark yellow.oMake sure the medicine is free of flakes or particles. Do not inject the medicine if it has flakes or particles.oNote: It is normal to see one or more bubbles in the medicine.Step - Attach needleoTake new needle and pull off the protective paper.oLine the needle up with your pen keeping them both straight.oGently push and then screw the needle onto your pen.Do not over tighten. Note: Be careful not to attach the needle at an angle. This may cause the pen to leak. Caution: Needles have sharp tips at both ends. Handle with care to make sure you do not prick yourself (or anyone else) with the needle.Step - Pull off outer needle coveroPull off the outer needle cover.oMake sure you keep the outer needle cover. You will need it later to remove the needle.Note: You should see an inner needle cap after you have removed the outer cover. If you do not see this, try to attach the needle again.Step - Pull off inner needle capoPull off the inner needle cap carefully to show the needle.oThrow away the inner needle cap in FDA-cleared sharps container. It is not needed again.Is this pen newYes: Go to new pen set upNoNew pen set up (priming) for the first use of new pen onlyYou must set up each new pen (priming) before using it for the first timeoNew pen set up is done before each new pen is used for the first time.oThe purpose of setting up new pen is to remove air bubbles and make sure you get the correct dose.Important: Skip Step-A through to Step-C if you have already set up your pen.A Set priming doseoTurn the dose knob to 0.4.oThis is the amount to prime the pen. Note: If you turn the dose knob too far, you can turn it back.B Tap cartridge holderoHold the pen with the needle pointing up so that the air bubbles can rise.oTap the cartridge holder gently to float any air bubbles to the top. Important: Follow Step-B even if you do not see air bubbles.C Press button and check for liquidoPress the injection button until it cannot go any further and 0 is shown in the dose window.oCheck for liquid at the needle tip. If liquid appears, your pen is set up.oAlways make sure that drop of liquid appears before you inject. If liquid has not appeared, repeat Step-A through to Step-C.oIf liquid does not appear after you have repeated Step-A through Step-C five (5) times, attach new needle and try more time. Do not use the pen if drop of liquid still does not appear. Contact your healthcare provider or pharmacist and use new pen.Setting your prescribed doseStep - Set your doseExample A:3.8 mg shown in the dose windowExample B:12.0 mg shown in the dose windowoTurn the dose knob to set your dose.oThe dose can be increased or decreased by turning the dose knob in either direction.oThe dose knob turns 0.2 mg at time.oYour pen contains 24 mg of medicine but you can only set dose of up to 12 mg for single injection.oThe dose window shows the dose in mg. See Examples and .oAlways check the dose window to make sure you have set the correct dose.Important: Do not press the injection button while setting your dose.What should do if cannot set the dose needoIf your dose is more than 12 mg you will need to split your dose into more than injection.oYou can give from 0.2 mg to 12 mg in single injection.oUse new needle for each injection (See Step 4: Attach needle).oIf you normally need to give injections for your full dose, be sure to give your second dose.What should do if do not have enough medicine left in my penoIf your pen contains less than 12 mg of medicine, the dose knob will stop with the remaining amount of medicine shown in the dose window.oIf there is not enough medicine left in your pen for your full dose, you may either:oInject the amount left in your pen, then prepare new pen to complete your dose in full. Remember to subtract the dose you have already received. For example, if the dose is 3.8 mg and you can only set the dose knob to 1.8 mg, you should inject another 2.0 mg with new pen.oOr get new pen and inject the full dose.Only split your dose if you have been trained or told by your healthcare provider on how to do this.Injecting your doseStep - Insert the needleoHold your pen so you can see the numbers in the dose window.oInsert the needle straight into your skin.Step - Inject your medicineoKeep holding the needle in the same position in your skin.oPress the injection button until it cannot go any further and 0 is shown in the dose window.Step 10 Count to 10oContinue to press the injection button while counting to 10. Counting to 10 will allow the full dose of medicine to be given.oAfter counting to 10, let go of the injection button and slowly remove the pen from the injection site by pulling the needle straight out.Note: You may see drop of medicine at the needle tip. This is normal and does not affect the dose you just received.Step 11 Attach outer needle coveroCarefully place the outer needle cover back on the needle.oPress on the outer needle cover until it is secure.Caution: Never try to put the inner needle cap back on the needle. You may prick yourself with the needle.Step 12 Remove the needleoUnscrew the capped needle from the pen.oGently pull until the capped needle comes off.Note: If the needle is still on, replace the outer needle cover and try again. Be sure to apply pressure when unscrewing the needle.oThrow away the needle in the FDA-cleared sharps container (See How should dispose of the pen needles and pens). oImportant: Always remove and throw away used needles. Do not reuse needles.Step 13 Replace the pen capoReplace the pen cap back onto your pen.oDo not recap the pen with needle attached.oIf there is any medicine left in your pen, store in the refrigerator between uses (See How should store my pen).Step 14 After your injectionoPress lightly on the injection site with clean cotton ball or gauze pad, and hold for few seconds.oDo not rub the injection site. You may have slight bleeding. This is normal.oYou may cover the injection site with small adhesive bandage, if needed.oIf your pen is empty or it has been more than 28 days after first use, throw it away even if it contains unused medicine. See Storage and disposal on the right side of this leaflet.Storage and disposal:How should store my penoDo not freeze your pen or expose it to heat.oDo not use your pen if it has been frozen or stored in direct sunlight.oDo not use after the expiration date printed on the label has passed or if it has been more than 28 days after first use.oKeep NGENLA and all medicines out of the reach of children.Before first use (unused pens):oStore in the original carton.oStore your pens in the refrigerator between 36F to 46F (2C to 8C).oUnused pens may be used until the expiration date printed on the label, only if the pen has been kept in the refrigerator.After first use (up to 28 days of use):oStore your pen in the refrigerator between 36F to 46F (2C to 8C) and away from direct sunlight.oKeep the pen cap on your pen when it is not in use.oDo not store the pen with needle attached.oIf your pen is empty or it has been more than 28 days after first use, throw it away even if it contains unused medicine.oTo help you remember when to dispose of your pen you can write the date of first use on the pen label and below:Date of first use / How should dispose of the pen needles and pensoThrow away your pen, and pen needles into FDA-cleared sharps disposal container or puncture resistant container.oIf you do not have FDA-cleared sharps disposal container, you may use household container that:ois made of heavy-duty plasticocan be closed with tight-fitting, puncture resistant lid, without sharps being able to come outois upright and stable during useois leak-resistant, and properly labeled to warn of hazardous waste inside the container.oWhen your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles, syringes, and prefilled syringes.oFor more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDAs website at: https://www.fda.gov/safesharpsdisposaloDo not throw away your used sharps disposal container in your household trash unless your community guidelines permit this.oKeep the sharps container out of the reach of children.Manufactured by:Pfizer Ireland PharmaceuticalsRingaskiddy,Cork,IrelandUS License No: 2060LAB-1452-1.0This Instructions for Use has been approved by the U.S. Food and Drug Administration. Issued: 6/2023. oThe NGENLA pen for injection is single-patient-use, disposable (throw away) prefilled pen containing 24 mg of medicine. You can give more than dose from the pen.. oNGENLA can be given by patient, caregiver or healthcare provider. Do not try to inject NGENLA yourself until you are shown the right way to give the injections and read and understand the Instructions for Use. If your healthcare provider decides that you or caregiver may be able to give your injections of NGENLA at home, you should receive training on the right way to prepare and inject NGENLA. It is important that you read, understand, and follow these instructions so that you inject NGENLA the right way.. oIt is important to talk to your healthcare provider to be sure you understand your NGENLA dosing instructions. To help you remember when to inject NGENLA, you can mark your calendar ahead of time. Call your healthcare provider if you or your caregiver have any questions about the right way to inject NGENLA, or call the helpline on 1-800-645-1280.. oDo not share your pen with other people, even if the needle has been changed. You may give other people serious infection or get serious infection from them.. oEach turn (click) of the dose knob dials 0.2 mg of medicine. You can give from 0.2 mg to 12 mg in single injection. If your dose is more than 12 mg, you will need to give more than injection.. oA new pen may contain slightly more than 24 mg of medicine, this is normal.. oAlways use new sterile needle for each injection. This will decrease the risk of contamination, infection, leakage of medicine, and blocked needles leading to the wrong dose.. oDo not shake your pen. Shaking can damage the medicine.. oThe pen is not recommended for use by the blind or visually impaired without the assistance of person trained in the proper use of the product.. o1 NGENLA prefilled pen. o1 new sterile needle for each injection. oAlcohol swabs. oCotton balls or gauze pads. oAdhesive bandage. o1 FDA-cleared sharps disposal container for disposal of pen needles and pens (See How should dispose of the pen needles and pens). oNeedles to use with your NGENLA pen:o32G (Novo Nordisk(R), NovoFine(R) Plus)o31G (Novo Nordisk(R), NovoFine(R))o31G (Becton Dickinson and Company, BD Ultra-Fine(TM) or BD Micro-Fine(TM)). o32G (Novo Nordisk(R), NovoFine(R) Plus). o31G (Novo Nordisk(R), NovoFine(R)). o31G (Becton Dickinson and Company, BD Ultra-Fine(TM) or BD Micro-Fine(TM)). oTalk with your healthcare provider about the right needle for you.. oWash and dry your hands.. oYou can use your pen straight from the refrigerator. For more comfortable injection, leave your pen at room temperature for up to 30 minutes.. oCheck the name, strength, and label of your pen to make sure it is the medicine your healthcare provider has prescribed for you.. oCheck the expiration date on the pen label. Do not use if the expiration date has passed.. oDo not use your pen if:oit has been frozen or exposed to heatoit has been droppedoit looks broken or damagedoit has been more than 28 days after first use of the pen. oit has been frozen or exposed to heat. oit has been dropped. oit looks broken or damaged. oit has been more than 28 days after first use of the pen.. oDo not remove the pen cap from your pen until you are ready to inject.. oNGENLA can be given in the abdomen, thighs, buttocks, or upper arms.. oChoose the best place to inject, as recommended by your healthcare provider.. oIf more than injection is needed to complete your full dose, each injection should be given in different injection site.. oDo not inject into bony areas, areas that are bruised, red, sore or hard, and areas that have scars or skin conditions.. oClean the injection site with an alcohol swab.. oAllow the injection site to dry.. oDo not touch injection site after cleaning.. oPull off the pen cap and keep it for after your injection.. oCheck the medicine inside the cartridge holder.. oMake sure the medicine is colorless to slightly light yellow. Do not inject the medicine if it is cloudy or dark yellow.. oMake sure the medicine is free of flakes or particles. Do not inject the medicine if it has flakes or particles.. oNote: It is normal to see one or more bubbles in the medicine.. oTake new needle and pull off the protective paper.. oLine the needle up with your pen keeping them both straight.. oGently push and then screw the needle onto your pen.Do not over tighten. Note: Be careful not to attach the needle at an angle. This may cause the pen to leak. Caution: Needles have sharp tips at both ends. Handle with care to make sure you do not prick yourself (or anyone else) with the needle.. oPull off the outer needle cover.. oMake sure you keep the outer needle cover. You will need it later to remove the needle.Note: You should see an inner needle cap after you have removed the outer cover. If you do not see this, try to attach the needle again.. oPull off the inner needle cap carefully to show the needle.. oThrow away the inner needle cap in FDA-cleared sharps container. It is not needed again.. oNew pen set up is done before each new pen is used for the first time.. oThe purpose of setting up new pen is to remove air bubbles and make sure you get the correct dose.Important: Skip Step-A through to Step-C if you have already set up your pen.. oTurn the dose knob to 0.4.oThis is the amount to prime the pen.. oThis is the amount to prime the pen.. Note: If you turn the dose knob too far, you can turn it back.. oHold the pen with the needle pointing up so that the air bubbles can rise.. oTap the cartridge holder gently to float any air bubbles to the top. Important: Follow Step-B even if you do not see air bubbles.. oPress the injection button until it cannot go any further and 0 is shown in the dose window.. oCheck for liquid at the needle tip. If liquid appears, your pen is set up.. oAlways make sure that drop of liquid appears before you inject. If liquid has not appeared, repeat Step-A through to Step-C.oIf liquid does not appear after you have repeated Step-A through Step-C five (5) times, attach new needle and try more time. Do not use the pen if drop of liquid still does not appear. Contact your healthcare provider or pharmacist and use new pen.. oIf liquid does not appear after you have repeated Step-A through Step-C five (5) times, attach new needle and try more time. Do not use the pen if drop of liquid still does not appear. Contact your healthcare provider or pharmacist and use new pen.. oTurn the dose knob to set your dose.oThe dose can be increased or decreased by turning the dose knob in either direction.oThe dose knob turns 0.2 mg at time.oYour pen contains 24 mg of medicine but you can only set dose of up to 12 mg for single injection.oThe dose window shows the dose in mg. See Examples and .. oThe dose can be increased or decreased by turning the dose knob in either direction.. oThe dose knob turns 0.2 mg at time.. oYour pen contains 24 mg of medicine but you can only set dose of up to 12 mg for single injection.. oThe dose window shows the dose in mg. See Examples and .. oAlways check the dose window to make sure you have set the correct dose.Important: Do not press the injection button while setting your dose.. oIf your dose is more than 12 mg you will need to split your dose into more than injection.. oYou can give from 0.2 mg to 12 mg in single injection.oUse new needle for each injection (See Step 4: Attach needle).oIf you normally need to give injections for your full dose, be sure to give your second dose.. oUse new needle for each injection (See Step 4: Attach needle).. oIf you normally need to give injections for your full dose, be sure to give your second dose.. oIf your pen contains less than 12 mg of medicine, the dose knob will stop with the remaining amount of medicine shown in the dose window.. oIf there is not enough medicine left in your pen for your full dose, you may either:oInject the amount left in your pen, then prepare new pen to complete your dose in full. Remember to subtract the dose you have already received. For example, if the dose is 3.8 mg and you can only set the dose knob to 1.8 mg, you should inject another 2.0 mg with new pen.oOr get new pen and inject the full dose.. oInject the amount left in your pen, then prepare new pen to complete your dose in full. Remember to subtract the dose you have already received. For example, if the dose is 3.8 mg and you can only set the dose knob to 1.8 mg, you should inject another 2.0 mg with new pen.. oOr get new pen and inject the full dose.. oHold your pen so you can see the numbers in the dose window.. oInsert the needle straight into your skin.. oKeep holding the needle in the same position in your skin.. oPress the injection button until it cannot go any further and 0 is shown in the dose window.. oContinue to press the injection button while counting to 10. Counting to 10 will allow the full dose of medicine to be given.. oAfter counting to 10, let go of the injection button and slowly remove the pen from the injection site by pulling the needle straight out.Note: You may see drop of medicine at the needle tip. This is normal and does not affect the dose you just received.. oCarefully place the outer needle cover back on the needle.. oPress on the outer needle cover until it is secure.Caution: Never try to put the inner needle cap back on the needle. You may prick yourself with the needle.. oUnscrew the capped needle from the pen.. oGently pull until the capped needle comes off.Note: If the needle is still on, replace the outer needle cover and try again. Be sure to apply pressure when unscrewing the needle.. oThrow away the needle in the FDA-cleared sharps container (See How should dispose of the pen needles and pens). oImportant: Always remove and throw away used needles. Do not reuse needles.. oReplace the pen cap back onto your pen.. oDo not recap the pen with needle attached.. oIf there is any medicine left in your pen, store in the refrigerator between uses (See How should store my pen).. oPress lightly on the injection site with clean cotton ball or gauze pad, and hold for few seconds.. oDo not rub the injection site. You may have slight bleeding. This is normal.. oYou may cover the injection site with small adhesive bandage, if needed.. oIf your pen is empty or it has been more than 28 days after first use, throw it away even if it contains unused medicine. See Storage and disposal on the right side of this leaflet.. oDo not freeze your pen or expose it to heat.. oDo not use your pen if it has been frozen or stored in direct sunlight.. oDo not use after the expiration date printed on the label has passed or if it has been more than 28 days after first use.. oKeep NGENLA and all medicines out of the reach of children.. oStore in the original carton.. oStore your pens in the refrigerator between 36F to 46F (2C to 8C).. oUnused pens may be used until the expiration date printed on the label, only if the pen has been kept in the refrigerator.. oStore your pen in the refrigerator between 36F to 46F (2C to 8C) and away from direct sunlight.. oKeep the pen cap on your pen when it is not in use.. oDo not store the pen with needle attached.. oIf your pen is empty or it has been more than 28 days after first use, throw it away even if it contains unused medicine.. oTo help you remember when to dispose of your pen you can write the date of first use on the pen label and below:Date of first use / oThrow away your pen, and pen needles into FDA-cleared sharps disposal container or puncture resistant container.. oIf you do not have FDA-cleared sharps disposal container, you may use household container that:ois made of heavy-duty plasticocan be closed with tight-fitting, puncture resistant lid, without sharps being able to come outois upright and stable during useois leak-resistant, and properly labeled to warn of hazardous waste inside the container.. ois made of heavy-duty plastic. ocan be closed with tight-fitting, puncture resistant lid, without sharps being able to come out. ois upright and stable during use. ois leak-resistant, and properly labeled to warn of hazardous waste inside the container.. oWhen your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles, syringes, and prefilled syringes.. oFor more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDAs website at: https://www.fda.gov/safesharpsdisposal. oDo not throw away your used sharps disposal container in your household trash unless your community guidelines permit this.. oKeep the sharps container out of the reach of children.. 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.

LACTATION SECTION.

8.2 Lactation. Risk SummaryThere 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 mothers clinical need for NGENLA and any potential adverse effects on the breastfed infant from NGENLA or from the underlying maternal condition.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Somatrogon-ghla binds to the GH receptor and initiates 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.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenesisNo long term carcinogenicity studies have been performed with somatrogon-ghla.. MutagenesisGenotoxicity studies have not been performed.. Impairment of FertilityThe 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).

OVERDOSAGE SECTION.

10 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.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 24 mg Cartridge Label. NDC 0069-0505-01Store refrigerated24mgNgenla(R) (somatrogon-ghla)Injection24 mg/1.2 mL (20 mg/mL)For Subcutaneous Injection OnlymgSingle-patient-useRx only. PRINCIPAL DISPLAY PANEL 24 mg Cartridge Label.

PEDIATRIC USE SECTION.

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 years and older [see Clinical Studies (14.1)]. The use of NGENLA for this indication is supported by evidence from 52-week, multi-center, randomized, open-label, active-controlled, parallel-group phase study in 224 treatment-naive, prepubertal pediatric subjects with growth hormone deficiency.Risks in pediatric patients associated with growth hormone use include:oIncreased risk of second neoplasm in pediatric cancer survivors treated with radiation to the brain and/or head [see Warnings and Precautions (5.3)]oSlipped capital femoral epiphysis [see Warnings and Precautions (5.9)]oProgression of preexisting scoliosis [see Warnings and Precautions (5.10)]oPancreatitis [see Warnings and Precautions (5.11)]oSudden 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)] oIncreased risk of second neoplasm in pediatric cancer survivors treated with radiation to the brain and/or head [see Warnings and Precautions (5.3)]. oSlipped capital femoral epiphysis [see Warnings and Precautions (5.9)]. oProgression of preexisting scoliosis [see Warnings and Precautions (5.10)]. oPancreatitis [see Warnings and Precautions (5.11)]. oSudden 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)].

PHARMACODYNAMICS SECTION.

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 days (48 hours) post-dose, with the average weekly IGF-1 occurring approximately days post-dose.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Somatrogon-ghla pharmacokinetics (PK) was assessed using population PK approach for NGENLA in 151 pediatric patients (aged to 15.5 years) with GHD.. AbsorptionFollowing subcutaneous injection, serum concentrations increased slowly, peaking to 25 hours with median of 11 hours after dosing.In pediatric patients with GHD, somatrogon-ghla exposure increases in 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.. DistributionIn 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.. EliminationIn 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 days after the last dose.. MetabolismThe metabolism of somatrogon-ghla is believed to be classical protein catabolism, with subsequent recovery of the amino acids and return to the systemic circulation.. ExcretionExcretion was not evaluated in clinical studies.. Specific PopulationsBased on population PK analyses, age, sex, race, and ethnicity do not have 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 ImpairmentNGENLA has not been studied in patients with hepatic or renal impairment.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryThere are no available data on NGENLA use in pregnant women to evaluate for 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 DataIn 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 days from gestation day (GD) to 18 at doses up to 30 mg/kg (45 times the maximum recommended human dose based on Cav exposure).In pre- and postnatal development study in rats, somatrogon-ghla was administered via subcutaneous injection to pregnant rats every days from GD 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 longer estrous cycle length. However, there were no effects on mating indices in F1 females.

SPL PATIENT PACKAGE INSERT SECTION.

PATIENT INFORMATIONNGENLA(R) (en JEN-lah)(somatrogon-ghla)injection, for subcutaneous useThis Patient Information has been approved by the U.S. Food and Drug Administration.Issued: 6/2023What is NGENLANGENLA is prescription medicine that contains form of human growth hormone, like the growth hormone made by the human body. NGENLA is given by injection under the skin (subcutaneous) in children who are not growing because of low or no growth hormone levels.Do not use NGENLA if:oyour child has critical illness caused by certain types of heart or stomach surgery, trauma or breathing (respiratory) problems.oyour child is allergic to somatrogon-ghla or any of the ingredients in NGENLA. See the end of this leaflet for complete list of ingredients in NGENLA.oyour child has closed bone growth plates (epiphyses).oyour child has cancer or other tumors.oyour childs healthcare provider tells you that your child has certain types of eye problems caused by diabetes (diabetic retinopathy).oyour child has Prader-Willi syndrome, is severely obese, or has breathing problems including sleep apnea (briefly stop breathing during sleep).Before using NGENLA, tell your childs healthcare provider about all of your childs medical conditions, including if your child:ohas had heart or stomach surgery, trauma or serious breathing (respiratory) problems.ohas had history of problems breathing while they slept (sleep apnea).ohas or has had cancer or any tumor.ohas diabetes.ois pregnant or plans to become pregnant. It is not known if NGENLA will harm your childs unborn baby. Talk to your childs healthcare provider if your child is pregnant or plans to become pregnant.ois breastfeeding or plans to breastfeed. It is not known if NGENLA passes into breast milk. You and your childs healthcare provider should decide if they will take NGENLA while breastfeeding.Tell your childs healthcare provider about all the medicines your child takes, including prescription and over-the-counter medicines, vitamins, and herbal supplements. NGENLA may affect how other medicines work, and other medicines may affect how NGENLA works.How should use NGENLAoRead the detailed Instructions for Use that come with NGENLA.oNGENLA comes in different dosage strengths. Your childs healthcare provider will prescribe the dose of medicine and the dosage strength that is right for your child.oYour childs healthcare provider will show you how to inject NGENLA before it is used for the first time. Do not try to inject NGENLA until you have been shown the right way by your childs healthcare provider.oInject NGENLA exactly as your childs healthcare provider tells you to.oNGENLA is injected under the skin (subcutaneously) and can be given in the stomach (abdomen), thighs, buttocks, or upper arms. Rotate the site of injection weekly.oInject NGENLA time each week, on the same day each week, at any time of the day.oYou may change the day of the week NGENLA is used as long as the last dose was injected or more days before. After the new day of the week has been chosen, continue with the time week schedule.oIf your child misses dose of NGENLA the missed dose should be injected as soon as possible within days after the missed dose. If more than days have passed, skip your childs missed dose. Inject the next dose on the regularly scheduled day.oNGENLA prefilled pens are for use by person only.oDo not share your childs NGENLA prefilled pens and needles with another person, even if the needle has been changed. Your child may give another person an infection or get an infection from them.What are the possible side effects of NGENLANGENLA may cause serious side effects, including:ohigh risk of death in people who have critical illnesses because of heart or stomach surgery, trauma or serious breathing (respiratory) problems.oserious allergic reactions. Get medical help right away if your child has the following symptoms:oswelling of the face, lips, mouth, or tongueotrouble breathingowheezingosevere itchingoskin rashes, redness, or swellingodizziness or faintingofast heartbeat or pounding in the chestosweatingoincreased risk of growth of cancer or tumor that is already present and increased risk of the return of cancer or tumor in people who were treated with radiation to the brain or head as children and who developed low growth hormone problems. Your childs healthcare provider will need to monitor your child for return of cancer or tumor. Contact your childs healthcare provider if your child starts to have headaches, or has changes in behavior, changes in vision, or changes in moles, birthmarks, or the color of the skin. onew or worsening high blood sugar (hyperglycemia) or diabetes. Your childs blood sugar may need to be monitored during treatment with NGENLA.oincrease in pressure inside the skull (intracranial hypertension). If your child has headaches, eye problems, nausea or vomiting, contact your childs healthcare provider.oyour childs body holding too much fluid (fluid retention) such as swelling in the hands and feet, pain in the joints or muscles or nerve problems that cause pain, burning or tingling in the hands, arms, legs and feet. Fluid retention can happen in children during treatment with NGENLA. Tell your childs healthcare provider if your child has any of these signs or symptoms of fluid retention.odecrease in hormone called cortisol. Your childs healthcare provider will do blood tests to check your childs cortisol levels. Tell your childs healthcare provider if your child has severe fatigue, dizziness, weakness, vomiting, dehydration, or weight loss.odecrease in thyroid hormone levels. Decreased thyroid hormone levels may affect how well NGENLA works. Your childs healthcare provider will do blood tests to check your childs hormone levels.ohip and knee pain or limp (slipped capital femoral epiphysis). Tell your childs healthcare provider if your child has any of these signs or symptoms.oworsening of curvature of the spine (scoliosis). If your child has scoliosis, your child will need to be checked often for an increase in the curve of the spine.osevere and constant stomach (abdominal) pain. This could be sign of pancreatitis. Tell your childs healthcare provider if your child has any new abdominal pain.oloss of fat and tissue weakness in the area of skin you inject. Talk to your childs healthcare provider about rotating the areas where you inject NGENLA.ohigh risk of sudden death in children with Prader-Willi syndrome who are severely obese or have breathing problems, including sleep apnea.oincrease in phosphorus, alkaline phosphatase and parathyroid hormone levels in the blood. Your childs healthcare provider will do blood tests to check this. The most common side effects of NGENLA include: oinjection site reactions (such as pain, swelling, rash, itching, bleeding)ocommon coldoheadacheofeverolow red blood cells (anemia)ocoughovomitingodecrease in thyroid hormone levelsostomach (abdominal) painorashothroat painThese are not all the possible side effects of NGENLA. You should tell your childs healthcare provider if your child has any side effect that bothers them or that does not go away. Call your childs doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store NGENLAoDo not freeze your pen or expose it to heat.oDo not use your pen if it has been frozen or stored in direct sunlight.oDo not use after the expiration date printed on the label has passed or if it has been more than 28 days after first use.Before you use NGENLA pens for the first time (unused pens):oStore in the original carton.oStore the new, unused NGENLA pen in the refrigerator between 36F to 46F (2C to 8C).oUnused prefilled pens may be used until the expiration date printed on the pen label, if kept in the refrigerator.After you use NGENLA pens and there is still medicine left (up to 28 days of use):oTo help you remember when to dispose of (throw away) the pen, write the date of first use on the pen label.oStore remaining NGENLA in the refrigerator between 36F to 46F (2C to 8C) and use within 28 days.oKeep the pen cap on the NGENLA pen when it is not in use.oDo not store the remaining NGENLA pen with needle attached.oDo not use the NGENLA pen if it has been more than 28 days after first use, even if it contains unused medicine.Keep NGENLA and all medicines out of the reach of children.General information about the safe and effective use of NGENLA.Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use NGENLA for condition for which it was not prescribed. Do not give NGENLA to other people, even if they have the same symptoms because it may harm them. You can ask your pharmacist or healthcare provider for information about NGENLA that is written for health professionals.What are the ingredients in NGENLAActive ingredient: somatrogon-ghlaInactive ingredients: citric acid monohydrate, histidine, metacresol (as preservative), poloxamer 188, sodium chloride, sodium citrate, water for injection.This products labeling may have been updated. For the most recent prescribing information, please visit www.pfizer.com.Manufactured by: Pfizer Ireland PharmaceuticalsRingaskiddy,Cork,IrelandUS License No: 2060LAB-1449-1.0 For more information, go to website www.NGENLA.com or call 1-800-438-1985.. oyour child has critical illness caused by certain types of heart or stomach surgery, trauma or breathing (respiratory) problems.. oyour child is allergic to somatrogon-ghla or any of the ingredients in NGENLA. See the end of this leaflet for complete list of ingredients in NGENLA.. oyour child has closed bone growth plates (epiphyses).. oyour child has cancer or other tumors.. oyour childs healthcare provider tells you that your child has certain types of eye problems caused by diabetes (diabetic retinopathy).. oyour child has Prader-Willi syndrome, is severely obese, or has breathing problems including sleep apnea (briefly stop breathing during sleep).. ohas had heart or stomach surgery, trauma or serious breathing (respiratory) problems.. ohas had history of problems breathing while they slept (sleep apnea).. ohas or has had cancer or any tumor.. ohas diabetes.. ois pregnant or plans to become pregnant. It is not known if NGENLA will harm your childs unborn baby. Talk to your childs healthcare provider if your child is pregnant or plans to become pregnant.. ois breastfeeding or plans to breastfeed. It is not known if NGENLA passes into breast milk. You and your childs healthcare provider should decide if they will take NGENLA while breastfeeding.. oRead the detailed Instructions for Use that come with NGENLA.. oNGENLA comes in different dosage strengths. Your childs healthcare provider will prescribe the dose of medicine and the dosage strength that is right for your child.. oYour childs healthcare provider will show you how to inject NGENLA before it is used for the first time. Do not try to inject NGENLA until you have been shown the right way by your childs healthcare provider.. oInject NGENLA exactly as your childs healthcare provider tells you to.. oNGENLA is injected under the skin (subcutaneously) and can be given in the stomach (abdomen), thighs, buttocks, or upper arms. Rotate the site of injection weekly.. oInject NGENLA time each week, on the same day each week, at any time of the day.. oYou may change the day of the week NGENLA is used as long as the last dose was injected or more days before. After the new day of the week has been chosen, continue with the time week schedule.. oIf your child misses dose of NGENLA the missed dose should be injected as soon as possible within days after the missed dose. If more than days have passed, skip your childs missed dose. Inject the next dose on the regularly scheduled day.. oNGENLA prefilled pens are for use by person only.. oDo not share your childs NGENLA prefilled pens and needles with another person, even if the needle has been changed. Your child may give another person an infection or get an infection from them.. ohigh risk of death in people who have critical illnesses because of heart or stomach surgery, trauma or serious breathing (respiratory) problems.. oserious allergic reactions. Get medical help right away if your child has the following symptoms:oswelling of the face, lips, mouth, or tongueotrouble breathingowheezingosevere itchingoskin rashes, redness, or swellingodizziness or faintingofast heartbeat or pounding in the chestosweating. oswelling of the face, lips, mouth, or tongue. otrouble breathing. owheezing. osevere itching. oskin rashes, redness, or swelling. odizziness or fainting. ofast heartbeat or pounding in the chest. osweating. oincreased risk of growth of cancer or tumor that is already present and increased risk of the return of cancer or tumor in people who were treated with radiation to the brain or head as children and who developed low growth hormone problems. Your childs healthcare provider will need to monitor your child for return of cancer or tumor. Contact your childs healthcare provider if your child starts to have headaches, or has changes in behavior, changes in vision, or changes in moles, birthmarks, or the color of the skin. onew or worsening high blood sugar (hyperglycemia) or diabetes. Your childs blood sugar may need to be monitored during treatment with NGENLA.. oincrease in pressure inside the skull (intracranial hypertension). If your child has headaches, eye problems, nausea or vomiting, contact your childs healthcare provider.. oyour childs body holding too much fluid (fluid retention) such as swelling in the hands and feet, pain in the joints or muscles or nerve problems that cause pain, burning or tingling in the hands, arms, legs and feet. Fluid retention can happen in children during treatment with NGENLA. Tell your childs healthcare provider if your child has any of these signs or symptoms of fluid retention.. odecrease in hormone called cortisol. Your childs healthcare provider will do blood tests to check your childs cortisol levels. Tell your childs healthcare provider if your child has severe fatigue, dizziness, weakness, vomiting, dehydration, or weight loss.. odecrease in thyroid hormone levels. Decreased thyroid hormone levels may affect how well NGENLA works. Your childs healthcare provider will do blood tests to check your childs hormone levels.. ohip and knee pain or limp (slipped capital femoral epiphysis). Tell your childs healthcare provider if your child has any of these signs or symptoms.. oworsening of curvature of the spine (scoliosis). If your child has scoliosis, your child will need to be checked often for an increase in the curve of the spine.. osevere and constant stomach (abdominal) pain. This could be sign of pancreatitis. Tell your childs healthcare provider if your child has any new abdominal pain.. oloss of fat and tissue weakness in the area of skin you inject. Talk to your childs healthcare provider about rotating the areas where you inject NGENLA.. ohigh risk of sudden death in children with Prader-Willi syndrome who are severely obese or have breathing problems, including sleep apnea.. oincrease in phosphorus, alkaline phosphatase and parathyroid hormone levels in the blood. Your childs healthcare provider will do blood tests to check this. oinjection site reactions (such as pain, swelling, rash, itching, bleeding)ocommon coldoheadacheofeverolow red blood cells (anemia)ocoughovomitingodecrease in thyroid hormone levelsostomach (abdominal) painorashothroat pain. oinjection site reactions (such as pain, swelling, rash, itching, bleeding). ocommon cold. oheadache. ofever. olow red blood cells (anemia). ocough. ovomiting. odecrease in thyroid hormone levels. ostomach (abdominal) pain. orash. othroat pain. oDo not freeze your pen or expose it to heat.. oDo not use your pen if it has been frozen or stored in direct sunlight.. oDo not use after the expiration date printed on the label has passed or if it has been more than 28 days after first use.. oStore in the original carton.. oStore the new, unused NGENLA pen in the refrigerator between 36F to 46F (2C to 8C).. oUnused prefilled pens may be used until the expiration date printed on the pen label, if kept in the refrigerator.. oTo help you remember when to dispose of (throw away) the pen, write the date of first use on the pen label.. oStore remaining NGENLA in the refrigerator between 36F to 46F (2C to 8C) and use within 28 days.. oKeep the pen cap on the NGENLA pen when it is not in use.. oDo not store the remaining NGENLA pen with needle attached.. oDo not use the NGENLA pen if it has been more than 28 days after first use, even if it contains unused medicine.. 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SPL UNCLASSIFIED SECTION.

2.1Important Dosing and Administration Information. oNGENLA treatment should be supervised by healthcare provider who is experienced in the diagnosis and management of pediatric patients aged years and older with growth failure due to growth hormone deficiency (GHD) [see Indications and Usage (1)].oRefer patient to the Instructions for Use for complete administration instructions.oAdminister 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.oParenteral 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.oPrefilled pens deliver somatrogon-ghla in 0.2 mg or 0.5 mg increments.. oNGENLA treatment should be supervised by healthcare provider who is experienced in the diagnosis and management of pediatric patients aged years and older with growth failure due to growth hormone deficiency (GHD) [see Indications and Usage (1)].. oRefer patient to the Instructions for Use for complete administration instructions.. oAdminister 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.. oParenteral 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.. oPrefilled pens deliver somatrogon-ghla in 0.2 mg or 0.5 mg increments.