Ngenla

Description for Ngenla

Somatrogon-ghla, a human growth hormone analog, is a fusion protein produced in Chinese Hamster Ovary (CHO) cells by recombinant DNA technology. It is comprised of the amino acid sequence of human growth hormone (hGH) with one copy of the C-terminal peptide (CTP) from the beta chain of human chorionic gonadotropin (hCG) at the N-terminus and 2 copies of CTP (in tandem) at the C-terminus. Somatrogon-ghla has an approximate molecular weight of 40 KDa.

NGENLA (somatrogon-ghla) injection is a sterile, clear and colorless to slightly light yellow solution for subcutaneous use supplied in a 24 mg/1.2 mL (20 mg/mL) or 60 mg/1.2 mL (50 mg/mL) single-patient-use prefilled pen.

Each 1.2 mL of solution contains either 24 mg or 60 mg of somatrogon-ghla, and the inactive ingredients citric acid monohydrate (0.3 mg), histidine (1.9 mg), metacresol (4 mg, as a preservative), poloxamer 188 (2 mg), sodium chloride (10 mg) and sodium citrate (2.8 mg) in water for injection. NGENLA has a pH of approximately 6.6.

ADVERSE REACTIONS

The following clinically significant adverse reactions are described elsewhere in the labeling:

• Increased mortality in patients with acute critical illness [see Warnings and Precautions (5.1)]
• Severe hypersensitivity [see Warnings and Precautions (5.2)]
• Increased risk of neoplasm [see Warnings and Precautions (5.3)]
• Glucose intolerance and diabetes mellitus [see Warnings and Precautions (5.4)]
• Intracranial hypertension [see Warnings and Precautions (5.5)]
• Fluid retention [see Warnings and Precautions (5.6)]
• Hypoadrenalism [see Warnings and Precautions (5.7)]
• Hypothyroidism [see Warnings and Precautions (5.8)]
• Slipped capital femoral epiphysis [see Warnings and Precautions (5.9)]
• Progression of preexisting scoliosis [see Warnings and Precautions (5.10)]
• Pancreatitis [see Warnings and Precautions (5.11)]
• Lipoatrophy [see Warnings and Precautions (5.12)]
• Sudden death in pediatric patients with Prader-Willi syndrome [see Warnings and Precautions (5.13)] 

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Safety data are derived from a safety and efficacy study in pediatric patients with GHD [see Clinical Studies (14.1)]. The data from the 12-month main study period reflect exposure of 109 patients to NGENLA administered once weekly (0.66 mg/kg/wk) and 115 patients to somatropin administered once daily (0.034 mg/kg/day).

The mean age across the treatment groups, was 7.7 years (min 3.01, max 11.96); 40.2% of patients were >3 years to ≤7 years, 59.8% were >7 years, 71.9% of patients were male, and 28.1% were female. In this study, 74.6% of patients were White, 20.1% were Asian, 0.9% were Black or African American, 0.5% were American Indian or Alaska Native, 0.5% were Native Hawaiian or Other Pacific Islander, and for 3.6% race information was missing; 10.7% of patients identified as Hispanic or Latino. Baseline disease characteristics were balanced across treatment groups.

Table 1 shows the adverse reactions that occurred in ≥5% of patients treated with NGENLA or daily somatropin during the 12-month main study period. Reporting of injection site reactions was solicited through the use of a patient diary after each weekly injection for patients administered NGENLA and once weekly for patients administered daily injections of somatropin.

Table 1 Adverse Reactions Occurring in ≥5% of NGENLA- or Somatropin-Treated Pediatric Patients (52 Weeks of Treatment)

Adverse Drug Reactions	Daily Somatropin (N=115) n (%)	NGENLA (N=109) n (%)
Injection site reactionsa	29 (25.2)	46 (42.2)
Nasopharyngitisb	33 (28.7)	36 (33)
Headache	25 (21.7)	18 (16.5)
Pyrexia	17 (14.8)	18 (16.5)
Anemia	10 (8.7)	10 (9.2)
Cough	9 (7.8)	9 (8.3)
Vomiting	9 (7.8)	8 (7.3)
Hypothyroidism	3 (2.6)	7 (6.4)
Abdominal pain	8 (7.0)	7 (6.4)
Rash	7 (6.1)	6 (5.5)
Oropharyngeal pain	4 (3.5)	6 (5.5)
Arthralgia	8 (7.0)	5 (4.6)
Otitis media	10 (8.7)	5 (4.6)
Tonsillitis	6 (5.2)	5 (4.6)
Bronchitis	9 (7.8)	3 (2.8)
Adverse reactions that are medically related were grouped to a single preferred term. a Injection site reactions included: injection site pain (39% somatrogon-ghla vs 25% daily somatropin), injection site swelling/induration/hypertrophy/inflammation (10% somatrogon-ghla vs 1% daily somatropin), injection site erythema (8% somatrogon-ghla vs none daily somatropin), injection site pruritus (5% somatrogon-ghla vs none daily somatropin), injection site hemorrhage (5% somatrogon-ghla vs none daily somatropin). b Nasopharyngitis included: rhinitis, pharyngitis, rhinitis allergic, pharyngitis streptococcal, viral pharyngitis, nasopharyngitis.

Laboratory Tests

More NGENLA-treated patients shifted from normal eosinophil levels at baseline to elevated eosinophil levels at the end of the 12-month study compared to the daily somatropin group (29% vs 12%).

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of somatropin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Musculoskeletal and connective tissue disorders – osteonecrosis in pediatric patients

Drug Interactions for Ngenla

Table 2 includes a list of drugs with clinically significant drug interactions when administered concomitantly with NGENLA and instructions for preventing or managing them.

Table 2 Clinically Significant Drug Interactions with NGENLA

Replacement Glucocorticoid Treatment
Clinical Impact:	Microsomal enzyme 11β-hydroxysteroid dehydrogenase type 1 (11βHSD-1) is required for conversion of cortisone to its active metabolite, cortisol, in hepatic and adipose tissue. Growth hormone inhibits 11βHSD-1. Consequently, individuals with untreated GH deficiency have relative increases in 11βHSD-1 and serum cortisol. Initiation of NGENLA may result in inhibition of 11βHSD-1 and reduced serum cortisol concentrations.
Intervention:	Patients treated with glucocorticoid replacement for hypoadrenalism may require an increase in their maintenance or stress doses following initiation of NGENLA [see Warnings and Precautions (5.7)].
Examples:	Cortisone acetate and prednisone may be affected more than others because conversion of these drugs to their biologically active metabolites is dependent on the activity of 11βHSD-1.
Supraphysiologic Glucocorticoid Treatment
Clinical Impact:	Supraphysiologic glucocorticoid treatment may attenuate the growth- promoting effects of NGENLA in pediatric patients.
Intervention:	Carefully adjust glucocorticoid replacement dosing in pediatric patients receiving glucocorticoid treatments to avoid hypoadrenalism and an inhibitory effect on growth.
Cytochrome P450-Metabolized Drugs
Clinical Impact:	Limited published data indicate that growth hormone treatment increases cytochrome P450 (CYP450)-mediated antipyrine clearance. NGENLA may alter the clearance of compounds known to be metabolized by CYP450 liver enzymes.
Intervention:	Careful monitoring is advisable when NGENLA is administered in combination with drugs metabolized by CYP450 liver enzymes.
Oral Estrogen
Clinical Impact:	Oral estrogens may reduce the serum IGF-1 response to NGENLA.
Intervention:	Patients receiving oral estrogen replacement may require higher NGENLA dosages.
Insulin and/or Other Antihyperglycemic Agents
Clinical Impact:	Treatment with NGENLA may decrease insulin sensitivity, particularly at higher doses.
Intervention:	Patients with diabetes mellitus may require adjustment of their doses of insulin and/or other antihyperglycemic agents [see Warnings and Precautions (5.4)].

Warnings for Ngenla

Included as part of the PRECAUTIONS section.

Precautions for Ngenla

Increased Mortality in Patients with Acute Critical Illness

Increased mortality in patients with acute critical illness due to complications following open heart surgery, abdominal surgery or multiple accidental trauma, or those with acute respiratory failure has been reported with somatropin [see Contraindications (4)]. The safety of continuing NGENLA treatment for the approved indication in patients who concurrently develop these illnesses has not been established.

Severe Hypersensitivity

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

Increased Risk of Neoplasms

Active Malignancy

There is an increased risk of malignancy progression with somatropin treatment in patients with active malignancy [see Contraindications (4)]. Any preexisting malignancy should be inactive, and its treatment should be completed prior to instituting therapy with NGENLA. Discontinue NGENLA if there is evidence of recurrent malignancy.

Risk of Second Neoplasm in Pediatric Patients

In childhood cancer survivors, who were treated with radiation to the brain/head for their first neoplasm and who developed subsequent GHD and were treated with somatropin, an increased risk of a second neoplasm has been reported. Intracranial tumors, in particular meningiomas, were the most common of these second neoplasms. Monitor all patients with a history of GHD secondary to an intracranial neoplasm while on NGENLA therapy for progression or recurrence of the tumor.

New Malignancy During Treatment

Because children with certain rare genetic causes of short stature have an increased risk of developing malignancies, thoroughly consider the risks and benefits of starting NGENLA in these patients. If treatment with NGENLA is initiated, carefully monitor these patients for development of neoplasms.

Monitor patients on NGENLA therapy carefully for increased growth or potential malignant changes of preexisting nevi. Advise patients and/or caregivers to report marked changes in behavior, onset of headaches, vision disturbances and/or changes in skin pigmentation or changes in the appearance of preexisting nevi.

Glucose Intolerance and Diabetes Mellitus

Treatment with growth hormone may decrease insulin sensitivity, particularly at higher doses. New onset type 2 diabetes mellitus has been reported in patients receiving growth hormone. Patients with undiagnosed pre- diabetes and diabetes mellitus may experience worsened glycemic control and become symptomatic. Monitor glucose levels periodically in all patients receiving NGENLA, especially in those with risk factors for diabetes mellitus, such as obesity, Turner syndrome, or a family history of diabetes mellitus. Patients with preexisting type 1 or type 2 diabetes mellitus or pre-diabetes should be monitored closely. The doses of antidiabetic agents may require adjustment when NGENLA is initiated.

Intracranial Hypertension

Intracranial hypertension (IH) with papilledema, visual changes, headache, nausea, and/or vomiting has been reported in patients treated with somatropin. Symptoms usually occurred within the first eight (8) weeks after the initiation of somatropin therapy. In all reported cases, IH-associated signs and symptoms rapidly resolved after cessation of therapy or a reduction of somatropin dose.

Perform fundoscopic examination before initiating treatment with NGENLA to exclude preexisting papilledema and periodically thereafter. If papilledema is identified prior to initiation, evaluate the etiology and treat the underlying cause before initiating NGENLA. NGENLA should be temporarily discontinued in patients with clinical or fundoscopic evidence of IH. If IH is confirmed, restart treatment with NGENLA at a lower dose after IH-associated signs and symptoms have resolved.

Fluid Retention

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

Hypoadrenalism

Patients receiving growth hormone therapy who have or are at risk for pituitary hormone deficiency(s) may be at risk for reduced serum cortisol levels and/or unmasking of central (secondary) hypoadrenalism. In addition, patients treated with glucocorticoid replacement for previously diagnosed hypoadrenalism may require an increase in their maintenance or stress doses following initiation of NGENLA treatment. Monitor patients for reduced serum cortisol levels and/or need for glucocorticoid dose increases in those with known hypoadrenalism [see Drug Interactions (7)].

Hypothyroidism

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

Slipped Capital Femoral Epiphysis

Slipped capital femoral epiphysis may occur more frequently in patients undergoing rapid growth. Slipped capital femoral epiphysis may lead to osteonecrosis. Cases of slipped capital femoral epiphysis with or without osteonecrosis have been reported in pediatric patients with short stature receiving somatropin. Evaluate pediatric patients receiving NGENLA with the onset of a limp or complaints of persistent hip or knee pain for slipped capital femoral epiphysis and osteonecrosis and manage accordingly.

Progression 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 a history of scoliosis for disease progression.

Pancreatitis

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.

Lipoatrophy

When NGENLA is administered subcutaneously at the same site over a long period of time, lipoatrophy may result. Rotate injection sites when administering NGENLA to reduce this risk [see Dosage and Administration (2.1)].

Sudden 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.

Laboratory Tests

Serum levels of phosphorus, alkaline phosphatase, and parathyroid hormone may increase with NGENLA therapy. If a patient is found to have abnormal laboratory tests, monitor as appropriate.

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

No long term carcinogenicity studies have been performed with somatrogon-ghla.

Mutagenesis

Genotoxicity studies have not been performed.

Impairment of Fertility

The potential for somatrogon-ghla to affect fertility and early embryonic development was evaluated in male and female rats administered subcutaneously before cohabitation, through mating to implantation.

Somatrogon-ghla elicited an increase in estrous cycle length, copulatory interval, and number of corpora lutea at exposures ≥22-fold the MRHD, but there was no impact on female fertility, mating indices, number of viable embryos or early embryonic development, or on male fertility up to 30 mg/kg every two days (45-fold the MRHD based on exposure).

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.

Contraindications for Ngenla

• Acute critical illness after open heart surgery, abdominal surgery or multiple accidental trauma, or those with acute respiratory failure due to the risk of increased mortality with somatropin [see Warnings and Precautions (5.1)].
• Hypersensitivity to somatrogon-ghla or any of the excipients in NGENLA [see Warnings and Precautions (5.2)].
• Closed
• Active malignancy due to the risk of malignancy progression [see Warnings and Precautions (5.3)].
• Active proliferative or severe non-proliferative diabetic retinopathy [see Warnings and Precautions (5.4)].
• Prader-Willi syndrome who are severely obese, have a history of upper airway obstruction or sleep apnea or have severe respiratory impairment due to the risk of sudden death [see Warnings and Precautions (5.13)].

Clinical Pharmacology for Ngenla

Mechanism of Action

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

Pharmacodynamics

Following single dose administration of somatrogon, dose-dependent increases in IGF-1 response were observed.

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

Pharmacokinetics

Somatrogon-ghla pharmacokinetics (PK) was assessed using a population PK approach for NGENLA in 151 pediatric patients (aged 3 to 15.5 years) with GHD.

Absorption

Following subcutaneous injection, serum concentrations increased slowly, peaking 6 to 25 hours with a median of 11 hours after dosing.

In pediatric patients with GHD, somatrogon-ghla exposure increases in a dose-proportional manner for doses of

0.25 mg/kg/wk, 0.48 mg/kg/wk, and 0.66 mg/kg/wk. There is no accumulation of somatrogon-ghla after once weekly administration. In pediatric patients with GHD, the mean population PK estimated steady-state peak concentrations (mean ± SD) following 0.66 mg/kg/wk was 495 ± 90 ng/mL.

Distribution

In pediatric patients with GHD, the mean population PK estimated apparent central volume of distribution was

0.342 L/kg and apparent peripheral volume of distribution was 0.671 L/kg.

Elimination

In pediatric patients with GHD, the mean population PK estimated apparent clearance was 0.0398 L/h/kg. The mean population PK estimated effective half-life was 37.7 hours, which allows for weekly dosing. Somatrogon- ghla will be present in the circulation for about 8 days after the last dose.

Metabolism

The metabolism of somatrogon-ghla is believed to be classical protein catabolism, with subsequent recovery of the amino acids and return to the systemic circulation.

Excretion

Excretion was not evaluated in clinical studies.

Specific Populations

Based on population PK analyses, age, sex, race, and ethnicity do not have a clinically meaningful effect on the pharmacokinetics of somatrogon-ghla in pediatric patients with GHD. The exposure of somatrogon-ghla decreases with an increase in body weight. However, the somatrogon-ghla dosing regimen of 0.66 mg/kg/wk provides adequate systemic exposure over the body weight range of 10 to 54 kg evaluated in the clinical studies.

Renal or Hepatic Impairment

NGENLA has not been studied in patients with hepatic or renal impairment.

Immunogenicity

The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of somatrogon or other growth hormone products.

During the 12-month main period of study NCT 02968004, 84/109 (77.1%) of somatrogon-ghla-treated patients tested positive for anti-drug antibodies, with most showing specificity to human growth hormone. The anti-drug antibodies persisted in most of the subjects during the study. Neutralizing antibodies developed in 8/217 (3.7%) of somatrogon-ghla-treated patients during the study for up to 42 months of exposure to somatrogon-ghla. The neutralizing antibodies were transient in all subjects. Anti-drug antibodies, including neutralizing-antibodies, did not appear to have a clinically significant impact on the safety or effectiveness of NGENLA during the

12-month randomized treatment period. Additionally, no apparent effect of anti-drug antibodies on growth was observed for additional 30 months of exposure to somatrogon-ghla in the uncontrolled extension period of study NCT 02968004.

Anti-Drug Antibody Effects on Pharmacokinetics

The population pharmacokinetic analysis of data from study NCT 02968004 showed that patients who tested positive for anti-drug antibodies had an approximately 26% decrease in apparent clearance. These anti-drug antibody-associated pharmacokinetic changes are not considered to be clinically significant.

PATIENT COUNSELING INFORMATION

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

• Hypersensitivity Reactions

  Advise patients and caregivers that serious systemic hypersensitivity reactions (anaphylaxis and angioedema) are possible and that prompt medical attention should be sought if an allergic reaction occurs [see Warnings and Precautions (5.2)].

• Neoplas

  Advise childhood cancer survivors and caregivers that individuals treated with radiation to the head are at increased risk of secondary neoplasms and, as a precaution, need to be monitored for recurrence. Advise patients to report marked changes in skin pigmentation or changes in the appearance of preexisting nevi [see Warnings and Precautions (5.3)].

• Glucose Intolerance/Diabetes Mellitus

  Advise patients and caregivers that new onset of insulin resistance and hyperglycemia may occur and monitoring of blood glucose during treatment with NGENLA in patients with glucose intolerance or who have risk factors for diabetes, may be needed [see Warnings and Precautions (5.4)].

• Intracranial Hypertension

  Advise patients and caregivers to report to their healthcare provider any visual changes, headache, and nausea and/or vomiting [see Warnings and Precautions (5.5)].

• Fluid Retention

  Advise patients and caregivers that fluid retention during NGENLA therapy may occur. Inform patients of the clinical manifestations of fluid retention (e.g. edema, arthralgia, myalgia, nerve compression syndromes including carpal tunnel syndrome/paresthesia) and to report to their healthcare provider if any of these signs or symptoms occur during treatment with NGENLA.

• Hypoadrenalism

  Advise patients and caregivers who have or who are at risk for corticotropin deficiency that hypoadrenalism may develop and to report to their healthcare provider if extreme fatigue, dizziness, weakness, vomiting, dehydration or weight loss is experienced during treatment with NGENLA [see Warnings and Precautions (5.7)].

• Hypothyroidism

  Advise patients and caregivers that undiagnosed/untreated hypothyroidism may prevent an optimal response to NGENLA. Advise patients and caregivers they may require periodic thyroid function tests during treatment with NGENLA [see Warnings and Precautions (5.8)].

• Pancreatitis

  Advise patients and caregivers that pancreatitis may develop and to report to their healthcare provider any new onset persistent severe abdominal pain.

• Lipoatrophy

  Advise patients and caregivers that lipoatrophy may occur if NGENLA is administered subcutaneously at the same site over a long period of time. Advise patients to rotate injection sites when administering NGENLA to reduce this risk.