DRUG INTERACTIONS-(summary)

 • Replacement Glucocorticoid Treatment Patients treated with glucocorticoid for hypoadrenalism may require an increase in their maintenance or stress dose following initiation of NGENLA

. • Pharmacologic Glucocorticoid Therapy and Supraphysiologic Glucocorticoid Treatment Adjust glucocorticoid dosing in pediatric

BRIEF SUMMARY

SOMATROGEN -(June 2023)

Indication-  treat failure due to inadequate seceretion  of  endogenous growth hormone                                                                                                                                        

Dosage-  recommended dosage is 0.66 mg/kg based on actual body weight administered once weekly

ADR--Adverse reactions reported  are: injection site reactions, nasopharyngitis, headache, pyrexia, anemia, cough, vomiting, hypothyroidism,

C/I- Acute critical sillness, Hypersensitivity to somatrogon-ghla or excipients,  Closed epiphyses, Active malignancy,

 Pat inform- Advise patients and caregivers that serious systemic hypersensitivity reactions  are possible and that prompt medical attention should be sought if an allergic reaction occurs

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U.S.  APPROVED DRUGS DURING 2023                                        

Serial No 26

Name-                       NGENIA

Acive  Ingredient -  Somatrogen-ghla

Pharmacological clssificiation-        To treat failure due to inadequate seceretion                                                                 of  endogenous growth hormone                                                                                                                                                                                

Date of Approval-         6/27/2023

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use                                  NGENLA safely and effectively.

See full prescribing information for NGENLA. NGENLA (somatrogon-ghla) injection, for subcutaneous use

Initial U.S. Approval: 2023

 INDICATIONS AND USAGE-

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

 ADVERSE REACTIONS

 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

CONTRAINDICATIONS -

 • Acute critical illness

 • Hypersensitivity to somatrogon-ghla or excipients

 • Closed epiphyses

 • Active malignancy

 • Active proliferative or severe non-proliferative diabetic retinopathy

. • Prader-Willi syndrome who are severely obese or have severe respiratory impairment

 WARNINGS AND PRECAUTIONS-

 • Severe Hypersensitivity: Severe hypersensitivity reactions may occur. In the event of an allergic reaction, seek prompt medical attention

• Increased Risk of Neoplasms: Monitor patients with preexisting tumors for progression or recurrence. Increased risk of a second neoplasm in childhood cancer survivors treated with somatropin – in particular meningiomas in patients treated with radiation to the head for their first ne

Glucose Intolerance and Diabetes Mellitus:                                                      NGENLA may decrease insulin sensitivity, particularly at higher doses. Monitor glucose levels periodically in all patients receiving NGENLA, especially in patients with existing diabetes mellitus or at risk for its development

 • Intracranial Hypertension: Perform fundoscopic examinations prior to initiation of treatment with NGENLA and periodically thereafter. If preexisting papilledema is identified, evaluate the etiology and treat the underlying cause before initiating. If papilledema occurs with NGENLA, stop treatment

 • Fluid Retention May occur and may be dose dependent. Reduce dose as necessary

. • Hypoadrenalism Monitor patients for reduced serum cortisol levels and/or need for glucocorticoid dose increases in those with known hypoadrenalism

 • Hypothyroidism: Monitor thyroid function periodically as hypothyroidism may become evident or worsen after initiation with NGENLA

 • Slipped Capital Femoral Epiphysis: May develop. Evaluate patients with the onset of a limp or persistent hip or knee pain

 • Progression of Preexisting Scoliosis: Monitor for development or progression of scoliosis

 • Pancreatitis: Consider pancreatitis in patients with persistent severe abdominal pain

 • Lipoatrophy May occur if NGENLA is administered in the same location over a long period of time. Rotate injection sites 

DOSAGE AND ADMINISTRATION-

 • NGENLA treatment should be supervised by a healthcare provider who is experienced in the diagnosis and management of pediatric patients with growth hormone deficiency

. • Administer NGENLA by subcutaneous injection once weekly, on the same day each week, at any time of the day in the abdomen, thighs, buttocks, or upper arms with weekly rotation of injection site

 • The recommended dosage is 0.66 mg/kg based on actual body weight administered once weekly

 • Individualize dosage for each patient based on the growth response

 • Patients switching from daily growth hormone may initiate treatment with once-weekly NGENLA on the day following their last daily injection

 • If more than one injection is required to deliver a complete dose, each injection should be administered at a different injection site

 DOSAGE FORMS AND STRENGTHS-

 Injection:

• 24 mg/1.2 mL (20 mg/mL) single-patient-use prefilled pen that delivers a dose in 0.2 mg increments

 • 60 mg/1.2 mL (50 mg/mL) single-patient-use prefilled pen that delivers a dose in 0.5 mg increments 

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

• Neoplasm-

 Advise childhood cancer survivors and caregivers that individuals treated with radiation to the head are at increased risk of secondary neoplasms and, as a precaution, need to be monitored for recurrence.

Advise patients to report marked changes in skin pigmentation or changes in the appearance of preexisting nevi

• 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

• Intracranial Hypertension -

Advise patients and caregivers to report to their healthcare provider any visual changes, headache, and nausea and/or vomiting

• 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

• 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

• 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.

Manufactured by: Pfizer Ireland Pharmaceuticals Ringaskiddy, Cork, Ireland US License No: 2060 This product’s labeling may have been updated. For the most recent prescribing information, please visit www.pfizer.com. LAB-1433-0.9

CLINICAL PHARMACOLOGY

1. Mechanism of Action-

Somatrogon-ghla binds to the GH receptor and initiates a signal transduction cascade culminating in changes in growth and metabolism.

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

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

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

3. Pharmacokinetics-

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

Absorption-

Following subcutaneous injection, serum concentrations increased slowly, peaking 6 to 25 hours with a median of 11 hours after dosing. In pediatric patients with GHD, somatrogon-ghla exposure increases in a dose-proportional manner for doses of 0.25 mg/kg/wk, 0.48 mg/kg/wk, and 0.66 mg/kg/wk.

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

Distribution 

In pediatric patients with GHD, the mean population PK estimated apparent central volume of distribution was 0.342 L/kg and apparent peripheral volume of distribution was 0.671 L/kg.

Elimination

In pediatric patients with GHD, the mean population PK estimated apparent clearance was 0.0398 L/h/kg. The mean population PK estimated effective half-life was 37.7 hours, which allows for weekly dosing. Somatrogonghla 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-

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.

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.

USE IN SPECIFIC POPULATIONS

1 Pregnancy Risk Summary

There are no available data on NGENLA use in pregnant women to evaluate for a drug associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes.

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.

2 Lactation Risk Summary-

There are no data on the presence of somatrogon-ghla in human or animal milk, the effects on the breastfed infant, or the effects on milk production

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for NGENLA and any potential adverse effects on the breastfed infant from NGENLA or from the underlying maternal condition.

3. Females and Males of Reproductive Potential-

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

4. Pediatric Use-

The safety and effectiveness of NGENLA have been established for the treatment of growth failure due to inadequate secretion of endogenous growth hormone (GH) in pediatric patients aged 3 years and older

Risks in pediatric patients associated with growth hormone use include

• Increased risk of second neoplasm in pediatric cancer survivors treated with radiation to the brain and/or head [see Warnings and Precautions (5.3)]

• Slipped capital femoral epiphysis 

• Progression of preexisting scoliosis

• Pancreatitis

• Sudden death in pediatric patients with Prader-Willi Syndrome. NGENLA is not indicated for the treatment of pediatric patients with growth failure secondary to genetically confirmed Prader-Willi syndrome.

 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.

11 DESCRIPTION Somatrogon-ghla, a human growth hormone analog, is a fusion protein produced in Chinese Hamster Ovary (CHO) cells by