DRUG INTERACTIONS-

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

. • Pharmacologic Glucocorticoid Therapy and Supraphysiologic Glucocorticoid Treatment:                                                                                                                  Adjust glucocorticoid replacement dosing in pediatric patients receiving glucocorticoid treatment to avoid both hypoadrenalism and an inhibitory effect on growth

• Cytochrome P450-Metabolized Drugs: SKYTROFA may alter the clearance. Monitor carefully if used with SKYTROFA

 • Oral Estrogen: Larger doses of SKYTROFA may be required

 • Insulin and/or Other Antihyperglycemic Agents: Dose adjustment of insulin or antihyperglycemic agent may be required

BRIEF SUMMARY

LONAPEGSOMATROPIN-(Aug 2021)

Indn-   To treat short stature due to inadequate secrection of endogenous growth hormone  

Comp-    a lyophilized powder available in single-dose, dual-chamber, prefilled cartridges containing lonapegsomatropin-tcgd and diluent, Water for Injection, as follows: For injection: 3 mg, 3.6 mg, 4.3 mg, 5.2 mg, 6.3 mg, 7.6 mg, 9.1 mg, 11 mg and 13.3 mg

ADR-  Most common adverse reactions in pediatric patients include: viral infection, pyrexia, cough, nausea and vomiting, hemorrhage, diarrhea, abdominal pain, and arthralgia and arthritis

CI-  Acute critical illness 

• Hypersensitivity to somatropin or any of the excipients                                                     • Children with closed epiphyses                                                                                        • Active malignancy                                                                                                              • Active proliferative or severe non-proliferative diabetic retinopathy                                  • Children with Prader-Willi syndrome who are severely obese or have severe respiratory impairment due to risk of sudden death

WARNINGS-

­ • Severe Hypersensitivity: Serious 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 progressions or recurrence. Increased risk of a second neoplasm in childhood cancer survivors treated with somatropin – in particular meningiomas in patients treated with radiation to the head for their first neoplasm

Pat Inform-

 Provide appropriate instructions for injection to the patient/caregiver, by providing the  Auto-Injector Instructions for Use  .

• Advise patients/caregivers to refer to the Instructions for Use that accompanies the  Auto-Injector for complete mixing and administration instructions with illustrations 

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 U.S. FDA APPROVED DRUGS SURING 2021                                          

Serial No 37

Name of the Drug-    SYTROFA

Active Ingredient -   Lonapegsomatropin

Pharmacological Classification- To treat short stature due to inadequate                                                                           secrection of endogenous growth hormone                                                                                                                                                                                                                                                                                                      

 Date of Approval-          8/25/2021

HIGHLIGHTS OF PRESCRIBING INFORMATION-                            

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

See full prescribing information for SKYTROFA™. SKYTROFA™ (lonapegsomatropin-tcgd) for injection, for subcutaneous use

Initial U.S. Approval: 2021 -

INDICATIONS AND USAGE-

­ SKYTROFA is a human growth hormone indicated for the treatment of pediatric patients 1 year and older who weigh at least 11.5 kg and have growth failure due to inadequate secretion of endogenous growth hormone (GH)

ADVERSE REACTIONS-

­ Most common adverse reactions (=5%) in pediatric patients include: viral infection, pyrexia, cough, nausea and vomiting, hemorrhage, diarrhea, abdominal pain, and arthralgia and arthritis

CONTRAINDICATIONS-

­ • Acute critical illness 

• Hypersensitivity to somatropin or any of the excipients in SKYTROFA 

• Children with closed epiphyses

 • Active malignancy

 • Active proliferative or severe non-proliferative diabetic retinopathy

 • Children with Prader-Willi syndrome who are severely obese or have severe respiratory impairment due to risk of sudden death

WARNINGS AND PRECAUTIONS-

­ • Severe Hypersensitivity: Serious 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 progressions or recurrence. Increased risk of a second neoplasm in childhood cancer survivors treated with somatropin – in particular meningiomas in patients treated with radiation to the head for their first neoplasm

Glucose Intolerance and Diabetes Mellitus: May be unmasked.Periodically monitor glucose levels in all patients. Doses of concurrent antihyperglycemic drugs in diabetics may require adjustment

 • Intracranial Hypertension: Exclude preexisting papilledema. May develop and is usually reversible after discontinuation or dose reduction

 • Fluid Retention (i.e., edema, arthralgia, carpal tunnel syndrome): May occur. 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: May first become evident or worsen

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

 • Progression of Preexisting Scoliosis: May develop

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

DOSAGE AND ADMINISTRATION

­ SKYTROFA should be administered subcutaneously into the abdomen, buttock, or thigh with regular rotation of the injection sites.The recommended dose is 0.24 mg/kg body weight once-weekly. See Full Prescribing Information for instructions on preparation and administration of drug

DOSAGE FORMS AND STRENGTHS-

­ SKYTROFA is a lyophilized powder available in single-dose, dual-chamber, prefilled cartridges containing lonapegsomatropin-tcgd and diluent, Water for Injection, as follows: For injection: 3 mg, 3.6 mg, 4.3 mg, 5.2 mg, 6.3 mg, 7.6 mg, 9.1 mg, 11 mg and 13.3 mg

PATIENT COUNSELING INFORMATION-

• Provide appropriate instructions for injection to the patient/caregiver, by providing the SKYTROFA Auto-Injector Instructions for Use (available at www.Skytrofa.com/IFU). Patients/caregivers and healthcare providers may also call the Ascendis Pharma Customer Support toll-free number at 1-844-442-7236 (1-844-44ASCENDIS) for assistance or additional training, if needed.

• Advise patients/caregivers to refer to the Instructions for Use that accompanies the SKYTROFA Auto-Injector for complete mixing and administration instructions with illustrations 

Instruct patients/caregivers of proper needle disposal and caution against any reuse of needles. An appropriate container for the disposal of used cartridge and needle should be used.

• Advise patients/caregivers to administer SKYTROFA once weekly, at any time of day. Advise patients/caregivers that doses can be taken 2 days before or 2 days after the scheduled dosing day.

Advise patients/caregivers to resume once-weekly dosing for the next dose. If more than 2 days have passed from the schedule dosing day, advise patients/caregivers to skip the missed dose and take the next dose on the regularly scheduled day.

If subsequently changing the regular dosing day to a different day of the week, advise patients/caregivers to ensure that at least 5 days will elapse between the last dose and the newly-established regular dosing day. 

• Neoplasms – Advise childhood cancer survivors/caregivers that individuals treated with brain/head radiation are at increased risk of secondary neoplasms and, as a precaution, need to be monitored for recurrence. Advise patients/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/Diabetes Mellitus – Advise patients/caregivers that new onset impaired glucose intolerance/type 2 diabetes mellitus or exacerbation of preexisting diabetes mellitus can occur and monitoring of blood glucose during treatment with SKYTROFA may be needed.

• Intracranial Hypertension – Advise patients/caregivers to report to their healthcare provider any visual changes, headache, and nausea and/or vomiting.

• Fluid Retention – Advise patients/caregivers that fluid retention during SKYTROFA replacement therapy may occur. Inform patients/caregivers 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 SKYTROFA.

• Hypoadrenalism – Advise patients/caregivers that patients who have or who are at risk for pituitary hormone deficiency(s) that hypoadrenalism may develop and to report to their healthcare provider if they experience hyperpigmentation, extreme fatigue, dizziness, weakness, or weight loss.

• Hypothyroidism – Advise patients/caregivers that undiagnosed/untreated hypothyroidism may prevent an optimal response to SKYTROFA. Advise patients/caregivers that patients may require periodic thyroid function tests.

• Pancreatitis – Advise patients/caregivers that pancreatitis may develop and to report to their healthcare provider any new onset abdominal pai

• Hypersensitivity Reactions – Advise patients/caregivers that serious systemic hypersensitivity reactions (anaphylaxis and angioedema) are possible, and to seek prompt medical attention should an allergic reaction occur.

• Administration: Counsel patients/caregivers that they should never share the SKYTROFA Auto-Injector with another person, even if the needle is changed. Sharing of the Auto-Injector between patients may pose a risk of transmission of infection.

© 2021 Ascendis Pharma. All rights reserved. SKYTROFA™, Ascendis®, TransCon®, the Ascendis Pharma logo and the company logo are trademarks owned by the Ascendis Pharma Group.

PATENT INFORMATION: www.ascendispharma.us/products/patents

Manufactured by: Ascendis Pharma Endocrinology Division A/S Tuborg Boulevard 12 Hellerup Denmark DK-2900 Reference ID: 4846899 Page 18 of 18 U.S. License Number XXXX For information about SKYTROFA contact: Ascendis Pharma, Inc. 500 Emerson Street Palo Alto, CA 94301, USA 1-844-442-7236 (1-844-44ASCENDIS)

CLINICAL PHARMACOLOGY

1 Mechanism of Action-

 SKYTROFA is a pegylated human growth hormone (somatropin) for once-weekly subcutaneous injection 

Somatropin binds to the growth hormone (GH) receptor in the cell membrane of target cells resulting in intracellular signal transduction and a host of pharmacodynamic effects.

Somatropin has direct tissue and metabolic effects, and indirect effects mediated by insulin-like growth factor-1 (IGF-1), including stimulation of chondrocyte differentiation and proliferation, stimulation of hepatic glucose output, protein synthesis and lipolysis.

Somatropin stimulates  skeletal growth in pediatric patients with growth hormone deficiency (GHD) as a result of effects on the growth plates (epiphyses) of long bones.

2. Pharmacodynamics- Somatropin released from SKYTROFA produces a dose linear IGF-1 response, with a change of 0.02 mg/kg on average resulting in a change in IGF-1 standard deviation score (SDS) of 0.17.

At steady-state, IGF-1 levels peak approximately 2 days post-dose, with the average weekly IGF-1 occurring approximately 4.5 days post-dose. IGF-1 levels are in the normal range for GHD patients for the majority of the week, similar to daily somatropin.

3. Pharmacokinetics-                                                                                             Absorption-                                                                                                              Following subcutaneous dose administration, SKYTROFA releases fully active somatropin via autocleavage of the TransCon linker that follows first-order kinetics. In pediatric patients with GHD, following subcutaneous dose administration of 0.24 mg/kg/week SKYTROFA, the observed mean (CV%) steady state peak serum concentration (Cmax) of lonapegsomatropin-tcgd was 1230 (86.3) ng hGH/mL, and the median time to reach maximum concentrations (Tmax) was 25 hours. For released somatropin, Cmax was 15.2 (83.4) ng/mL with a median Tmax of 12 hours.

The mean (CV%) somatropin exposure over the one-week dose interval (area under the curve) was 500 (83.8) h*ng/mL. No significant accumulation of lonapegsomatropin-tcgd and somatropin following repeat dose administration was observed. Cmax of the methoxypolyethylene glycol carrier was 13.1 (28.1) µg /mL with a median Tmax of 36 hours. In healthy adults, following single subcutaneous dose administration in the range of 0.24 to 0.42 mg/kg of SKYTROFA, exposure of released somatropin increased greater than proportional to dose.

Distribution-                                                                                                                      In pediatric patients with GHD, the mean (CV%) steady state apparent volume of distribution of lonapegsomatropin-tcgd after subcutaneous administration of 0.24 mg/kg/week SKYTROFA was 0.13 (109) L/kg. A similar distribution pattern as observed for daily somatropin is expected once somatropin is released from lonapegsomatropin-tcgd.

Elimination-                                                                                                               Metabolism -                                                                                                                      The metabolism of somatropin involves protein catabolism in both the liver and kidneys. The methoxypolyethylene glycol carrier is cleared by the kidneys.

Excretion-                                                                                                                          In pediatric patients with GHD, the mean (CV%) lonapegsomatropin-tcgd apparent clearance at steady state was 3.2 (67) mL/h/kg following subcutaneous administration of 0.24 mg/kg/week SKYTROFA with a mean (±SD) observed half-life of 30.7 (±12.7) hours.

The apparent half-life of somatropin released from lonapegsomatropin-tcgd was approximately 25 hours. 

Specific Populations-                                                                                                Based on a population pharmacokinetic analysis, age, sex, race, and body weight do not have clinically meaningful effects on pharmacokinetics. Male and Female Patients — No sex-specific pharmacokinetic studies have been performed with SKYTROFA.

The available literature indicates that the pharmacokinetics of somatropin are similar in men and women. 

USE IN SPECIFIC POPULATIONS

1. Pregnancy Risk Summary-

 There are no available data on lonapegsomatropin-tcgd use in pregnant patients to evaluate a drug-as

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

In the U.S. general population, the estimated background risk of major birth defects and miscarriages in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

2.-Lactation-                                                                                                                There are no data on the presence of lonapegsomatropin-tcgd in human milk, effects on the breastfed infant, or effects on milk production. High molecular weight therapeutic proteins, including lonapegsomatropin-tcgd, are expected to have low passage into human milk and limited systemic exposure in the breastfed infant

 Additionally, published data indicate that exogenous somatropin does not increase normal human milk concentrations of growth hormone. No adverse effects on the breastfed infant have been reported with somatropin.

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

3. Pediatric Use-                                                                                                        Safety and effectiveness of SKYTROFA have been established in pediatric patients 1 year and older and who weigh at least 11.5 kg.

Pediatric use was established in a controlled study of 161 treatment-naïve pediatric patients ages 3 to 13 years and by supportive data in pediatric patients 1 year and older 

The safety and effectiveness of SKYTROFA in children less than 1 year of age have not been established. Use of somatropin in pediatric patients with Prader-Willi syndrome has been associated with reports of sudden death. SKYTROFA is not indicated for the treatment of pediatric patients with growth failure due to genetically confirmed Prader-Willi syndrome 

 DRUG ABUSE AND DEPENDENCE -

1. Controlled Substance SKYTROFA is a prodrug of somatropin. Somatropin is not a controlled substance.

2 Abuse- Inappropriate use of somatropin may result in significant negative health consequences.

3. Dependence- Somatropin is not associated with drug related withdrawal adverse reactions.

OVERDOSAGE -

Acute overdosage may lead initially to hypoglycemia and subsequently to hyperglycemia. Overdose with somatropin may cause fluid retention. Long-term overdosage may result in signs and symptoms of gigantism consistent with the known effects of excess growth hormone.