Lonapegsomatropin-tcgd

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# Overview
Lonapegsomatropin-tcgd is a human growth hormone that is FDA approved for the treatment of short stature due to inadequate secretion of endogenous growth hormone.   Common adverse reactions include pyrexia, vomiting, abdominal pain, viral infection, nausea, arthralgia, hemorrhage, arthritis, and hemorrhage.

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)
- 0.24 mg/kg body weight is the recommended dosage given once weekly for patients switching from daily somatropin therapy and naive patients.
- Dosage of Lonapegsomatropin-tcgd should be titrated and individualized based on response of patient.
- Patients should be advised to wait at least 8 hours after final dose of somatropin and first dose of Lonapegsomatropin-tcgd if switching to Lonapegsomatropin-tcgd from somatropin therapy.
- During the first year of Lonapegsomatropin-tcgd treatment, monitor causes if patient experiences failure to increase height velocity.
- Patients who experience epiphyseal fusion should stop Lonapegsomatropin-tcgd treatment.

## Off-Label Use and Dosage (Adult)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Lonapegsomatropin-tcgd in adult patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Lonapegsomatropin-tcgd in adult patients.

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Lonapegsomatropin-tcgd FDA-Labeled Indications and Dosage (Pediatric) in the drug label.

## Off-Label Use and Dosage (Pediatric)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Lonapegsomatropin-tcgd in pediatric patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Lonapegsomatropin-tcgd in pediatric patients.

# Contraindications
- Patients with abdominal surgery, acute critical illness after open heart surgery, or acute respiratory failure due to the risk of increased mortality with use of somatropin.
- Patients with post-marketing use of somatropin products have experienced systemic hypersensitivity reactions.
- Patients with hypersensitivity to somatropin or any of the excipients in Lonapegsomatropin-tcgd.
- Patients with closed epiphyses and active malignancy.
- Patients with active proliferative or severe non-proliferative diabetic retinopathy as a result of somatropin treatment that may worsen these conditions.
- Patients with Prader-Willi syndrome who have a history of upper airway obstruction, are severely obese, have severe respiratory impairment, or have sleep apnea.

# Warnings
Increased Mortality in Patients with Acute Critical Illness
- After treatment with pharmacologic doses of somatropin, complications in patients following abdominal surgery, open heart surgery, or multiple accidental trauma have increased mortality risk due to acute critical illness.
- After treatment with pharmacologic doses of somatropin, complications in patients with acute respiratory failure have increased mortality risk due to acute critical illness.
- Data on safety of patients receiving replacement doses with Lonapegsomatropin-tcgd treatment have not been established.
Severe Hypersensitivity
- Post-marketing use of somatropin products have caused angioedema and anaphylactic reactions in patients.
- Advise patients to seek medical attention if they experience severe allergic reactions.
- Advise patients with known hypersensitivity to excipients in Lonapegsomatropin-tcgd or somatropin to not take Lonapegsomatropin-tcgd.
Increased Risk of Neoplasms
Active Malignancy
- Patients with active malignancy that are being treated with somatropin have a high risk of malignancy progression.
- When treated with Lonapegsomatropin-tcgd, there should be no active preexisting malignancy.
- Advise patients that display evidence of recurrent malignancy to stop Lonapegsomatropin-tcgd treatment.
Risk of Second Neoplasm in Pediatric Patients
- There is an increased risk second neoplasm in patients that had childhood cancer which was treated with radiation for their first neoplasm. These patients used somatropin treatment to deal with GHD.
- The most common second neoplasms reported in patients were intracranial tumors.
- Patients with a history of GHD secondary to an intracranial neoplasm that is during somatropin therapy should be monitored.
New Malignancy During Treatment
- Advise patients that have high risk malignancies to monitor the risks of somatropin therapy.
- Monitor patients for neoplasms, potential malignant changes of preexisting nevi, and increased growth of preexisting nevi with somatropin treatment.
- Report any changes in behavior and appearance preexisting nevi during somatropin treatment.
Glucose Intolerance and Diabetes Mellitus
- A decrease in insulin sensitivity may occur in patients taking high doses of somatropin.
- Monitor the glucose levels in patients taking Lonapegsomatropin-tcgd.
- Adjust the doses of antihyperglycemic drugs during Lonapegsomatropin-tcgd treatment in patients with impaired glucose tolerance, preexisting type 1 diabetes mellitus or preexisting type 2 diabetes mellitus.
Intracranial Hypertension
- Small number of patients treated with somatropin have reported intracranial hypertension with headache, papilledema, vomiting, and/or visual changes.
- Reduction or cessation of somatropin resolved IH-associated symptoms and signs.
- Somatropin treatment should be stopped if papilledema is observed.
- When IH-associated symptoms and signs are resolved, Lonapegsomatropin-tcgd treatment may be restarted at low doses.
Fluid Retention
- Somatropin therapy may cause fluid retention.
- Fluid retention are usually dose dependent and transient.
Hypoadrenalism
- Unmasking of central hypoadrenalism and reduced serum cortisol levels may occur in patients at risk for pituitary hormone deficiency when taking somatropin.
- After starting Lonapegsomatropin-tcgd treatment, patients with glucocorticoid replacement for previously diagnosed hypoadrenalism may require stress dose increase.
- Monitor hypoadrenalism patients taking Lonapegsomatropin-tcgd for reduced serum cortisol levels.
- Monitor hypoadrenalism patients taking Lonapegsomatropin-tcgd for an increase in glucocorticoid dose.
Hypothyroidism
- Optimal response by Lonapegsomatropin-tcgd in patients may be prevented by untreated or undiagnosed hypothyroidism.
- Advise patients to take periodic thyroid function tests.
- Monitor thyroid levels and adjust or initiate thyroid hormone replacement therapy if necessary.
Slipped Capital Femoral Epiphysis
- Rapid growth may cause more frequent slipped capital femoral epiphysis in patients.
- Monitor persistent hip or knee pain.
Progression of Preexisting Scoliosis
- Rapid growth may cause progression of existing scoliosis in patients.
- Monitor patients that have a history of scoliosis.
Pancreatitis
- Pediatric patients have experienced pancreatitis when taking somatropin.
- Monitor patients with persistent severe abdominal pain which can be a sign of pancreatitis.
Lipoatrophy
- Lipoatrophy may occur when Lonapegsomatropin-tcgd is given subcutaneously at the same site over a long period of time.
- Reduce the risk of lipoatrophy by rotating Lonapegsomatropin-tcgd injection sites.
Sudden Death in Pediatric Patients with Prader-Willi Syndrome
- Pediatric patients with Prader-Willi syndrome have experienced fatalities when starting somatropin therapy.
- Advise pediatric patients with genetically confirmed Prader-Willi syndrome to not be treated with Lonapegsomatropin-tcgd.
Laboratory Tests
- Somatropin treatment may cause an increase in serum levels of alkaline phosphatase, phosphate, and parathyroid hormone.
- Monitor patients that display abnormal laboratory tests.

# Adverse Reactions

## Clinical Trials Experience
Adverse Reactions
- Increased risk of neoplasms
- Hypothyroidism
- Sudden death in pediatric patients with Prader-Willi syndrome
- Glucose intolerance and diabetes mellitus
- Increased mortality in patients with acute critical illness
- Progression of preexisting scoliosis in pediatric patients
- Intracranial hypertension
- Hypoadrenalism
- Lipoatrophy
- Slipped capital femoral epiphysis in pediatric patients
- Pancreatitis
- Fluid retention
- Severe hypersensitivity
Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions and durations of follow up, 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.
- 161 treatment-naive, prepubertal pediatric patients with GHD were used in a 52-week, open-label, active-controlled trial to study Lonapegsomatropin-tcgd.
- The patient population was ranging from 3.2 to 13.1 years of age, largely Caucasian (152 out of 161), and included 82% males.
Table 2 shows the most common Adverse Reactions reported in the study on Lonapegsomatropin-tcgd.
Laboratory Tests
- Alkaline phosphatase levels and phosphate levels were elevated at the end of the trial in patients receiving Lonapegsomatropin-tcgd compared to patients taking daily somatropin.
Immunogenicity
- Data may be misleading when comparing incidence of antibodies to other products with incidence of antibodies to Lonapegsomatropin-tcgd.
- During phase 3 trials, Anti-lonapegsomatropin-tcgd antibodies in pediatric patients with GHD who were taking Lonapegsomatropin-tcgd were collected and evaluated every 3 months.
- 70.2 weeks is the mean duration of exposure to Lonapegsomatropin-tcgd.
- Detectable binding antibodies to Lonapegsomatropin-tcgd were found in 6.3% of patients with post-baseline assessments.
- Loss of efficacy or adverse events were not correlated with anti-lonapegsomatropin-tcgd antibodies.
- The detection of neutralizing antibodies to Lonapegsomatropin-tcgd were not seen in studies.

## Postmarketing Experience
- Angioedema and anaphylactic reactions are some of the many systemic hypersensitivity reactions observed with post-marketing use of somatropin products including Lonapegsomatropin-tcgd.

# Drug Interactions
Important Drug Interactions with Lonapegsomatropin-tcgd
Table 3 shows the Drug Interactions of Lonapegsomatropin-tcgd

# Use in Specific Populations

### Pregnancy
Pregnancy Category (FDA): 
The data on risk association of miscarriage or adverse maternal or fetal outcomes and major birth defects in pregnant patients when taking Lonapegsomatropin-tcgd have not been established. The data on risk association of miscarriage or adverse maternal or fetal outcomes and major birth defects in pregnant patients when taking somatropin have shown no indication for causation. Pregnant rat studies show administration of doses up to 13-fold the clinical dose of 0.24 mg/kg/week of Lonapegsomatropin-tcgd are not correlated with either neonatal or embryo-fetal harm.  No adverse effects were seen on development of the conceptus and the offspring as well as pregnant/lactating female rats in a peri- and post-natal developmental study when given Lonapegsomatropin-tcgd.
Pregnancy Category (AUS): 
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Lonapegsomatropin-tcgd in women who are pregnant.

### Labor and Delivery
There is no FDA guidance on use of Lonapegsomatropin-tcgd during labor and delivery.

### Nursing Mothers
Data on Lonapegsomatropin-tcgd effects on milk production or on the breastfed infant are not present. Limited systemic exposure in breastfed infant is expected when taking Lonapegsomatropin-tcgd. Low passage into human milk is also expected when taking Lonapegsomatropin-tcgd. Growth hormone in normal human milk concentrations does not increase due to exogenous somatropin. Adverse effects when taking somatropin has not been seen in breastfed infants.

### Pediatric Use
The safety and effectiveness of Lonapegsomatropin-tcgd have been established in pediatric patients weighing at least 11.5 kg with an age 1 year or older. The safety and effectiveness of Lonapegsomatropin-tcgd have not been established in pediatric patients under the age of 1 years old. Death has been seen in pediatric patients with Prader-Willi syndrome when using somatropin. Pediatric patients with growth failure due to genetically confirmed Prader-Willi syndrome should not be treated with Lonapegsomatropin-tcgd.

### Geriatic Use
There is no FDA guidance on the use of Lonapegsomatropin-tcgd in geriatric settings.

### Gender
There is no FDA guidance on the use of Lonapegsomatropin-tcgd with respect to specific gender populations.

### Race
There is no FDA guidance on the use of Lonapegsomatropin-tcgd with respect to specific racial populations.

### Renal Impairment
There is no FDA guidance on the use of Lonapegsomatropin-tcgd in patients with renal impairment.

### Hepatic Impairment
There is no FDA guidance on the use of Lonapegsomatropin-tcgd in patients with hepatic impairment.

### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Lonapegsomatropin-tcgd in women of reproductive potentials and males.

### Immunocompromised Patients
There is no FDA guidance one the use of Lonapegsomatropin-tcgd in patients who are immunocompromised.

# Administration and Monitoring

### Administration
Administration Instructions
- There are 9 cartridges of Lonapegsomatropin-tcgd.
- Use table 1 if the prescribing dose is 0.24 mg/kg/week and the patient's weight is 11.5 to 100 kg to determine the appropriate cartridge given.
- The total weekly dose must be calculated if the prescribing dose is not 0.24 mg/kg/week. This is done by using the following equation: Total weekly dose (mg) = prescribed weekly dose (mg/kg)  patient's body weight (kg). Round to closest cartridge dose if necessary.
Table 1 shows the Recommended Dosing of Lonapegsomatropin-tcgd based on Weight.
Preparation and Administration
- Lonapegsomatropin-tcgd must be put for 15 minutes at room temperature if refrigerated.
- Lonapegsomatropin-tcgd Auto-Injector must be used to inject cartridges.
- Reconstitution of the lyophilized drug product and manual mixing step is done by the auto injector.
- Injector automatically delivers drug product when needle is inserted into the skin.
- Mixed solution used should be colorless and clear, it is okay of there are some air bubbles.
- Advise patients to not inject mixed solution if it contains particulate matter or is not clear.
- Lonapegsomatropin-tcgd cartridges must be used up to 4 hours after reconstitution.
- Lonapegsomatropin-tcgd should be injected and rotated within the buttock, thigh or abdomen.

### Monitoring
Missed Doses
- Advise patients to administer missed doses as immediately or as soon as possible.
- Advise patients to skip dose if the missed dose is later than 2 days and resume next dose on regularly scheduled day.
- Lonapegsomatropin-tcgd can be given 2 days before or 2 days after the scheduled dosing day.
- Doses of Lonapegsomatropin-tcgd should be separated by at least 5 days.

# IV Compatibility
There is limited information regarding the compatibility of Lonapegsomatropin-tcgd and IV administrations.

# Overdosage
- Hypoglycemia and hyperglycemia may occur as a result of acute overdosage.
- Fluid retention may occur due to somatropin overdosage.
- Gigantism can be a result of long-term overdosage.

# Pharmacology

## Mechanism of Action
- Lonapegsomatropin-tcgd is a pegylated human growth hormone.
- Somatropin causes a host of pharmacodynamic effects and intracellular signal transduction to the target cells when it binds to the GH receptor in the cell membrane of those target cells.
- Somatropin has direct impacts on metabolic and tissue effects.
- Somatropin has indirect impacts on stimulation of hepatic glucose output, stimulation of chondrocyte differentiation and proliferation, lipolysis and protein synthesis.
- Skeletal growth is stimulated by Somatropin in pediatric patients with GHD.

## Structure
- Lonapegsomatropin-tcgd is a long-acting prodrug of a human growth hormone.

## Pharmacodynamics
- A dose linear IGF-1 response is produced by Somatropin with a change of 0.02 mg/kg on average.
- 2 days post-dose is when IGF-1 levels peak at steady state.
- 4.5 days post-dose is when the average weekly IGF-1 occurs.

## Pharmacokinetics
Absorption
- In Lonapegsomatropin-tcgd, 1230 ng hGH/mL is the observed mean steady state peak serum concentration.
- In Lonapegsomatropin-tcgd, 25 hours is the median time to reach maximum concentrations.
- 15.2 ng/mL is the Cmax in released somatropin.
- 12 hours is the median Tmax in released somatropin.
- Over a one-week dose interval, 500 h*ng/mL is the mean somatropin exposure.
- For the methoxypolyethylene glycol carrier, 13.1 g /mL is the Cmax.
- For the methoxypolyethylene glycol carrier, 36 hours is the median Tmax.
Distribution
- After subcutaneous administration of 0.24 mg/kg/week Lonapegsomatropin-tcgd, 0.13 L/kg is the mean steady state apparent volume of distribution.
Elimination
Metabolism
- Protein catabolism occurs in both the kidneys and liver during metabolism of somatropin.
- The kidneys clear methoxypolyethylene glycol carrier.
Excretion
- In pediatric patients with GHD treated with Lonapegsomatropin-tcgd, 3.2 mL/h/kg is the mean apparent clearance at steady state.
- In pediatric patients with GHD treated with Lonapegsomatropin-tcgd, 30.7 hours is the mean observed half-life.
- 25 hours is the apparent half-life of somatropin when released from Lonapegsomatropin-tcgd.
Specific Populations
- No clinically meaningful effects on pharmacokinetics when looking at race, age, body weight and sex analysis.

## Nonclinical Toxicology
- For Lonapegsomatropin-tcgd, no studies on carcinogenicity have been conducted.
- In the human chromosomal aberration assay, Ames test, or rat bone marrow micronucleus test, Lonapegsomatropin-tcgd was not mutagenic.
- Early embryo-fetal development or fertility is not affected by Lonapegsomatropin-tcgd in an animal fertility study.

# Clinical Studies
Treatment-Naive Pediatric Patients with Growth Hormone Deficiency
- This study is a multi-center randomized, open-label, active-controlled, parallel-group phase 3 study. The study included 161 treatment-naive, prepubertal pediatric subjects with GHD where 56 patients received daily somatropin and 105 patients received once-weekly Lonapegsomatropin-tcgd. The patient population was largely Caucasian (152 patients),included 82% men, and had a mean age of 8.5 years old.
- The study showed 11.2 cm/year is the annualized height velocity after 52 weeks of Lonapegsomatropin-tcgd treatment. 10.3 cm/year s the annualized height velocity after 52 weeks of daily somatropin.
Table 4 summarizes the annualized height velocity found after 52 weeks in the 161 treatment-naive, prepubertal pediatric patients.
- At 52 weeks, 1.1 is the height SDS in patients treated with Lonapegsomatropin-tcgd.
- At 52 weeks, 0.96 is the height SDS in patients treated with daily somatropin.
Table 5 summarizes the height SDS found after 52 weeks in the 161 treatment-naive, prepubertal pediatric patients.

# How Supplied
- Lonapegsomatropin-tcgd is supplied as a preservative-free, sterile, dual-chamber, white to off-white lyophilized powder available in a single-dose, prefilled cartridge containing Lonapegsomatropin-tcgd in one chamber and the diluent, water for injection, in the second chamber.
- 6 sterile, single-use, disposable 0.25 mm  4 mm needles and  4 single-dose prefilled cartridges are found in each carton.
- A separate carton contains the Lonapegsomatropin-tcgd Auto-Injector which can be received by patients with a prescription for Lonapegsomatropin-tcgd.
- There are 9 different dual-chamber glass cartridge strengths.
Table 6 summarizes the 9 different cartridge strengths for Lonapegsomatropin-tcgd.

## Storage
Patients
- Lonapegsomatropin-tcgd cartridges should be refrigerated at 36F to 46F (2C to 8C).
- The cartridges should not be frozen.
- For up to 6 months, Lonapegsomatropin-tcgd cartridges can be stored at room temperature , and can be returned to refrigeration within the 6 months.
- Advise patients to stop Lonapegsomatropin-tcgd medication use beyond the expiration date.
- Advise patients to stop Lonapegsomatropin-tcgd medication use 6 months after the date it was first removed from refrigeration.
For pharmacy long-term storage
- Lonapegsomatropin-tcgd cartridges should be refrigerated at 36F to 46F (2C to 8C).
- The cartridges should not be frozen.

# Images

## Drug Images

## Package and Label Display Panel

# Patient Counseling Information
Usage
- Provide patients with the Lonapegsomatropin-tcgd Auto-Injector Instructions for use.
- Advise patients to call the Ascendis Pharma Customer Support toll-free number at 1-844-442-7236 for additional training or assistance.
- Advise patients to review instructions for complete mixing and administration of Lonapegsomatropin-tcgd.
- Instruct patients on reuse of needles and proper needle disposal.
- Advise patients that doses can be taken 2 days before or 2 days after the scheduled dosing day.
- Advise patients to skip dose and take the next dose on the regularly scheduled day if they missed a dose more than 2 days.
- Advise patients that there should be at least 5 days between doses taken.
Neoplasms
- Advise patients that there is an increased risk of secondary neoplasms in patients that were treated with brain/head radiation for childhood cancer.
- Monitor patients who have an increased risk of secondary neoplasms.
- Monitor patients for symptoms such as onset of headache, changes in skin pigmentation, changes in behavior, or vision disturbances.
Glucose Intolerance/Diabetes Mellitus
- Advise patients that exacerbation of preexisting diabetes mellitus or impaired glucose intolerance/type 2 diabetes mellitus may occur when treated with Lonapegsomatropin-tcgd.
- Monitor patients blood glucose levels during Lonapegsomatropin-tcgd treatment.
Intracranial Hypertension
- Advise patients to report symptoms such as headache, vomiting, visual changes, and nausea to their doctor.
Fluid Retention
- Advise patients during Lonapegsomatropin-tcgd replacement therapy, fluid retention may occur.
- Advise patients to report any symptoms of fluid retention such as nerve compression syndromes, arthralgia, edema, or myalgia to their doctor.
Hypoadrenalism
- Advise patients that hypoadrenalism may occur in patients at risk for pituitary hormone deficiency.
- Advise patients to report symptoms such as dizziness, weight loss, extreme fatigue, weakness, or hyperpigmentation to their doctor.
Hypothyroidism
- Advise patients that an optimal response to Lonapegsomatropin-tcgd may be inhibited by undiagnosed/untreated hypothyroidism.
- Monitor patients through periodic thyroid function tests.
Pancreatitis
- Advise patients that treatment with Lonapegsomatropin-tcgd may cause the development of pancreatitis.
- Advise patients to report new onset abdominal pain to their doctor when treated with Lonapegsomatropin-tcgd.
Hypersensitivity Reactions
- Advise patients that treatment with Lonapegsomatropin-tcgd may cause serious systemic hypersensitivity reactions such as angioedema or anaphylaxis to occur.
- Advise patients with allergic reactions to seek immediate medical attention.
Administration
- Advise patients to not share Lonapegsomatropin-tcgd Auto-Injector as it may cause transmission of infection to another person.

# Precautions with Alcohol
Alcohol-Lonapegsomatropin-tcgd interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

# Brand Names
- Skytrofa

# Look-Alike Drug Names
There is limited information regarding Lonapegsomatropin-tcgd Look-Alike Drug Names in the drug label.

# Drug Shortage Status

# Price