Lonapegsomatropin-tcgd (Monograph)

Brand name: Skytrofa
Drug class: Pituitary

Introduction

Recombinant human growth hormone (rhGH, somatropin) conjugated to a methoxypolyethylene glycol (mPEG) carrier via a TransCon linker resulting in a long-acting pro-drug.

Uses for Lonapegsomatropin-tcgd

Growth Hormone Deficiency, Pediatric

Treatment of pediatric patients ≥1 year of age who weigh ≥11.5 kg and have growth failure due to inadequate secretion of endogenous growth hormone (GH). Designated an orphan drug by FDA.

Pediatric Endocrine Society (PES) guideline strongly recommends GH to normalize adult height and avoid extreme shortness in children and adolescents with growth hormone deficiency (GHD).

Lonapegsomatropin-tcgd Dosage and Administration

General

Pretreatment Screening

• Perform fundoscopic examination to exclude preexisting papilledema.

• Measure body weight.

• Measure height.

• Consult Pediatric Endocrine Society (PES) guidelines on the need for provocative testing, including the need for sex steroid priming prior to testing, to diagnose GHD.

Patient Monitoring

• Perform periodic fundoscopic examination.

• Measure body weight.

• Measure height.

• Monitor for signs and symptoms of intracranial hypertension (e.g., visual changes, headache, nausea and/or vomiting).

• Assess compliance and evaluate other causes of poor growth such as hypothyroidism, under-nutrition, advanced bone age, and antibodies to recombinant human growth hormone (hGH) if patients experience failure to increase height velocity, particularly during the first year of treatment.

• Closely monitor patients with preexisting type 1/type 2 diabetes mellitus or impaired glucose tolerance, and adjust antihyperglycemic drugs dosages as needed.

Dispensing and Administration Precautions

• Commercially available as a prefilled cartridge for use only with the Skytrofa Auto-Injector.

Other General Considerations

• Therapy with lonapegsomatropin-tcgd should be supervised by a physician experienced in the diagnosis and management of GHD in pediatric patients.

Administration

Sub-Q Injection

Administer by sub-Q injection into the abdomen, buttock, or thigh.

Rotate injection sites.

The lonapegsomatropin-tcgd prefilled cartridge has been designed for use only with the Skytrofa Auto-Injector which is not supplied with the cartridges, but available with a prescription through Ascendis Pharma Customer Support. The Auto-Injector automates reconstitution of the lyophilized powder, automatic drug delivery when the injection needle is inserted in the skin, and the built-in electronics and software assist the patient/caregiver during the entire process, including providing confirmation that the full dose has been delivered.

If refrigerated, allow cartridge to sit at room temperature for 15 minutes before use.

Reconstituted solution should be clear and colorless to opalescent and may occasionally contain air bubbles; do not inject if the solution is cloudy or contains particulate matter.

Use cartridges within 4 hours of reconstitution; discard reconstituted cartridges after 4 hours when stored at room temperature up to 30°C.

May administer 2 days before or after the scheduled dosing day. Resume once-weekly dosing on the previously scheduled day.

Administer a missed dose as soon as possible, but not >2 days later than the scheduled day. If >2 days have passed from the scheduled day, skip the dose and administer on the next regularly scheduled day.

At least 5 days should elapse between doses.

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

Dosage

Pediatric Patients

Growth Hormone Deficiency

Sub-Q

Treatment-naive: 0.24 mg/kg body weight administered once a week. Switching from daily somatropin: 0.24 mg/kg body weight administered once a week at least 8 hours from the final somatropin dose.

Individualize and titrate the dosage based on response and/or IGF-1 levels.

Discontinue once epiphyseal fusion has occurred.

See Table 1 for recommended dosage based on body weight.

If the dosage is not 0.24 mg/kg per week, calculate the total weekly dose and select the appropriate cartridge as follows:

• Total weekly dose (mg) = prescribed weekly dose (mg/kg) × patient body weight (kg).

• Round total weekly dosage (mg) to the closest cartridge dose while also considering treatment goals and clinical response.

Special Populations

Hepatic Impairment

No specific dosage recommendations for patients with hepatic impairment.

Renal Impairment

No specific dosage recommendations for patients with renal impairment.

Geriatric Patients

No specific dosage recommendations for geriatric patients.

Related/similar drugs

Genotropin, Omnitrope, Norditropin, Nutropin, Saizen, Zomacton, Ngenla

Cautions for Lonapegsomatropin-tcgd

Contraindications

• Acute critical illness after open heart surgery, abdominal surgery, or multiple accidental trauma, or those with acute respiratory failure.

• Hypersensitivity to somatropin or any of the excipients; post-marketing systemic hypersensitivity reactions to somatropin have been reported.

• Closed epiphyses.

• Active malignancy.

• Active proliferative or severe non-proliferative diabetic retinopathy.

• Patients with 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.

Warnings/Precautions

Increased Mortality in Patients with Acute Critical Illness

Increased mortality reported in patients continuing somatropin while experiencing acute critical illness following open heart surgery, abdominal surgery, or multiple accidental trauma, or those with acute respiratory failure.

Safety of continuing lonapegsomatropin-tcgd in those patients has not been established.

Severe Hypersensitivity

Serious systemic hypersensitivity reactions including anaphylactic reactions and angioedema reported with the use of somatropin preparations.

If allergic reaction occurs, discontinue lonapegsomatropin-tcgd, initiate appropriate treatment and seek medical attention.

Do not use in patients with known hypersensitivity to somatropin or any of the excipients in lonapegsomatropin-tcgd.

Increased Risk of Neoplasms - Active Malignancy

Increased risk of malignancy progression with somatropin treatment in patients with active malignancy.

Complete malignancy treatment; the preexisting malignancy should be inactive before initiating lonapegsomatropin-tcgd. Discontinue if malignancy recurs.

Increased Risk of Neoplasms – Risk of Second Neoplasm in Pediatric Patients

Increased risk of a second neoplasm reported in childhood cancer survivors with acquired GHD treated with somatropin following radiation to the brain/head for their first neoplasm.

Intracranial tumors, in particular meningiomas, were reported.

Monitor for progression or recurrence in those with history of intracranial neoplasm.

Increased Risk of Neoplasms - New Malignancy During Treatment

Consider risks and benefits of initiating GH in children with certain rare genetic causes of short stature with an increased risk of developing malignancies.

Monitor carefully for increased growth or potential malignant changes of preexisting nevi.

Advice 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 to treating physician.

Glucose Intolerance and Diabetes Mellitus

May decrease insulin sensitivity and/or unmask undiagnosed impaired glucose tolerance or type 2 diabetes mellitus (DM).

Monitor glucose levels, especially in those with risk factors for type 2 DM.

Monitor patients with preexisting type 1/2 DM, or impaired glucose tolerance; adjust antihyperglycemic drugs dosages as needed.

Intracranial Hypertension

Intracranial hypertension (IH) with papilledema, visual changes, headache, nausea, and/or vomiting reported.

Symptoms usually occur within 8 weeks; signs and symptoms resolve rapidly after cessation or somatropin dose reduction.

Perform fundoscopic examination before initiating treatment. Reassess periodically. Stop treatment if papilledema observed.

If IH symptoms (e.g., visual changes, headache, nausea and/or vomiting) occur, perform fundoscopic examination. Stop treatment if papilledema is observed.

May restart treatment at a lower dose after signs and symptoms have resolved.

Fluid Retention

Fluid retention may occur, usually transient and dose-dependent.

Hypoadrenalism

Patients who have or are at risk for pituitary hormone deficiency may be at risk for reduced serum cortisol levels and/or unmasking of central (secondary) hypoadrenalism.

Patients treated with glucocorticoid replacement may require an increase in their maintenance or stress doses.

Monitor for reduced serum cortisol levels and/or need for glucocorticoid dose increases.

Hypothyroidism

Undiagnosed or untreated hypothyroidism may prevent optimal response.

Central (secondary) hypothyroidism may first become evident or worsen during treatment.

Perform periodic thyroid function tests; initiate or adjust thyroid hormone replacement.

Slipped Capital Femoral Epiphysis

Slipped capital femoral epiphysis (SCFE) may occur.

Evaluate pediatric patients with the onset of a limp or complaints of persistent hip or knee pain.

Progression of Preexisting Scoliosis

Somatropin has not been shown to increase the occurrence of scoliosis.

Progression of existing scoliosis can occur; monitor for scoliosis progression.

Pancreatitis

Pancreatitis has been reported.

Consider pancreatitis in patients who develop persistent severe abdominal pain.

Lipoatrophy

Rotate injection sites to reduce the risk of lipoatrophy.

Sudden Death in Pediatric Patients with Prader-Willi Syndrome

Fatalities reported after somatropin initiation in pediatric patients with Prader-Willi syndrome who had ≥1 risk factor: severe obesity, history of upper airway obstruction or sleep apnea, or unidentified respiratory infection.

Males with one or more of these factors may be at greater risk.

Lonapegsomatropin-tcgd is not indicated for growth failure due to genetically confirmed Prader-Willi syndrome.

Immunogenicity

Detectable anti-human growth hormone (hGH) binding antibodies similar and transient (<16 weeks duration) between lonapegsomatropin-tcgd and somatropin.

No neutralizing antibodies were detected, hypersensitivity adverse events or injection site reactions did not occur, and there was no evidence of decreased efficacy.

Anti-mPEG antibodies were also detected.

Laboratory Tests

Monitor patients with increased serum levels of phosphate, alkaline phosphatase, and parathyroid hormone.

Specific Populations

Pregnancy

No available data on lonapegsomatropin-tcgd to inform a risk of major birth defects or other adverse pregnancy outcomes; no evidence of embryo-fetal or neonatal harm in rats.

Available data for somatropin have not identified a risk of major birth defects or other adverse pregnancy outcomes.

Lactation

No data on the presence of lonapegsomatropin-tcgd in human milk, effects on infants fed human milk, or effects on human milk production.

Data indicate somatropin does not increase normal human milk GH concentrations.

No adverse effects on infants fed human milk have been reported with somatropin.

Consider developmental and health benefits of breastfeeding along with the mother’s clinical need for lonapegsomatropin-tcgd and any potential adverse effects on the breastfed infant from the drug or underlying maternal condition.

Pediatric Use

Safety and efficacy established in pediatric patients ≥1 year of age with GHD who weigh ≥11.5 kg.

Safety and efficacy not established in pediatric patients <1 year of age.

Not indicated in pediatric patients with genetically confirmed Prader-Willi syndrome.

Geriatric Use

No specific studies have been performed.

Hepatic Impairment

No specific studies have been performed.

Renal Impairment

No specific studies have been performed.

Common Adverse Effects

Adverse effects reported in ≥5% of pediatric patients: viral infection, pyrexia, cough, nausea and vomiting, hemorrhage, diarrhea, abdominal pain, and arthralgia and arthritis.

Drug Interactions

No formal studies with lonapegsomatropin-tcgd conducted.

Drugs Affecting Hepatic Microsomal Enzymes

Concern for growth hormone-induced changes in cytochrome P-450 (CYP) isoenzyme activity.

Monitor drugs metabolized by CYP isoenzymes.

Specific Drugs

Lonapegsomatropin-tcgd Pharmacokinetics

Absorption

Somatropin is slowly released from pegylated hGH lonapegsomatropin-tcgd.

Distribution

Extent

Not known whether lonapegsomatropin-tcgd is distributed into human milk. Estimated mean Vd of lonapegsomatropin-tcgd in a pediatric patient weighing approximately 20 kg: 1.3 L.

Elimination

Metabolism

Somatropin is metabolized via liver and kidney protein catabolism.

Elimination Route

mPEG is cleared by the kidneys.

Half-life

Pediatric patients: Mean half-life is approximately 30.7 hours. Somatropin released from lonapegsomatropin-tcgd is approximately 25 hours.

Special Populations

Somatropin pharmacokinetics similar in men and women.

Age, sex, race, and body weight do not have clinically meaningful effects.

Stability

Storage

Parenteral

Injection cartridges

2–8°C. Do not freeze.

Protect from light; store in original carton until the expiration date.

Alternative: Room temperature up to 30°C <6 months.

May return to 2–8°C within the 6 months. Write date removed from refrigerator; do not use beyond the expiration date or 6 months after the date it was first removed from refrigeration (whichever is earlier).

Discard reconstituted cartridges after 4 hours when stored at room temperature up to 30°C.

Actions

• Long-acting prodrug of a human growth hormone (hGH, somatropin).

• Recombinant somatropin is conjugated to methoxypolyethylene glycol (mPEG).

• Somatropin released from lonapegsomatropin-tcgd produces a dose linear insulin-like growth factor-1 (IGF-1) response.

Advice to Patients

• Advise patients and caregivers to refer to the instructions for use that accompanies the Skytrofa Auto-Injector for complete mixing and administration instructions with illustrations. Instructions for use are also available at www.Skytrofa.com/IFU or by calling the Ascendis Pharma Customer Support toll-free number at 1-844-442-7236 for assistance or additional training, if needed.

• Advise patients and caregivers of proper needle and used cartridge disposal in an appropriate container and caution against any reuse or sharing of needles.

• Inform patients and caregivers on how to administer lonapegsomatropin-tcgd, and what to do for missed doses or dosing schedule changes.

• Advise childhood cancer survivors and caregivers of the increased risk of secondary neoplasms and to immediately report marked changes in behavior, onset of headaches, vision disturbances, and/or changes in skin pigmentation or changes in the appearance of preexisting nevi.

• Advise patients and caregivers that new-onset impaired glucose intolerance/type 2 diabetes mellitus or exacerbation of preexisting diabetes mellitus can occur and to monitor blood glucose.

• Advise patients and caregivers that lonapegsomatropin-tcgd can cause intracranial hypertension and to immediately report any visual changes, headache, and nausea and/or vomiting to their healthcare provider.

• Advise patients and caregivers that fluid retention may occur and to contact their healthcare provider if symptoms (e.g., edema, arthralgia, myalgia, nerve compression syndromes including carpal tunnel syndrome/paresthesia) occur.

• Advise patients and caregivers that hypoadrenalism may develop in those at risk and to report hyperpigmentation, extreme fatigue, dizziness, weakness, or weight loss to their healthcare provider.

• Advise patients and caregivers that periodic thyroid function tests in those at risk may be required.

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

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

• Advise patients and caregivers to rotate injection sites to decrease the risk of lipoatrophy.

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.

• Importance of informing patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Lonapegsomatropin-tcgd can only be obtained through specialty distributors. Clinicians may consult the Ascendis Signature Access Program website for specific availability information ([Web]).

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