2.1 General Dosing Information

• For subcutaneous injection, once-weekly.
• Therapy with SKYTROFA should be supervised by a physician who is experienced in the diagnosis and management of pediatric patients with growth failure due to growth hormone deficiency (GHD).
• To exclude preexisting papilledema, perform fundoscopic examination before initiating treatment with SKYTROFA and reassess periodically thereafter [see Warnings and Precautions (5.5)].

2.2 Dosage Recommendations

• The recommended dose of SKYTROFA for treatment-naïve patients and patients switching from daily somatropin therapy is 0.24 mg/kg body weight, given once-weekly.
• Individualize and titrate the dosage of SKYTROFA based on response.
• When changing from daily somatropin therapy to once-weekly SKYTROFA, wait at least 8 hours between the final dose of daily somatropin and the first dose of once-weekly SKYTROFA.
• Assess compliance and evaluate other causes of poor growth such as hypothyroidism, under-nutrition, advanced bone age and antibodies to recombinant human growth hormone if patients experience failure to increase height velocity, particularly during the first year of treatment.
• Discontinue SKYTROFA once epiphyseal fusion has occurred.

2.3 Missed Doses

• Administer a missed dose as soon as possible and not more than 2 days after the missed dose.
• To avoid missed doses, SKYTROFA can be taken 2 days before or 2 days after the scheduled dosing day. Resume once-weekly dosing for the next dose at the previously scheduled dosing day.
• If more than 2 days have passed from the scheduled day, skip the dose and administer the next dose on the regularly scheduled day.
• At least 5 days should elapse between doses.

2.4 Administration Instructions

SKYTROFA is available in 9 cartridges (dosage strengths in somatropin equivalents). Selection of the appropriate cartridge is based on the prescribed dose (mg/kg) and the patient's body weight (kg).

• If prescribing a dose of 0.24 mg/kg/week and the patient's weight is 11.5 to 100 kg, follow the recommended dosing in Table 1.
• If prescribing a dose other than 0.24 mg/kg/week, calculate the total weekly dose (in mg) and select the appropriate cartridge as follows:

  –

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

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

2.5 Preparation and Administration

• The SKYTROFA cartridge has been designed for use only with the SKYTROFA Auto-Injector.
• If refrigerated, the SKYTROFA cartridge must be kept at room temperature for 15 minutes before use.
• The SKYTROFA Auto-Injector provides a fully automated reconstitution of the lyophilized drug product which is followed by a manual mixing step controlled by the device. When the injection needle is inserted into the skin, the device automatically delivers the drug product. The built-in electronics and software assist the user during the entire preparation and injection sequence and provide confirmation that the full dose has been delivered.
• The mixed 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 SKYTROFA cartridges within 4 hours after reconstitution. Discard reconstituted SKYTROFA cartridges after 4 hours when stored at room temperature up to 86°F (30°C).
• Inject SKYTROFA subcutaneously into the abdomen, buttock, or thigh. Rotate injection sites between and within regions to reduce the risk of lipoatrophy.
• Refer to the Instructions for Use for complete administration instructions with illustrations. The instructions can also be found on www.Skytrofa.com/IFU.

5.1 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 after treatment with pharmacologic doses of somatropin [see Contraindications (4)]. The safety of continuing SKYTROFA treatment in patients receiving replacement doses for the approved indication who concurrently develop these illnesses has not been established.

5.2 Severe Hypersensitivity

Serious systemic hypersensitivity reactions including anaphylactic reactions and angioedema have been reported with postmarketing use of somatropin products, including SKYTROFA. Inform patients and/or caregivers that such reactions are possible, and that prompt medical attention should be sought if an allergic reaction occurs. SKYTROFA is contraindicated in patients with known hypersensitivity to somatropin or any of the excipients in SKYTROFA.

5.3 Increased Risk of Neoplasms

5.4 Glucose Intolerance and Diabetes Mellitus

Treatment with somatropin may decrease insulin sensitivity, particularly at higher doses. Previously undiagnosed impaired glucose tolerance and overt type 2 diabetes mellitus may be unmasked. Monitor glucose levels in all patients receiving SKYTROFA, especially in those with risk factors for type 2 diabetes mellitus, such as obesity or a family history of type 2 diabetes mellitus. When initiating SKYTROFA, monitor closely patients with preexisting type 1 or type 2 diabetes mellitus or impaired glucose tolerance and adjust the doses of antihyperglycemic drugs as needed.

5.5 Intracranial Hypertension

Intracranial hypertension (IH) with papilledema, visual changes, headache, nausea, and/or vomiting has been reported in a small number of patients treated with somatropin. Symptoms usually occurred within 8 weeks after the initiation of somatropin. In all reported cases, IH-associated signs and symptoms resolved rapidly after cessation of therapy or a reduction of the somatropin dose. To exclude preexisting papilledema, perform fundoscopic examination before initiating treatment with SKYTROFA, and reassess periodically thereafter. If papilledema is observed by fundoscopy, stop somatropin treatment. If somatropin-induced IH is confirmed, restart treatment with SKYTROFA at a lower dose after IH-associated signs and symptoms have resolved.

5.6 Fluid Retention

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

5.7 Hypoadrenalism

Patients receiving somatropin 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 SKYTROFA therapy. Monitor patients for reduced serum cortisol levels and/or need for glucocorticoid dose increases in patients with known hypoadrenalism [see Drug Interactions (7)].

5.8 Hypothyroidism

Undiagnosed or untreated hypothyroidism may prevent optimal response to SKYTROFA. In patients with GHD, central (secondary) hypothyroidism may first become evident or worsen during SKYTROFA treatment. Therefore, perform periodic thyroid function tests in patients and initiate or appropriately adjust thyroid hormone replacement therapy when indicated.

5.9 Slipped Capital Femoral Epiphysis

Slipped capital femoral epiphysis may occur more frequently in patients undergoing rapid growth. Evaluate pediatric patients with the onset of a limp or complaints of persistent hip or knee pain.

5.10 Progression of Preexisting Scoliosis

Somatropin increases growth rate, and progression of existing scoliosis can occur in patients who experience rapid growth. Somatropin has not been shown to increase the occurrence of scoliosis. Monitor patients with a history of scoliosis for disease progression.

5.11 Pancreatitis

Pancreatitis has been reported in pediatric patients receiving somatropin. The risk may be greater in pediatric patients than adults. Consider pancreatitis in patients who develop persistent severe abdominal pain.

5.12 Lipoatrophy

When SKYTROFA is administered subcutaneously at the same site over a long period of time, lipoatrophy may result. Rotate injection sites when administering SKYTROFA to reduce this risk [see Preparation and Administration (2.5)].

5.13 Sudden Death in Pediatric Patients with Prader-Willi Syndrome

There have been reports of fatalities 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. SKYTROFA is not indicated for the treatment of pediatric patients who have growth failure due to genetically confirmed Prader-Willi syndrome.

5.14 Laboratory Tests

Serum levels of phosphate, alkaline phosphatase, and parathyroid hormone may increase after somatropin treatment. If a patient is found to have abnormal laboratory tests, monitor as appropriate.

6.1 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 studies of another drug and may not reflect the rates observed in clinical practice.

SKYTROFA was studied in a 52-week, open-label, active-controlled trial in 161 treatment-naïve, prepubertal pediatric patients with growth hormone deficiency (GHD) [see Clinical Studies (14.1)]. The subjects ranged in age from 3.2 to 13.1 years with a mean of 8.5 years. One hundred thirty-two (82%) of the subjects were male and 29 (18%) were female. One subject was Asian, 3 were Black or African American, 152 were Caucasian, and 5 were categorized as "other."

Table 2 shows common adverse reactions that occurred in ≥5% of patients treated with SKYTROFA in this trial.

6.2 Immunogenicity

As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to SKYTROFA with the incidence of antibodies to other products may be misleading.

Anti-lonapegsomatropin-tcgd antibodies were evaluated in samples collected every 3 months in phase 3 trials in pediatric patients with GHD receiving lonapegsomatropin-tcgd. Mean duration of exposure to SKYTROFA was 70.2 weeks. Of the 304 patients with post-baseline assessments, 19 (6.3%) showed detectable binding antibodies to lonapegsomatropin-tcgd at any time. No apparent correlation of anti-lonapegsomatropin-tcgd antibodies to adverse events or loss of efficacy was observed. No neutralizing antibodies to SKYTROFA were detected.

6.3 Postmarketing Experience

The following adverse reactions have been identified during post approval use of somatropin products, including SKYTROFA. 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.

• Severe systemic hypersensitivity reactions including anaphylactic reactions and angioedema

8.1 Pregnancy

8.2 Lactation

8.4 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 [see Adverse Reactions (6) and Clinical Studies (14)].

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 [see Warnings and Precautions (5.13)].

9.1 Controlled Substance

SKYTROFA is a prodrug of somatropin. Somatropin is not a controlled substance.

9.2 Abuse

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

9.3 Dependence

Somatropin is not associated with drug related withdrawal adverse reactions.

12.1 Mechanism of Action

SKYTROFA is a pegylated human growth hormone (somatropin) for once-weekly subcutaneous injection [see Pharmacokinetics (12.3)].

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.

12.2 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.

12.3 Pharmacokinetics

13.1 Carcinogenicity, Mutagenesis, Impairment of Fertility

Carcinogenicity studies have not been conducted with lonapegsomatropin-tcgd.

Lonapegsomatropin-tcgd was not mutagenic in the Ames test, in the human chromosomal aberration assay or in the rat bone marrow micronucleus test.

In an animal fertility study, lonapegsomatropin-tcgd was administered via subcutaneous injection to male and female rats before cohabitation, through mating to implantation.

Lonapegsomatropin-tcgd did not affect fertility or early embryo-fetal development at doses up to 20-fold the clinical dose of 0.24 mg/kg/week.

14.1 Treatment-Naïve Pediatric Patients with Growth Hormone Deficiency (NCT02781727)

A multi-center randomized, open-label, active-controlled, parallel-group phase 3 study was conducted in 161 treatment-naïve, prepubertal pediatric subjects with growth hormone deficiency (GHD); 105 subjects received once-weekly SKYTROFA, and 56 received daily somatropin. The dose in both arms was 0.24 mg/kg/week. The primary efficacy endpoint was annualized height velocity at Week 52.

The subjects ranged in age from 3.2 to 13.1 years with a mean of 8.5 years. One hundred thirty-two (82%) subjects were male and 29 (18%) were female. One subject was Asian, three were Black or African American, 152 were Caucasian, and five were categorized as "other." The subjects had a mean baseline height SDS (standard deviation score) of -2.9.

Treatment with once-weekly SKYTROFA for 52 weeks resulted in an annualized height velocity of 11.2 cm/year. Subjects treated with daily somatropin achieved an annualized height velocity of 10.3 cm/year after 52 weeks of treatment. Refer to Table 4.

Height SDS (change from baseline) was 1.1 in the SKYTROFA arm and 0.96 in the daily somatropin arm at Week 52. Refer to Table 5.

16.1 How Supplied

SKYTROFA (lonapegsomatropin-tcgd) for injection is a sterile, preservative-free, white to off-white lyophilized powder available in a single-dose, dual-chamber, prefilled cartridge containing lonapegsomatropin-tcgd in one chamber and the diluent, Water for Injection, in the second chamber. The dual-chamber glass cartridge is available in 9 strengths (in somatropin equivalents) as described in Table 6.

Each carton contains 4 single-dose prefilled cartridges and 6 sterile, single-use, disposable 0.25 mm × 4 mm (31-gauge × 5/32 inch) needles. The cartridges are for use only with the SKYTROFA Auto-Injector, packaged in a separate carton. The SKYTROFA Auto-Injector is not supplied with SKYTROFA cartridges but is available for patients with a prescription for SKYTROFA through the Ascendis Pharma Customer Support by calling the toll-free number at 1-844-442-7236 (1-844-44ASCENDIS).

16.2 Storage and Handling

• For patients: Refrigerate SKYTROFA cartridges at 36°F to 46°F (2°C to 8°C) in the outer carton to protect from light until the expiration date. Do not freeze. Alternatively, SKYTROFA outer carton containing blistered cartridges may be stored at room temperature [up to 86°F (30°C)] for up to 6 months and can be returned to refrigeration within the 6 months. Write the date first removed from the refrigerator in the space provided on the outer carton. Do not use SKYTROFA beyond the expiration date or 6 months after the date it was first removed from refrigeration (whichever is earlier).
• For pharmacy long-term storage: Store SKYTROFA cartridges refrigerated at 36°F to 46°F (2°C to 8°C) in the outer carton to protect from light until the expiration date. Do not freeze.

Administration Instructions

• Advise patients and/or caregivers to read the FDA-approved patient labeling (SKYTROFA Auto-Injector Instructions for Use (available at www.Skytrofa.com/IFU)). Advise patients and/or caregivers to 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 and/or caregivers to refer to the Instructions for Use that accompanies the SKYTROFA Auto-Injector for complete mixing and administration instructions with illustrations [see Preparation and Administration (2.5)]. Instruct patients and/or 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 and/or caregivers to administer SKYTROFA once weekly, at any time of day. Advise patients and/or caregivers that doses can be taken 2 days before or 2 days after the scheduled dosing day. Advise patients and/or caregivers to resume once-weekly dosing for the next dose. If more than 2 days have passed from the schedule dosing day, advise patients and/or 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 and/or caregivers to ensure that at least 5 days will elapse between the last dose and the newly established regular dosing day.

Hypersensitivity Reactions

Advise patients and/or caregivers that severe and/or serious systemic hypersensitivity reactions (anaphylaxis and angioedema) have been reported, and to seek prompt medical attention should an allergic reaction occur [see Warnings and Precautions (5.2)].

Neoplasms

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

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

Fluid Retention

Advise patients and/or caregivers that fluid retention during SKYTROFA replacement therapy may occur. Inform patients and/or 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 and/or 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 and/or 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 and/or caregivers that pancreatitis may develop and to report to their healthcare provider any new onset abdominal pain.