2.1 General Dosing Information

• For subcutaneous injection, once weekly.
• Therapy with SKYTROFA should be supervised by a healthcare provider who is experienced in the diagnosis and management of patients with growth hormone deficiency (GHD).
• Perform fundoscopic examination before initiating treatment with SKYTROFA to exclude preexisting papilledema. If papilledema is identified, evaluate the etiology and treat the underlying cause before initiating treatment with SKYTROFA [see Warnings and Precautions (5.5)].

2.2 Recommended Dosage for Pediatric Patients

• The recommended dose of SKYTROFA for treatment-naïve patients and patients switching from another growth hormone product 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 SKYTROFA.
• When changing from another once-weekly growth hormone therapy to once-weekly SKYTROFA, wait at least 7 days between the final dose of the previous growth hormone therapy and the first dose of 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.
• Patients who were treated with SKYTROFA for GH deficiency in childhood and whose epiphyses are closed should be reevaluated before continuing SKYTROFA.

2.3 Recommended Dosage for Adults

• The recommended starting dose of SKYTROFA in adults with GHD is based on age and concomitant use of oral estrogen [see Dosage Forms and Strengths (3)]. For treatment-naïve patients or for patients switching from another growth hormone product, start SKYTROFA as described below:
  • 1.4 mg once weekly for adults 30 to 60 years old, with no oral estrogen intake
  • 2.1 mg once weekly for adults under 30 years old, or adults of any age intaking oral estrogen
  • 0.7 mg once weekly for adults over 60 years old, with no oral estrogen intake
• 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 SKYTROFA.
• When changing from another once-weekly growth hormone therapy to once-weekly SKYTROFA, wait at least 7 days between the final dose of the previous growth hormone therapy and the first dose of SKYTROFA.
• Increase the dose monthly to a higher strength cartridge based on the clinical response and/or IGF-1 concentration. Draw IGF-1 serum sample 4 to 5 days after the prior dose.
• Decrease the dose to a lower strength cartridge as needed based on adverse reactions or a weekly average IGF-1 concentration above the age- and sex-specific normal range.
• The maximum recommended dose is 6.3 mg once weekly.

2.4 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.

2.5 Administration Instructions for Pediatric Patients

SKYTROFA is available in 9 cartridges (dosage strengths in somatropin equivalents) for pediatric patients.

Selection of the appropriate cartridge (mg) is based on the prescribed dose (mg/kg) and the patient's body weight (kg) [see Dosage Forms and Strengths (3)].

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

2.6 Administration Instructions for Adults

SKYTROFA is available in 14 cartridges (dosage strengths in somatropin equivalents) for adults.

Selection of the appropriate cartridge (mg) is based on the prescribed dose (mg/week) [see Dosage Forms and Strengths (3)].

2.7 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. The solution may contain air bubbles and this is acceptable. 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 [see Warnings and Precautions (5.12)].
• Refer to the Instructions for Use for complete administration instructions with illustrations. The instructions can also be found on www.Skytrofa.com/IFU.
• Patients and/or caregivers who will administer SKYTROFA should receive appropriate training and instruction on the proper use of SKYTROFA from their healthcare provider.

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

Severe 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 in Pediatric Patients

Slipped capital femoral epiphysis may occur more frequently in patients undergoing rapid growth. Slipped capital femoral epiphysis may lead to osteonecrosis. Cases of slipped capital femoral epiphysis with or without osteonecrosis have been reported in pediatric patients with short stature receiving somatropin. Evaluate pediatric patients receiving SKYTROFA with the onset of a limp or complaints of persistent hip or knee pain for slipped capital femoral epiphysis and osteonecrosis and manage accordingly.

5.10 Progression of Preexisting Scoliosis in Pediatric Patients

Somatropin increases growth rate in pediatric patients, 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 Dosage and Administration (2.7)].

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 alkaline phosphatase and phosphate may increase after SKYTROFA therapy. Serum levels of 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.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post approval use of somatropin products or 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
• Musculoskeletal and connective tissue disorders – osteonecrosis in pediatric patients

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)].

8.5 Geriatric Use

Of the 249 patients who received SKYTROFA in clinical studies, 24 (10%) patients were 65 years of age and older, and 4 (2%) patients were 75 years of age and older. Geriatric patients may be at an increased risk for adverse reactions. Initiate SKYTROFA at 0.7 mg once weekly in patients 60 years of age and older, not on estrogen therapy [see Dosage and Administration (2.3)].

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 Clinical Pharmacology (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 linear IGF-1 dose response. In pediatric patients with GHD, with a dose change of 0.02 mg/kg/week on average resulting in a mean change in weekly average IGF-1 standard deviation score (SDS) of 0.17. In adults with GHD, a dose change of 1 mg/week results in a mean change in weekly average IGF-1 SDS of 0.7 (range, 0.3 to 1.2).

At steady state, IGF-1 levels peak approximately 2 days post-dose, with the weekly average 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

12.6 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 SKYTROFA or other growth hormone products.

Anti-lonapegsomatropin-tcgd antibodies were evaluated in samples collected every 3 months in phase 3 trials in pediatric patients with GHD receiving SKYTROFA. 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. No apparent correlation of anti-lonapegsomatropin-tcgd antibodies to adverse events or loss of efficacy was observed. No neutralizing antibodies to SKYTROFA were detected.

Of the 247 adult patients with GHD, treated with SKYTROFA and with post-baseline assessments, antibodies against lonapegsomatropin-tcgd were detected in 14 patients (5.7%, mean duration of exposure was 47.7 weeks). There was no identified clinically significant effect of anti-lonapegsomatropin-tcgd antibodies on the safety and efficacy of SKYTROFA. No neutralizing antibodies to SKYTROFA were detected.

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 pediatric dose of 0.24 mg/kg/week and approximately 46-fold the maximum clinical therapeutic dose for adult GHD of 6.3 mg hGH/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 5.

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 6.

14.2 Adults With Growth Hormone Deficiency (NCT05171855)

A multi-center, randomized, parallel-group, placebo-controlled (double-blind), phase 3 study was conducted in 259 adults with GHD. Eighty-nine subjects received once-weekly SKYTROFA, 84 subjects received once-weekly placebo, and 86 subjects received open-label daily somatropin.

The mean (range) age at enrollment was 43 (23 to 81) years old, with 119 (46%) females (55 on oral estrogen) and 140 (54%) males, and the (SD) baseline body mass index of 28 (6.3) kg/m2. One subject was American Indian or Alaska Native, 1 was Black or African American, 28 were Asian, and 218 were Caucasian.

The primary efficacy endpoint, change in trunk percent (%) fat was measured by dual X-ray absorptiometry from baseline to Week 38 in the SKYTROFA group, compared to the placebo group (see Table 7).

Patients treated with daily somatropin achieved a change in trunk percent fat of -3.1% after 38 weeks. No formal statistical comparison between SKYTROFA and daily somatropin was conducted.

Change in total body lean mass and trunk fat mass from baseline after 38 weeks of treatment were secondary efficacy endpoints.

At 38 weeks, the change from baseline in total body lean mass was +1.6 kg for lonapegsomatropin and -0.1 kg for placebo (LS mean difference of 1.7 kg with 95% CI of 1.0 to 2.5, p-value < 0.0001).

At 38 weeks, the change from baseline in trunk fat mass was -0.5 kg for lonapegsomatropin and +0.2 kg for placebo (LS mean difference of -0.7 kg with 95% CI of -1.2 to -0.2, p-value = 0.005).

After 38 weeks, SKYTROFA treatment in adults with GHD resulted in normalization of IGF-1 SDS to 1.4 compared to -2.6 in placebo-treated patients. See Table 8.

The mean (SD) IGF-1 SDS level in daily somatropin treated patients was -2.82 (1) at baseline and 0.49 (1.98) at 38 weeks. No formal statistical comparison between SKYTROFA and daily somatropin was conducted.

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 14 strengths (in somatropin equivalents) as described in Table 9.

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).

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 accompanying FDA-approved patient labeling SKYTROFA Auto-Injector Instructions for Use (also available at www.Skytrofa.com/IFU) prior to administration. 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 Dosage and Administration (2.7)]. 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.