SKYTROFA Powder for solution for injection Ref.[28361] Active ingredients: Lonapegsomatropin

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 post-marketing use of somatropin products. Inform patients and caregivers that such reactions are possible, and that prompt medical attention should be sought if an allergic reaction occurs [see Contraindications (4)]. Do not use SKYTROFA in patients with known hypersensitivity to somatropin or any of the excipients in SKYTROFA.

5.3 Increased Risk of Neoplasms

Active Malignancy

There is an increased risk of malignancy progression with somatropin treatment in patients with active malignancy [see Contraindications (4)]. Any preexisting malignancy should be inactive, and its treatment should be completed prior to instituting therapy with SKYTROFA. Discontinue SKYTROFA if there is evidence of recurrent malignancy.

Risk of Second Neoplasm in Pediatric Patients

In childhood cancer survivors who were treated with radiation to the brain/head for their first neoplasm and who developed subsequent growth hormone deficiency (GHD) and were treated with somatropin, an increased risk of a second neoplasm has been reported. Intracranial tumors, in particular meningiomas, were the most common of these second neoplasms. Monitor all patients with a history of GHD secondary to an intracranial neoplasm while on somatropin therapy for progression or recurrence of the tumor.

New Malignancy During Treatment

Because children with certain rare genetic causes of short stature have an increased risk of developing malignancies, thoroughly consider the risks and benefits of starting somatropin in these patients. If treatment with somatropin is initiated, carefully monitor these patients for development of neoplasms.

Monitor patients on somatropin therapy carefully for increased growth or potential malignant changes of preexisting nevi. 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.

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.

The following important adverse reactions are described elsewhere in the labeling:

• Increased mortality in patients with acute critical illness [see Warnings and Precautions (5.1)]
• Severe hypersensitivity [see Warnings and Precautions (5.2)]
• Increased risk of neoplasms [see Warnings and Precautions (5.3)]
• Glucose intolerance and diabetes mellitus [see Warnings and Precautions (5.4)]
• Intracranial hypertension [see Warnings and Precautions (5.5)]
• Fluid retention [see Warnings and Precautions (5.6)]
• Hypoadrenalism [see Warnings and Precautions (5.7)]
• Hypothyroidism [see Warnings and Precautions (5.8)]
• Slipped capital femoral epiphysis in pediatric patients [see Warnings and Precautions (5.9)]
• Progression of preexisting scoliosis in pediatric patients [see Warnings and Precautions (5.10)]
• Pancreatitis [see Warnings and Precautions (5.11)]
• Lipoatrophy [see Warnings and Precautions (5.12)]
• Sudden death in pediatric patients with Prader-Willi syndrome [see Warnings and Precautions (5.13)]

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies 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.

Table 2. Adverse Reactions Occurring in ≥5% SKYTROFA-Treated Pediatric Patients and More Frequently than in Daily Somatropin-Treated Pediatric Patients (52 Weeks of Treatment):

Adverse reactions that are medically related were grouped to a single preferred term.

^* Hemorrhage in the SKYTROFA treatment group included epistaxis (3), contusion (2), petechiae (1) and eye hemorrhage (1).
^† Arthralgia and arthritis in the SKYTROFA treatment group included arthralgia (5) and reactive arthritis (1).

Laboratory Tests

More SKYTROFA-treated patients shifted from normal baseline levels to elevated phosphate and alkaline phosphatase levels at the end of the trial compared to the daily somatropin group (44.2% vs. 30.2% and 19.2% vs. 9.4%, respectively); these laboratory changes occurred intermittently [see Warnings and Precautions (5.14)].

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.

Table 3 includes a list of drugs with clinically important drug interactions when administered concomitantly with SKYTROFA and instructions for preventing or managing them.

Table 3. Clinically Important Drug Interactions with SKYTROFA:

Risk Summary

There are no available data on lonapegsomatropin-tcgd use in pregnant patients to evaluate a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Available published data over several decades for somatropin, the active component of lonapegsomatropin-tcgd, have not identified a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. In animal reproduction studies, there was no evidence of embryo-fetal or neonatal harm when pregnant rats were administered subcutaneous lonapegsomatropin-tcgd at doses up to 13-fold the clinical dose of 0.24 mg/kg/week (see Data).

The estimated background risk of birth defects and miscarriages for the indicated population is unknown. 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.

Data

Animal Data

No embryonic or fetal development toxicities occurred in rats administered subcutaneous lonapegsomatropin-tcgd at doses up to 13-fold the clinical dose of 0.24 mg/kg/week.

In a peri- and post-natal developmental study in rats, there were no adverse effects on the pregnant/lactating female or on development of the conceptus and the offspring following exposure of the female from implantation through weaning to doses of a structurally related pegylated somatropin prodrug up to 13-fold the clinical dose of 0.24 mg/kg/week.

Risk Summary

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.

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)].

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

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

Somatropin is not associated with drug related withdrawal adverse reactions.