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Lonapegsomatropin-tcgd is a long-acting prodrug of a human growth hormone (somatropin) produced by recombinant DNA technology using E. coli. Lonapegsomatropin-tcgd consists of a parent drug, somatropin, that is conjugated to a methoxypolyethylene glycol carrier (4 x 10 kDa mPEG) via a proprietary TransCon Linker and has a molecular weight of 63 kDa (released somatropin is 22 kDa). In vitro assay confirms the minimum potency of released somatropin is NLT 2.5 IU/mg.
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 other chamber. SKYTROFA prefilled cartridge must be used with SKYTROFA Auto-Injector to provide an automatic mixing step for reconstitution prior to subcutaneous use.
After reconstitution, each prefilled cartridge delivers:
The following important adverse reactions are described elsewhere in the labeling:
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-naive, 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 | Daily somatropin (N = 56) n (%) |
SKYTROFA (N = 105) n (%) |
| Infection, viral | 6 (11%) | 16 (15%) |
| Pyrexia | 5 (9%) | 16 (15%) |
| Cough | 4 (7%) | 11 (11%) |
| Nausea and vomiting | 4 (7%) | 11 (11%) |
| Hemorrhagea | 1 (2%) | 7 (7%) |
| Diarrhea | 3 (5%) | 6 (6%) |
| Abdominal pain | 2 (4%) | 6 (6%) |
| Arthralgia and arthritisb | 1 (2%) | 6 (6%) |
| Adverse reactions that are medically related were grouped to a single preferred term. aHemorrhage in the SKYTROFA treatment group included epistaxis (3), contusion (2), petechiae (1) and eye hemorrhage (1). bArthralgia and arthritis in the SKYTROFA treatment group included arthralgia (5) and reactive arthritis (1). |
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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.
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.
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
| Replacement Glucocorticoid Treatment | |
| Clinical Impact: | Microsomal enzyme 11β-hydroxysteroid dehydrogenase type 1 (11βHSD-1) is required for conversion of cortisone to its active metabolite, cortisol, in hepatic and adipose tissue. Somatropin inhibits 11βHSD-1. Consequently, individuals with untreated growth hormone deficiency (GHD) have relative increases in 11βHSD-1 and serum cortisol. Initiation of SKYTROFA may result in inhibition of 11βHSD-1 and reduced serum cortisol concentrations. |
| Intervention: | Patients treated with glucocorticoid replacement for hypoadrenalism may require an increase in their maintenance or stress doses following initiation of SKYTROFA [see Warnings and Precautions (5.7)] |
| Examples | Cortisone acetate and prednisone may be affected more than others because conversion of these drugs to their biologically active metabolites is dependent on the activity of 11βHSD-1. |
| Pharmacologic Glucocorticoid Therapy and Supraphysiologic Glucocorticoid Treatment | |
| Clinical Impact: | Pharmacologic glucocorticoid therapy and supraphysiologic glucocorticoid treatment may attenuate the growth-promoting effects of SKYTROFA in pediatric patients. |
| Intervention: | Carefully adjust glucocorticoid replacement dosing in pediatric patients receiving glucocorticoid treatments to avoid both hypoadrenalism and an inhibitory effect on growth. |
| Cytochrome P450-Metabolized Drugs | |
| Clinical Impact: | Limited published data indicate that somatropin treatment increases cytochrome P450 (CYP450)-mediated antipyrine clearance. SKYTROFA may alter the clearance of compounds known to be metabolized by CYP450 liver enzymes. |
| Intervention: | Careful monitoring is advisable when SKYTROFA is administered in combination with drugs metabolized by CYP450 liver enzymes. |
| Oral Estrogen | |
| Clinical Impact: | Oral estrogens may reduce the serum insulin-like growth factor-1 (IGF-1) response to SKYTROFA. |
| Intervention: | Patients receiving oral estrogen replacement may require higher SKYTROFA dosages. |
| Insulin and/or Other Antihyperglycemic Agents | |
| Clinical Impact: | Treatment with SKYTROFA may decrease insulin sensitivity, particularly at higher doses. |
| Intervention: | Patients with diabetes mellitus may require adjustment of their doses of insulin and/or other antihyperglycemic agents [see Warnings and Precautions (5.4)]. |
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.
Included as part of the PRECAUTIONS section.
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.
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.
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.
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.
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.
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.
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)].
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.
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.
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.
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.
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 (2.5)].
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.
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.
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.
Acute overdosage may lead initially to hypoglycemia and subsequently to hyperglycemia. Overdose with somatropin may cause fluid retention. Long-term overdosage may result in signs and symptoms of gigantism consistent with the known effects of excess growth hormone.
SKYTROFA is contraindicated in patients with:
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.
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.
Following subcutaneous dose administration, SKYTROFA releases fully active somatropin via autocleavage of the TransCon linker that follows first-order kinetics.
In pediatric patients with GHD, following subcutaneous dose administration of 0.24 mg/kg/week SKYTROFA, the observed mean (CV%) steady state peak serum concentration (Cmax) of lonapegsomatropin-tcgd was 1230 (86.3) ng hGH/mL, and the median time to reach maximum concentrations (Tmax) was 25 hours. For released somatropin, Cmax was 15.2 (83.4) ng/mL with a median Tmax of 12 hours. The mean (CV%) somatropin exposure over the one-week dose interval (area under the curve) was 500 (83.8) h*ng/mL. No significant accumulation of lonapegsomatropin-tcgd and somatropin following repeat dose administration was observed.
Cmax of the methoxypolyethylene glycol carrier was 13.1 (28.1) μg/mL with a median Tmax of 36 hours.
In healthy adults, following single subcutaneous dose administration in the range of 0.24 to 0.42 mg/kg of SKYTROFA, exposure of released somatropin increased greater than proportional to dose.
In pediatric patients with GHD, the mean (CV%) steady state apparent volume of distribution of lonapegsomatropin-tcgd after subcutaneous administration of 0.24 mg/kg/week SKYTROFA was 0.13 (109) L/kg. A similar distribution pattern as observed for daily somatropin is expected once somatropin is released from lonapegsomatropin-tcgd.
Metabolism
The metabolism of somatropin involves protein catabolism in both the liver and kidneys. The methoxypolyethylene glycol carrier is cleared by the kidneys.
Excretion
In pediatric patients with GHD, the mean (CV%) lonapegsomatropin-tcgd apparent clearance at steady state was 3.2 (67) mL/h/kg following subcutaneous administration of 0.24 mg/kg/week SKYTROFA with a mean (±SD) observed half-life of 30.7 (±12.7) hours. The apparent half-life of somatropin released from lonapegsomatropin-tcgd was approximately 25 hours.
Based on a population pharmacokinetic analysis, age, sex, race, and body weight do not have clinically meaningful effects on pharmacokinetics.
Male and Female Patients — No sex-specific pharmacokinetic studies have been performed with SKYTROFA. The available literature indicates that the pharmacokinetics of somatropin are similar in men and women.
Patients with Renal or Hepatic Impairment — No specific studies have been performed with SKYTROFA.
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)].
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.
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.
Advise patients and/or caregivers to report to their healthcare provider any visual changes, headache, and nausea and/or vomiting.
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.
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.
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.
Advise patients and/or caregivers that pancreatitis may develop and to report to their healthcare provider any new onset abdominal pain.
