SKYTROFA™ (lonapegsomatropin-tcgd) for injection

Gafacom February 26, 2023

SKYTROFA (lonapegsomatropin-tcgd)

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.

SKYTROFA (lonapegsomatropin-tcgd)


INDICATIONS AND USAGE

SKYTROFA (lonapegsomatropin-tcgd) is a human growth hormone indicated for the treatment of pediatric patients 1 year and older who weigh at least 11.5 kg and have growth failure due to inadequate secretion of endogenous growth hormone (GH).

Mechanism of Action

SKYTROFA is a pegylated human growth hormone (somatropin) for once-weekly subcutaneous injection.

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.

DOSAGE AND ADMINISTRATION

  • 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

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, undernutrition, 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.

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.

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.

CONTRAINDICATIONS

SKYTROFA is contraindicated in patients with:

  • Acute critical illness after open heart surgery, abdominal surgery or multiple accidental trauma, or those with acute respiratory failure due to the risk of increased mortality with use of pharmacologic doses of somatropin.
  • Hypersensitivity to somatropin or any of the excipients in SKYTROFA. Systemic hypersensitivity reactions have been reported with post-marketing use of somatropin products.
  • Closed epiphyses.
  • Active malignancy due to the risk of malignancy progression.
  • Active proliferative or severe non-proliferative diabetic retinopathy because treatment with somatropin may worsen this condition.
  • 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 AND PRECAUTIONS

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

Increased Risk of Neoplasms

Active Malignancy: There is an increased risk of malignancy progression with somatropin treatment in patients with active malignancy. 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.

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.

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.

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.

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

Hypothyroidism: Undiagnosed or untreated hypothyroidism may prevent optimal response to SKYTROFA. Inpatients 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: 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.

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.

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.

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.

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.

Laboratory Tests: Serum levels of phosphate, alkaline phosphatase, and parathyroid hormone may increase aftersomatropin treatment. If a patient is found to have abnormal laboratory tests, monitor asappropriate.

USE IN SPECIFIC POPULATIONS

Pregnancy: 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

OVERDOSAGE

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.

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